<?xml version="1.0" encoding="UTF-8" standalone="no"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" "journalpublishing.dtd">
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" article-type="research-article" dtd-version="2.3" xml:lang="EN">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Oncol.</journal-id>
<journal-title>Frontiers in Oncology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Oncol.</abbrev-journal-title>
<issn pub-type="epub">2234-943X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fonc.2024.1375648</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Oncology</subject>
<subj-group>
<subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Dynamic three-dimensional liver volume assessment of liver regeneration in hilar cholangiocarcinoma patients undergoing hemi-hepatectomy</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Zhao</surname>
<given-names>Haoyu</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2610708"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
<role content-type="https://credit.niso.org/contributor-roles/visualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Li</surname>
<given-names>Baifeng</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2421353"/>
<role content-type="https://credit.niso.org/contributor-roles/project-administration/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Li</surname>
<given-names>Xiaohang</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lv</surname>
<given-names>Xiangning</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
<role content-type="https://credit.niso.org/contributor-roles/visualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Guo</surname>
<given-names>Tingwei</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Dai</surname>
<given-names>Zongbo</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2393711"/>
<role content-type="https://credit.niso.org/contributor-roles/data-curation/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Zhang</surname>
<given-names>Chengshuo</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2518643"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/validation/"/>
<role content-type="https://credit.niso.org/contributor-roles/visualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Zhang</surname>
<given-names>Jialin</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/734445"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/resources/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Department of Hepatobiliary Surgery, The First Hospital of China Medical University</institution>, <addr-line>Shenyang</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Radiology, The First Hospital of China Medical University</institution>, <addr-line>Shenyang</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: John Gibbs, Hackensack Meridian Health, United States</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Kanan Yusif-Zada, Independent Researcher, Baku, Azerbaijan</p>
<p>Khachatur Badalyan, Head of the Department of Surgery and Modern Surgical Technologies, Armenia</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Jialin Zhang, <email xlink:href="mailto:jlz2000@yeah.net">jlz2000@yeah.net</email>; Chengshuo Zhang, <email xlink:href="mailto:cszhang@cmu.edu.cn">cszhang@cmu.edu.cn</email>
</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>19</day>
<month>04</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>14</volume>
<elocation-id>1375648</elocation-id>
<history>
<date date-type="received">
<day>24</day>
<month>01</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>04</day>
<month>04</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Zhao, Li, Li, Lv, Guo, Dai, Zhang and Zhang</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Zhao, Li, Li, Lv, Guo, Dai, Zhang and Zhang</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>For patients with hilar cholangiocarcinoma (HC) undergoing hemi-hepatectomy, there are controversies regarding the requirement of, indications for, and timing of preoperative biliary drainage (PBD). Dynamic three-dimensional volume reconstruction could effectively evaluate the regeneration of liver after surgery, which may provide assistance for exploring indications for PBD and optimal preoperative bilirubin value. The purpose of this study was to explore the indications for PBD and the optimal preoperative bilirubin value to improve prognosis for HC patients undergoing hemi-hepatectomy.</p>
</sec>
<sec>
<title>Methods</title>
<p>We retrospectively analyzed the data of HC patients who underwent hemi-hepatectomy in the First Affiliated Hospital of China Medical University from 2012 to 2023. The liver regeneration rate was calculated using three-dimensional volume reconstruction. We analyzed the factors affecting the liver regeneration rate and occurrence of postoperative liver insufficiency.</p>
</sec>
<sec>
<title>Results</title>
<p>This study involved 83 patients with HC, which were divided into PBD group (n=36) and non-PBD group (n=47). The preoperative bilirubin level may be an independent risk factor affecting the liver regeneration rate (<italic>P</italic>=0.014) and postoperative liver insufficiency (<italic>P</italic>=0.016, odds ratio=1.016, &#x3b2;=0.016, 95% CI=1.003&#x2013;1.029). For patients whose initial bilirubin level was &gt;200 &#x3bc;mol/L (n=45), PBD resulted in better liver regeneration in the early stage (<italic>P</italic>=0.006) and reduced the incidence of postoperative liver insufficiency [<italic>P</italic>=0.012, odds ratio=0.144, 95% confidence interval (CI)=0.031&#x2013;0.657]. The cut-off value of bilirubin was 103.15 &#x3bc;mol/L based on the liver regeneration rate. Patients with a preoperative bilirubin level of &#x2264;103.15 &#x3bc;mol/L shown a better liver regeneration (<italic>P</italic>&lt;0.01) and lower incidence of postoperative hepatic insufficiency (<italic>P</italic>=0.011, odds ratio=0.067, 95% CI=0.008&#x2013;0.537).</p>
</sec>
<sec>
<title>Conclusion</title>
<p>For HC patients undergoing hemi-hepatectomy whose initial bilirubin level is &gt;200 &#x3bc;mol/L, PBD may result in better liver regeneration and reduce the incidence of postoperative liver insufficiency. Preoperative bilirubin levels &#x2264;103.15 &#x3bc;mol/L maybe recommended for leading to a better liver regeneration and lower incidence of postoperative hepatic insufficiency.</p>
</sec>
</abstract>
<kwd-group>
<kwd>hilar cholangiocarcinoma</kwd>
<kwd>liver regeneration</kwd>
<kwd>bilirubin</kwd>
<kwd>preoperative biliary drainage</kwd>
<kwd>liver insufficiency</kwd>
</kwd-group>
<counts>
<fig-count count="3"/>
<table-count count="4"/>
<equation-count count="0"/>
<ref-count count="55"/>
<page-count count="11"/>
<word-count count="5505"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-in-acceptance</meta-name>
<meta-value>Gastrointestinal Cancers: Hepato Pancreatic Biliary Cancers</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>Hilar cholangiocarcinoma (HC) refers to cholangiocarcinoma involving the common hepatic duct, right and left hepatic ducts, and confluence. HC is also known as proximal cholangiocarcinoma or Klatskin tumor, and it accounts for 50% to 70% of all biliary tract tumors (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B2">2</xref>). Patients with HC usually have a poor prognosis, with a 5-year survival rate of approximately 40% and a recurrence rate of up to 75% after resection (<xref ref-type="bibr" rid="B3">3</xref>, <xref ref-type="bibr" rid="B4">4</xref>).</p>
<p>For patients with HC who are suitable candidates for surgery, the ideal treatment is resection of the extrahepatic and intrahepatic bile ducts and the involved ipsilateral liver (<xref ref-type="bibr" rid="B1">1</xref>). Patients with HC usually develop related postoperative complications such as liver dysfunction or liver failure, and such complications are accompanied by high mortality rates of about 10% in Western referral centers (<xref ref-type="bibr" rid="B5">5</xref>&#x2013;<xref ref-type="bibr" rid="B7">7</xref>). Postoperative liver regeneration is an important repair mechanism that is attracting increasingly more attention because of its ability to lessen liver damage and avoid liver failure after hepatectomy (<xref ref-type="bibr" rid="B8">8</xref>, <xref ref-type="bibr" rid="B9">9</xref>). The change in liver volume is a reliable way to evaluate liver regeneration. Many studies have explored the change in liver volume as an important reference index in clinical analysis (<xref ref-type="bibr" rid="B10">10</xref>, <xref ref-type="bibr" rid="B11">11</xref>).</p>
<p>Patients with HC who develop severe jaundice usually need biliary drainage before hemi-hepatectomy. The high risk of complications and mortality after surgery in patients with HC are closely related to preoperative jaundice (<xref ref-type="bibr" rid="B12">12</xref>, <xref ref-type="bibr" rid="B13">13</xref>). PBD can palliate jaundice and reduce the incidence of postoperative complications and mortality by promoting liver regeneration (<xref ref-type="bibr" rid="B14">14</xref>). To date, studies on liver regeneration after hepatectomy for HC have mainly been based on animal experiments; few clinical studies have been performed (<xref ref-type="bibr" rid="B15">15</xref>, <xref ref-type="bibr" rid="B16">16</xref>). Research has shown that the relative liver weight, expression of proliferating cell nuclear antigen, DNA synthesis rate, and mitotic index are important indicators of liver regeneration (<xref ref-type="bibr" rid="B16">16</xref>&#x2013;<xref ref-type="bibr" rid="B18">18</xref>). Whether patients with HC need biliary drainage and the degree and timing of such biliary drainage remain controversial (<xref ref-type="bibr" rid="B19">19</xref>&#x2013;<xref ref-type="bibr" rid="B21">21</xref>). This study was performed to evaluate the postoperative liver regeneration of patients with HC and analyze the related factors affecting postoperative liver regeneration and liver insufficiency. The overall goal is to provide a reference for preoperative clinical decision-making for patients with HC.</p>
</sec>
<sec id="s2" sec-type="materials|methods">
<label>2</label>
<title>Materials and methods</title>
<sec id="s2_1">
<label>2.1</label>
<title>Patient selection</title>
<p>This study retrospectively evaluated the data of patients who were diagnosed with HC and underwent liver resection in the First Affiliated Hospital of China Medical University from 1 January 2012 to 1 April 2023. The records of 1317 patients were retrieved. Of these patients, we excluded 611 who only received jaundice reduction treatment or extrahepatic bile duct resection without hemi-hepatectomy, 499 with incomplete imaging or clinical data, and 124 with a computed tomography (CT) follow-up duration of &gt;24 weeks or &lt;1 week. This study was approved by the Institutional Review Committee of the First Affiliated Hospital of China Medical University This study was approved by the Institutional Review Committee of the First Affiliated Hospital of China Medical University (Approved number: 2024-4).</p>
</sec>
<sec id="s2_2">
<label>2.2</label>
<title>Definitions</title>
<p>HC was defined as cholangiocarcinoma arising from the common hepatic duct, left and right hepatic ducts, or confluence of the hepatic ducts, and intrahepatic cholangiocarcinoma invading the hepatic hilus (<xref ref-type="bibr" rid="B22">22</xref>). The Bismuth&#x2013;Corlette classification was used to classify the tumors (<xref ref-type="bibr" rid="B23">23</xref>). Liver insufficiency was defined as a postoperative total bilirubin level of &gt;119.7 &#x3bc;mol/L or, in patients with preoperative jaundice, as a total bilirubin level on postoperative day 5 to 10 that was higher than the preoperative level (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B25">25</xref>). In this study, the initial bilirubin was measured on the day before or most recently to PBD treatment, and the preoperative bilirubin was the bilirubin value measured on the day before or most recently to the surgery in the PBD group. Meanwhile, in the non-PBD group, the initial bilirubin value, which is equal to preoperative bilirubin value, was measured on the day before or most recently to the surgical treatment. Using the standard liver volume (SLV) formula for Chinese adults, the SLV (mL) was calculated as 11.5 &#xd7; body weight (kg) + 334 (<xref ref-type="bibr" rid="B26">26</xref>).</p>
</sec>
<sec id="s2_3">
<label>2.3</label>
<title>Imaging</title>
<p>Three CT scanners were used in this study: Somatom Definition Flash CT (Siemens Healthineers, Erlangen, Germany), Brilliance CT (Royal Philips Electronics, Amsterdam, Netherlands), and Aquilion ONE CT (Toshiba Corporation, Tokyo, Japan). All patients underwent a plain or enhanced scan in the conventional supine position. The arterial phase, portal venous phase, and delayed phase were performed at 25 to 30s, 60 to 70s, and 160 to 180s, respectively, after the injection of a non-ionic contrast agent.</p>
</sec>
<sec id="s2_4">
<label>2.4</label>
<title>Segmentation</title>
<p>The sampled sequence of CT images was imported into a structural software application (3D Slicer, version 5.3.0; <ext-link ext-link-type="uri" xlink:href="http://www.slicer.org">http://www.slicer.org</ext-link>). The volumes of interest [i.e., baseline liver volume (V<sub>BLV</sub>) and postoperative liver volume (V<sub>PRO</sub>)] were manually delineated by physicians with many years of experience in radiology. The surgical segmentations were carefully reviewed and delineated by senior physicians with 30 years of experience in radiology and hepatobiliary surgery according to the surgical records. In hemi-hepatectomy, the segmentation was performed along the middle hepatic vein; in hemi-hepatectomy combined with caudate lobectomy, the segmentation included the caudate lobe of the liver. The volume of future liver remnant after resection was defined as V<sub>FLR</sub> (Future liver remnant, FLR). The rate of liver regeneration is calculated by dividing the changes between the V<sub>PRO</sub> and V<sub>FLR</sub> by weeks (<xref ref-type="bibr" rid="B10">10</xref>). These reviews were performed without access to the patients&#x2019; clinical information.</p>
</sec>
<sec id="s2_5">
<label>2.5</label>
<title>Statistical analysis</title>
<p>Numerical variables are expressed as mean &#xb1; standard deviation. Student&#x2019;s t-test or the Mann&#x2013;Whitney U test was used to analyze continuous variables. Categorical variables were analyzed using Pearson&#x2019;s chi-square test or Fisher&#x2019;s exact test. Factors associated with the liver regeneration rate were analyzed by univariate analysis and multiple linear regression analysis. The cut-off value of preoperative bilirubin was estimated by Youden&#x2019;s index. Univariate and multifactorial logistic regression analyses were performed to explore the factors affecting postoperative liver insufficiency. A <italic>P</italic> value of &lt;0.05 was considered statistically significant. SPSS version 27.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis.</p>
</sec>
</sec>
<sec id="s3" sec-type="results">
<label>3</label>
<title>Results</title>
<sec id="s3_1">
<label>3.1</label>
<title>Patient characteristics</title>
<p>This study involved 83 patients with HC who underwent hemi-hepatectomy. Of these 83 patients, 36 underwent hemi-hepatectomy after PBD (PBD group) and 47 underwent hemi-hepatectomy alone (non-PBD group). The patients&#x2019; mean age was 64.54 &#xb1; 9.56 years, and the male:female ratio was 52:31. The ratio of patients with an initial bilirubin level of &gt;200: &#x2264;200 &#x3bc;mol/L was 34:2 in the PBD group and 11:36 in the non-PBD group. Among all 83 patients, the ratio of patients with a preoperative bilirubin level of&#xa0;&gt;103.15: &#x2264;103.15 &#x3bc;mol/L was 45:38. All patients underwent hemi-hepatectomy, and the ratio of left hemi-hepatectomy or extended left hemi-hepatectomy to right hemi-hepatectomy or extended right hemi-hepatectomy was 55:28. No patients underwent preoperative portal vein embolization. In the PBD group, the mean age and male:female ratio was 62.94 &#xb1; 8.77 years and 25:11, respectively. In the non-PBD group, these values were 65.77 &#xb1; 10.05 years and 27:20, respectively. The study flow chart is shown in <xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>, and the patients&#x2019; clinical details are shown in <xref ref-type="supplementary-material" rid="SM1">
<bold>Supplementary Table&#xa0;1</bold>
</xref>.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Flow chart of patient enrollment in this study.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1375648-g001.tif"/>
</fig>
<p>In the PBD group, the initial bilirubin level was 332.83 &#xb1; 98.31 &#x3bc;mol/L (31.00&#x2013;470.92 &#x3bc;mol/L), and the preoperative bilirubin level was 108.68 &#xb1; 51.24 &#x3bc;mol/L (7.60&#x2013;209.90 &#x3bc;mol/L). In the non-PBD group, the initial bilirubin or preoperative bilirubin level was 125.16 &#xb1; 110.00 &#x3bc;mol/L (5.20&#x2013;438.30 &#x3bc;mol/L). Compared with the initial bilirubin level, the preoperative bilirubin level showed a significant decline in the PBD group (<italic>P</italic>&lt;0.001). The initial bilirubin level was significantly higher in the PBD than non-PBD group (<italic>P</italic>&lt;0.001). No significant difference was found in the preoperative bilirubin level between the two groups (<italic>P</italic>=0.368).</p>
</sec>
<sec id="s3_2">
<label>3.2</label>
<title>Liver volume measurement</title>
<p>Among all patients, the mean time of liver regeneration (from operation to follow-up CT) was 4.65 &#xb1; 4.77 weeks (1&#x2013;20.86 weeks), the mean V<sub>BLV</sub> was 1547.17 &#xb1; 407.69 mL, the mean future liver remnant volume (V<sub>FLR</sub>) was 983.60 &#xb1; 264.91 mL, and the mean V<sub>PRO</sub> was 1153.43 &#xb1; 281.32mL. Compared with the V<sub>FLR</sub>, there was a significant increase in V<sub>PRO</sub> (<italic>P</italic>&lt;0.001), and the liver regeneration volume accounted for 15.74% &#xb1; 9.34% of the SLV. In the PBD group, the liver volume proliferated 186.36 &#xb1; 100.18 mL within 5.38 &#xb1; 5.66 weeks (<italic>P</italic>&lt;0.001), and liver regeneration accounted for 17.20% &#xb1; 8.62% of the SLV. In the non-PBD group, the liver volume increased 157.17 &#xb1; 106.48 mL within 4.09 &#xb1; 3.92 weeks (<italic>P</italic>&lt;0.001), with 14.62% &#xb1; 9.81% regeneration. The changes in liver volume are shown in <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>. Four sets of three-dimensional images including a preoperative CT image, baseline liver model, surgical planning liver model, FLR model, and postoperative liver model are shown in <xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2</bold>
</xref>.</p>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Changes in liver volume according to PBD in hilar cholangiocarcinoma.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="center"/>
<th valign="top" align="center">Baseline liver volume (mL)</th>
<th valign="top" align="center">Future liver remnant volume (mL)</th>
<th valign="top" align="center">Duration (wk)</th>
<th valign="top" align="center">Postoperative liver volume (mL)</th>
<th valign="top" align="center">Liver volume changes (mL)</th>
<th valign="top" align="center">Liver volume change, %</th>
<th valign="top" align="center">Rate of liver regeneration</th>
<th valign="top" align="center">
<italic>P</italic> value</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">PBD group (n=36)</td>
<td valign="top" align="left">1676.57 &#xb1; 478.71</td>
<td valign="top" align="left">989.97 &#xb1; 299.95</td>
<td valign="top" align="left">5.38 &#xb1; 5.66</td>
<td valign="top" align="left">1176.33 &#xb1; 330.25</td>
<td valign="top" align="left">186.36 &#xb1; 100.18</td>
<td valign="top" align="left">17.20 &#xb1; 8.62</td>
<td valign="top" align="left">59.77 &#xb1; 36.75</td>
<td valign="top" align="left">
<italic>P</italic>&lt;0.001</td>
</tr>
<tr>
<td valign="top" align="left">Non-PBD group (n=47)</td>
<td valign="top" align="left">1448.06 &#xb1; 314.31</td>
<td valign="top" align="left">978.72 &#xb1; 237.88</td>
<td valign="top" align="left">4.09 &#xb1; 3.92</td>
<td valign="top" align="left">1135.89 &#xb1; 239.51</td>
<td valign="top" align="left">157.17 &#xb1; 106.48</td>
<td valign="top" align="left">14.62 &#xb1; 9.81</td>
<td valign="top" align="left">55.32 &#xb1; 33.83</td>
<td valign="top" align="left">
<italic>P</italic>&lt;0.001</td>
</tr>
<tr>
<td valign="top" align="left">All (n=83)</td>
<td valign="top" align="left">1547.17 &#xb1; 407.69</td>
<td valign="top" align="left">983.60 &#xb1; 264.91</td>
<td valign="top" align="left">4.65 &#xb1; 4.77</td>
<td valign="top" align="left">1153.43 &#xb1; 281.32</td>
<td valign="top" align="left">169.83 &#xb1; 104.19</td>
<td valign="top" align="left">15.74 &#xb1; 9.34</td>
<td valign="top" align="left">57.25 &#xb1; 34.98</td>
<td valign="top" align="left">
<italic>P</italic>&lt;0.001</td>
</tr>
</tbody>
</table>
</table-wrap>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>Four sets of three-dimensional images including a preoperative CT image, baseline liver model, surgical planning liver model, FLR model, and postoperative liver model. <bold>(A)</bold> Patient A in PBD group: the initial bilirubin was 467.1&#x3bc;mol/L, and the level of preoperative bilirubin was 199.2&#x3bc;mol/L. The rate of liver regeneration was 28.19 mL/wk, with a regeneration of 27.74% in 9.80wk; <bold>(B)</bold> Patient B in PBD group: the initial bilirubin was 462.9&#x3bc;mol/L, and the level of preoperative bilirubin was 37.5&#x3bc;mol/L. The rate of liver regeneration was 125.61 mL/wk, with a regeneration of 16.30% in 1.57w; <bold>(C)</bold> Patient C in non-PBD group: the preoperative bilirubin was 160.9&#x3bc;mol/L. The rate of liver regeneration was 11.97mL/wk, with a regeneration of 8.78% in 7.43w; <bold>(D)</bold> Patient D in non-PBD group: the preoperative bilirubin was 59.7&#x3bc;mol/L. The rate of liver regeneration was 78.73mL/wk, with a regeneration of 15.80% in 2.29w.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1375648-g002.tif"/>
</fig>
</sec>
<sec id="s3_3">
<label>3.3</label>
<title>Rate of liver growth</title>
<p>Among all patients, the mean liver regeneration rate was 57.25 &#xb1; 34.98 mL/week, with rapid growth of 71.44 &#xb1; 31.85 mL/week in the first 4 weeks. The liver volume increase slowed to 42.93 &#xb1; 26.06 mL/week from 4 to 8 weeks. After 8 weeks, the rate of liver growth was 17.89 &#xb1; 10.37 mL/week. The liver regeneration rate within 4 weeks (71.44 &#xb1; 31.85 mL/week, n=54) was significantly higher than that after 4 weeks (30.84 &#xb1; 23.49 mL/week, n=29) (<italic>P</italic>&lt;0.001); likewise, growth was significantly higher in the first 8 weeks (65.24 &#xb1; 32.72 mL/week, n=69) than after 8 weeks (17.89 &#xb1; 10.37 mL/week, n=14) (<italic>P</italic>&lt;0.001).</p>
<p>No significant difference was found in the liver regeneration rate between the PBD group (59.77 &#xb1; 36.75 mL/week) and the non-PBD group (55.32 &#xb1; 33.83mL/week) (<italic>P</italic>=0.569). Within 4 weeks, the mean rate of liver growth in the PBD group (79.77 &#xb1; 30.90 mL/week, n=22) was higher than that in the non-PBD group (65.71 &#xb1; 31.69 mL/week, n=32) (<italic>P</italic>=0.112). Within 8 weeks, the mean liver regeneration rate in the PBD group (73.74 &#xb1; 31.23 mL/week, n=27) was higher than that in the non-PBD group (59.78 &#xb1; 32.86 mL/week, n=42) (<italic>P</italic>=0.112). <xref ref-type="fig" rid="f3">
<bold>Figures&#xa0;3A-C</bold>
</xref> shows the changes in the liver regeneration rate with time in the two groups, with each point showing the liver regeneration rate of individuals, as well as a comparison between the two groups.</p>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p>Rate of liver regeneration rate in patients with hilar cholangiocarcinoma undergoing hemi-hepatectomy. <bold>(A-C)</bold> Changes in liver regeneration rate in PBD group and non-PBD group and comparison between the two groups; <bold>(D)</bold> Comparison of liver regeneration rate in patients with initial bilirubin level of &gt;200 &#x3bc;mol/L (within 4 weeks/within 8 weeks/all) between the non-PBD group and the PBD group; <bold>(E)</bold> Cut-off value of preoperative bilirubin level (&#x3bc;mol/L) based on Youden&#x2019;s index. **<italic>P</italic> &lt; 0.01.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-14-1375648-g003.tif"/>
</fig>
</sec>
<sec id="s3_4">
<label>3.4</label>
<title>Univariate and multivariate analyses of factors associated with liver growth rate</title>
<p>The univariate analysis showed that the clinical indicators significantly affecting the liver regeneration rate (<italic>P</italic>&lt;0.05) were body weight (B=1.133, <italic>P</italic>=0.001), body mass index (B=3.241, <italic>P</italic>=0.007), long-term alcohol drinking (B=30.184, <italic>P</italic>=0.010), pathological vascular or neurological invasion (B=18.840, <italic>P</italic>=0.014), preoperative bilirubin level (B=&#x2212;0.107, <italic>P</italic>=0.013), weeks of liver regeneration (B=&#x2212;4.294, <italic>P</italic>&lt;0.001), V<sub>PRO</sub> (B=0.038 <italic>P</italic>=0.005), and V<sub>FLR</sub> (B=0.032, <italic>P</italic>=0.026).</p>
<p>The factors with a <italic>P</italic> value of &lt;0.05 in the univariate regression analysis were analyzed by multivariate regression analysis. The preoperative bilirubin level (B=&#x2212;0.191, <italic>P</italic>=0.014), weeks of liver regeneration (B=&#x2212;0.732, <italic>P</italic>&lt;0.001), V<sub>PRO</sub> (B=1.151, <italic>P</italic>&lt;0.001), and V<sub>FLR</sub> (B=&#x2212;0.969, <italic>P</italic>&lt;0.001) independently affected the liver regeneration rate (<xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref>).</p>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Univariate and multivariate analysis of factors of rate of liver growth.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="center">Variable</th>
<th valign="top" align="center">Univariate analysis <italic>P</italic>-value</th>
<th valign="top" align="center">Multivariate analysis <italic>P</italic>-value</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">Weight</td>
<td valign="top" align="center">0.001</td>
<td valign="top" align="center">0.504</td>
</tr>
<tr>
<td valign="top" align="left">BMI</td>
<td valign="top" align="center">0.007</td>
<td valign="top" align="center">0.303</td>
</tr>
<tr>
<td valign="top" align="left">Drinking history</td>
<td valign="top" align="center">0.010</td>
<td valign="top" align="center">0.303</td>
</tr>
<tr>
<td valign="top" align="left">Vascular or nerve invasion</td>
<td valign="top" align="center">0.014</td>
<td valign="top" align="center">0.291</td>
</tr>
<tr>
<td valign="top" align="left">Preoperative bilirubin</td>
<td valign="top" align="center">0.013</td>
<td valign="top" align="center">0.014</td>
</tr>
<tr>
<td valign="top" align="left">Weeks of liver regeneration</td>
<td valign="top" align="center">0.001</td>
<td valign="top" align="center">&lt;0.001</td>
</tr>
<tr>
<td valign="top" align="left">Postoperative liver volume</td>
<td valign="top" align="center">0.005</td>
<td valign="top" align="center">&lt;0.001</td>
</tr>
<tr>
<td valign="top" align="left">Future liver remnant volume</td>
<td valign="top" align="center">0.026</td>
<td valign="top" align="center">&lt;0.001</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="s3_5">
<label>3.5</label>
<title>Analysis of preoperative factors affecting liver regeneration rate</title>
<sec id="s3_5_1">
<label>3.5.1</label>
<title>Effect of PBD on liver regeneration in patients with HC and severe jaundice</title>
<p>For patients with an initial bilirubin level of &gt;200 &#x3bc;mol/L (n=45), the initial bilirubin in the PBD group was significantly higher than that in the non-PBD group (349.05 &#xb1; 73.00&#x3bc;mol/L, n=34 vs. 285.15 &#xb1; 72.25&#x3bc;mol/L, n=11, respectively; <italic>P</italic>=0.015). The liver regeneration volume and ratio in PBD group (183.51 &#xb1; 93.93mL, 17.01 &#xb1; 8.24%) was higher than that in non-PBD group (106.23 &#xb1; 44.32mL, 10.49 &#xb1; 4.45%) by linear regression analysis (<italic>P</italic>=0.012, <italic>P</italic>=0.016). The liver regeneration rate was higher in the PBD group (62.39 &#xb1; 36.05 mL/week, n=34) than in the non-PBD group (45.11 &#xb1; 13.16 mL/week, n=11) (<italic>P</italic>=0.129). Within 4 weeks, the liver regeneration rate was significantly higher in the PBD group (79.77 &#xb1; 30.90 mL/week, n=22) than in the non-PBD group (46.00 &#xb1; 13.53 mL/week, n=10) (<italic>P</italic>=0.003). Within 8 weeks, the liver regeneration rate was significantly higher in the PBD group (73.74 &#xb1; 31.23 mL/week, n=27) than in the non-PBD group (45.11 &#xb1; 13.16 mL/week, n=11) (<italic>P</italic>=0.006). The comparison of the two groups is shown in <xref ref-type="table" rid="T3">
<bold>Table&#xa0;3</bold>
</xref> and <xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3D</bold>
</xref>.</p>
<table-wrap id="T3" position="float">
<label>Table&#xa0;3</label>
<caption>
<p>Comparison of PBD and non-PBD in patients with hilar cholangiocarcinoma whose initial bilirubin &gt; 200&#x3bc;mol/L.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="left">Parameters</th>
<th valign="middle" align="left">Level</th>
<th valign="middle" align="left">PBD (n=34)</th>
<th valign="middle" align="left">Non-PBD (n=11)</th>
<th valign="middle" align="left">P value</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="left">Age  (yrs)</td>
<td valign="middle" align="left"/>
<td valign="middle" align="left">63.32 &#xb1; 8.89</td>
<td valign="middle" align="left">61.45 &#xb1; 12.23</td>
<td valign="middle" align="left">0.584</td>
</tr>
<tr>
<td valign="middle" align="left">Gender</td>
<td valign="middle" align="left">Male</td>
<td valign="middle" align="left">24 (70.59)</td>
<td valign="middle" align="left">9 (81.82)</td>
<td valign="middle" align="left">0.734</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">Female</td>
<td valign="middle" align="left">10 (29.41)</td>
<td valign="middle" align="left">2 (18.18)</td>
<td valign="middle" align="left"/>
</tr>
<tr>
<td valign="middle" align="left">Initial bilirubin  (&#x3bc;mol/L)</td>
<td valign="middle" align="left"/>
<td valign="middle" align="left">349.05 &#xb1; 73.00</td>
<td valign="middle" align="left">285.15 &#xb1; 72.25</td>
<td valign="middle" align="left">0.015</td>
</tr>
<tr>
<td valign="middle" align="left">Preoperative bilirubin  (&#x3bc;mol/L)</td>
<td valign="middle" align="left"/>
<td valign="middle" align="left">114.06 &#xb1; 47.35</td>
<td valign="middle" align="left">285.15 &#xb1; 72.25</td>
<td valign="middle" align="left">&lt;0.001</td>
</tr>
<tr>
<td valign="middle" align="left">Postoperative liver insufficiency</td>
<td valign="middle" align="left">with</td>
<td valign="middle" align="left">5 (14.71)</td>
<td valign="middle" align="left">6 (54.55)</td>
<td valign="middle" align="left">0.008</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">without</td>
<td valign="middle" align="left">29 (85.29)</td>
<td valign="middle" align="left">5 (45.45)</td>
<td valign="middle" align="left"/>
</tr>
<tr>
<td valign="middle" align="left">Liver volume</td>
<td valign="middle" align="left">Baseline liver volume  (mL)</td>
<td valign="middle" align="left">1669.67 &#xb1; 456.05</td>
<td valign="middle" align="left">1546.72 &#xb1; 431.89</td>
<td valign="middle" align="left">0.436</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">Future liver remnant volume  (mL)</td>
<td valign="middle" align="left">989.77 &#xb1; 307.56</td>
<td valign="middle" align="left">1008.60 &#xb1; 228.63</td>
<td valign="middle" align="left">0.853</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">Duration  (wk)</td>
<td valign="middle" align="left">4.84 &#xb1; 5.35</td>
<td valign="middle" align="left">2.45 &#xb1; 1.10</td>
<td valign="middle" align="left">0.019</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">Postoperative liver volume  (mL)</td>
<td valign="middle" align="left">1173.28 &#xb1; 332.64</td>
<td valign="middle" align="left">1114.83 &#xb1; 217.68</td>
<td valign="middle" align="left">0.589</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">Liver volume changes  (mL)</td>
<td valign="middle" align="left">183.51 &#xb1; 93.93</td>
<td valign="middle" align="left">106.23 &#xb1; 44.32</td>
<td valign="middle" align="left">0.012</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">Liver volume change, %</td>
<td valign="middle" align="left">17.01 &#xb1; 8.24</td>
<td valign="middle" align="left">10.49 &#xb1; 4.45</td>
<td valign="middle" align="left">0.016</td>
</tr>
<tr>
<td valign="middle" align="right"/>
<td valign="middle" align="left">Rate of liver regeneration</td>
<td valign="middle" align="left">62.39 &#xb1; 36.05</td>
<td valign="middle" align="left">45.11 &#xb1; 13.16</td>
<td valign="middle" align="left">0.023</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="s3_5_2">
<label>3.5.2</label>
<title>Obtaining optimal preoperative bilirubin level based on liver regeneration rate</title>
<p>Taking the mean liver regeneration rate of 57.25 &#xb1; 34.98 mL/week in all 83 patients as the boundary value, patients with a liver regeneration rate of &#x2264;57.25 mL/week were defined as the lower liver regeneration rate group (n=48), and those with a rate of &gt;57.25 mL/week were defined as the higher liver regeneration rate group (n=35). The preoperative bilirubin cut-off value calculated by Youden&#x2019;s index was 103.15 &#x3bc;mol/L (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3E</bold>
</xref>), with sensitivity of 0.688 and specificity of 0.657.</p>
<p>For patients with preoperative bilirubin &#x2264;103.15&#x3bc;mol/L (n=38), the rate of liver regeneration (71.77 &#xb1; 35.99 mL/week), liver regeneration volume (210.27 &#xb1; 116.96mL) and ratio (19.18 &#xb1; 10.35%) were higher than those with preoperative bilirubin&gt;103.15&#x3bc;mol/L (n=45,45.00 &#xb1; 29.25mL/week, 135.69 &#xb1; 78.25mL, 12.84 &#xb1; 7.34%) (<italic>P</italic>&lt;0.01, <italic>P</italic>&lt;0.01, <italic>P</italic>=0.02).</p>
<p>In the PBD group (n=36), the liver regeneration rate was significantly higher in patients with a preoperative bilirubin level of &#x2264;103.15 than &gt;103.15 &#x3bc;mol/L (76.14 &#xb1; 38.96 mL/week, n=20 vs. 46.68 &#xb1; 29.72 mL/week, n=16, respectively; <italic>P</italic>=0.015).</p>
</sec>
</sec>
<sec id="s3_6">
<label>3.6</label>
<title>Univariate and multivariate analyses of factors affecting postoperative liver insufficiency</title>
<p>Among all 83 patients, 14 developed postoperative liver insufficiency, including 5 of 36 in the PBD group and 9 of 47 in the non-PBD group. Among patients with a preoperative bilirubin level of &gt;200 &#x3bc;mol/L (n=45), the probability of postoperative hepatic insufficiency was significantly lower in the PBD group (5/34) than in the non-PBD group (6/11) (<italic>P</italic>=0.012, odds ratio=0.144, 95%CI=0.031&#x2013;0.657). When examining the effect of a preoperative bilirubin level of 103.15 &#x3bc;mol/L (cut-off value) on postoperative hepatic insufficiency, we found that patients with a preoperative bilirubin level of &gt;103.15 &#x3bc;mol/L in the logistic regression analysis (13/45) had a higher probability of postoperative liver insufficiency than those with a lower preoperative bilirubin level (1/38) (<italic>P</italic>=0.011, odds ratio=0.067, 95% CI=0.008&#x2013;0.537).</p>
<p>The factors affecting postoperative liver insufficiency in the univariate analysis included the initial bilirubin level (<italic>P</italic>=0.026), preoperative albumin&#x2013;bilirubin score (<italic>P</italic>=0.003), whether the preoperative albumin&#x2013;bilirubin score reached grade 3 (<italic>P</italic>=0.006), bilirubin cut-off value of 103.15 &#xb5;mol/L (<italic>P</italic>=0.011), whether the ALB was &lt;30g/L (<italic>P</italic>=0.048), and preoperative bilirubin level (<italic>P</italic>=0.026). The multivariate analysis showed that the preoperative bilirubin level significantly affected postoperative liver insufficiency (<italic>P</italic>=0.016, odds ratio=1.016, &#x3b2;=0.016, 95% CI=1.003&#x2013;1.029) (<xref ref-type="table" rid="T4">
<bold>Table&#xa0;4</bold>
</xref>).</p>
<table-wrap id="T4" position="float">
<label>Table&#xa0;4</label>
<caption>
<p>Univariate and multivariate analysis of factors of postoperative liver insufficiency.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">Variable</th>
<th valign="top" align="center">Univariate analysis <italic>P</italic>-value</th>
<th valign="top" align="center">Multivariate analysis <italic>P</italic>-value</th>
<th valign="top" align="center">&#x3b2;</th>
<th valign="top" align="center">Exp(B)</th>
<th valign="top" align="center">EXP(B) 95%CI</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">Initial bilirubin</td>
<td valign="top" align="center">0.026</td>
<td valign="top" align="center">0.315</td>
<td valign="top" align="center">0.004</td>
<td valign="top" align="center">1.004</td>
<td valign="top" align="center">0.997-1.011</td>
</tr>
<tr>
<td valign="top" align="left">ALBI score</td>
<td valign="top" align="center">0.003</td>
<td valign="top" align="center">0.277</td>
<td valign="top" align="center">-2.301</td>
<td valign="top" align="center">0.100</td>
<td valign="top" align="center">0.002-6.333</td>
</tr>
<tr>
<td valign="top" align="left">ALBI reached Grade3 (yes/no)</td>
<td valign="top" align="center">0.006</td>
<td valign="top" align="center">0.708</td>
<td valign="top" align="center">0.496</td>
<td valign="top" align="center">1.642</td>
<td valign="top" align="center">0.123-21.964</td>
</tr>
<tr>
<td valign="top" align="left">Preoperative bilirubin &#x2264; 103.15&#x3bc;mol/L</td>
<td valign="top" align="center">0.011</td>
<td valign="top" align="center">0.302</td>
<td valign="top" align="center">1.529</td>
<td valign="top" align="center">4.613</td>
<td valign="top" align="center">0.253-84.074</td>
</tr>
<tr>
<td valign="top" align="left">ALB below 30g/L (yes/no)</td>
<td valign="top" align="center">0.048</td>
<td valign="top" align="center">0.140</td>
<td valign="top" align="center">2.074</td>
<td valign="top" align="center">7.953</td>
<td valign="top" align="center">0.506-125.086</td>
</tr>
<tr>
<td valign="top" align="left">Preoperative bilirubin</td>
<td valign="top" align="center">&lt;0.001</td>
<td valign="top" align="center">0.016</td>
<td valign="top" align="center">0.016</td>
<td valign="top" align="center">1.016</td>
<td valign="top" align="center">1.003-1.029</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
</sec>
<sec id="s4" sec-type="discussion">
<label>4</label>
<title>Discussion</title>
<p>The standard of PBD for patients with HC has long been controversial (<xref ref-type="bibr" rid="B27">27</xref>, <xref ref-type="bibr" rid="B28">28</xref>). Recent studies have considered postoperative liver function, postoperative complications, survival time, and mortality as evaluation indicators to explore the best choice of preoperative treatment for patients with HC (<xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B30">30</xref>). However, these indicators are not comprehensive enough to reflect the function and potential growth of the postoperative liver. The function of the residual liver after liver resection is difficult to predict, but the change in liver volume is an important indicator of liver function. The speed at which the liver volume increases may also reflect the potential for liver regeneration (<xref ref-type="bibr" rid="B31">31</xref>&#x2013;<xref ref-type="bibr" rid="B33">33</xref>). Calculation of the liver volume based on CT images is widely used in clinical practice to assess the size of liver grafts, prevent postoperative liver failure, and predict postoperative mortality (<xref ref-type="bibr" rid="B34">34</xref>&#x2013;<xref ref-type="bibr" rid="B36">36</xref>). Lee et&#xa0;al. showed that the change in liver volume can be used as an effective tool to evaluate the effect of stent implantation in patients with cholangiocarcinoma (<xref ref-type="bibr" rid="B10">10</xref>). Because the V<sub>PRO</sub> of patients with HC changes dynamically with time, we used the rate of liver growth to evaluate the postoperative liver regeneration status and prognosis and to explore the influence of preoperative factors on the change in liver volume, with the goal of providing new ideas for clinical treatment in the future. To our knowledge, this is the first clinical study to focus on the change in liver volume and its influencing factors in patients with HC who have undergone hemi-hepatectomy.</p>
<p>The endpoint of liver regeneration time is still controversial. Lee CH et&#xa0;al. studied the regeneration of the liver from 4 to 20 weeks after biliary stent (<xref ref-type="bibr" rid="B10">10</xref>); Zhang Y et&#xa0;al. explored liver volume change in donors and recipients from 0.5 to 6 months after liver transplantation (<xref ref-type="bibr" rid="B37">37</xref>); and Gong WF et&#xa0;al. analyzed the liver growth in hepatocellular carcinoma patients at 1, 5, 9, and 13 weeks after liver surgery (<xref ref-type="bibr" rid="B38">38</xref>). In this study, we retrospectively analyzed the liver volume changes before and after hepatectomy in 83 patients with HC. The follow-up duration ranged from 1 to 20.86 weeks. Compared with V<sub>FLR</sub>, V<sub>PRO</sub> increased significantly (<italic>P</italic>&lt;0.001) (increase of 169.83 &#xb1; 104.19 mL, which accounted for 15.74% &#xb1; 9.34%). A more rapid liver regeneration rate was found within 4 weeks or 8 weeks than after 4 weeks or 8 weeks (<italic>P</italic>&lt;0.001), suggesting that liver regeneration mainly occurs in the early stage after liver resection; this is consistent with the results reported by Lee et&#xa0;al. (<xref ref-type="bibr" rid="B10">10</xref>). <xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2</bold>
</xref> shows that the liver morphologically increased in volume after hepatectomy, which may be attributed to the fulfillment of liver function needs, the stimulation by surgery, the relief of biliary obstruction, or other factors. Therefore, this study suggests that the increase in liver volume is a response to the regenerative capacity of the liver. The liver regeneration rate differs among individual patients, which may be explained by the patient&#x2019;s preoperative state, operative approach, function of the liver, and other factors. We therefore believe that the liver regeneration rate may be used as an effective index to appraise postoperative hepatic function.</p>
<p>The preoperative bilirubin level is an essential factor affecting postoperative liver regeneration (<xref ref-type="bibr" rid="B39">39</xref>, <xref ref-type="bibr" rid="B40">40</xref>), and hyperbilirubinemia is considered an independent risk factor for mortality and complications after hepatectomy (<xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B41">41</xref>). A recent study showed that obstructive jaundice can induce the proliferation and activation of hepatic stellate cells, resulting in up-regulation of transforming growth factor-&#x3b2;1 mRNA and inhibition of hepatocyte growth factor mRNA in the liver, thus causing delayed liver regeneration after liver resection in rats (<xref ref-type="bibr" rid="B42">42</xref>). Kim et&#xa0;al. retrospectively analyzed 112 living donors who underwent right hepatectomy and proposed that liver regeneration can be predicted by combining the preoperative serum total bilirubin level, residual liver volume, and CT texture analysis and that V<sub>FLR</sub> is an independent predictor of liver regeneration (<xref ref-type="bibr" rid="B43">43</xref>). Through univariate and multivariate analyses of factors affecting the liver regeneration rate, we found that a higher preoperative bilirubin level (B=&#x2212;0.191, <italic>P</italic>=0.014), larger V<sub>FLR</sub> (B=&#x2212;0.969, <italic>P</italic>&lt;0.001), longer liver regeneration time (B=&#x2212;0.732, <italic>P</italic>&lt;0.001), and smaller V<sub>PRO</sub> (B=1.151, <italic>P</italic>&lt;0.001) led to a lower postoperative liver regeneration rate. These results may suggest that a high preoperative bilirubin level is associated with poor preoperative liver function, which reduces the potential for liver regeneration; that large V<sub>FLR</sub> indicates the need for smaller liver resection, also reducing the potential for liver regeneration; that the liver regenerative potential decreases over time; and that small V<sub>PRO</sub> indicates poorer liver regeneration outcomes and predicts poorer liver regeneration potential. Interestingly, our analysis of factors affecting postoperative liver insufficiency showed that preoperative bilirubin was an independent factor affecting postoperative hepatic insufficiency (<italic>P</italic>=0.016, odds ratio=1.016, &#x3b2;=0.016, 95% CI=1.003&#x2013;1.029). As the preoperative bilirubin level increased, the probability of postoperative hepatic insufficiency also increased. Higher preoperative bilirubin may lead to poor preoperative liver function, which will affect the recovery of postoperative liver function. Therefore, the preoperative bilirubin level may be an important indicator that affects the liver regeneration rate and postoperative liver function.</p>
<p>Whether to perform biliary drainage in the preoperative management of patients with HC is controversial. Many Asian centers advocate routine extensive biliary drainage to reduce jaundice and improve liver function before surgery (<xref ref-type="bibr" rid="B21">21</xref>, <xref ref-type="bibr" rid="B44">44</xref>&#x2013;<xref ref-type="bibr" rid="B46">46</xref>). However, it has also been suggested that catheter-implanted metastatic cancer caused by preoperative percutaneous transhepatic biliary drainage is not an uncommon complication (<xref ref-type="bibr" rid="B47">47</xref>). Ramanathan et&#xa0;al. proposed that preoperative PBD is associated with increased postoperative complications (<xref ref-type="bibr" rid="B48">48</xref>). Our study compared the efficacy of PBD in patients with HD who underwent hemi-hepatectomy from the perspective of the liver regeneration rate. Interestingly, no significant difference in the liver regeneration rate was found between the PBD and non-PBD group (<italic>P</italic>=0.569). We found that although the rate of liver growth was higher in the PBD than non-PBD group within 4 weeks or 8 weeks, the difference was not statistically significant (&lt;4 weeks, <italic>P</italic>=0.112; &lt;8 weeks, <italic>P</italic>=0.084) by further comparing the difference in the liver regeneration rate between the two groups in the early stage of liver regeneration.</p>
<p>Patients with severe jaundice usually require preoperative biliary drainage, but the cut-off value is controversial (<xref ref-type="bibr" rid="B41">41</xref>, <xref ref-type="bibr" rid="B49">49</xref>, <xref ref-type="bibr" rid="B50">50</xref>). Cai et&#xa0;al. considered 218.75 &#x3bc;mol/L as the cut-off value of total bilirubin for PBD by retrospectively analyzing 218 patients with HC (<xref ref-type="bibr" rid="B49">49</xref>). Another study suggested that biliary drainage is required when the bilirubin level reaches 171.0 &#x3bc;mol/L, considering the patients&#x2019; condition and surgical extent (<xref ref-type="bibr" rid="B50">50</xref>). Hemming et&#xa0;al. performed palliation of jaundice before liver resection for patients whose preoperative bilirubin level was &gt;85.5 &#x3bc;mol/L (<xref ref-type="bibr" rid="B51">51</xref>). Wronka et&#xa0;al. proposed that patients with a total bilirubin level of &#x2265;102.6 &#x3bc;mol/L who underwent PBD may have lower rates of mortality and severe complications (<xref ref-type="bibr" rid="B41">41</xref>). We analyzed the liver growth in patients with an initial bilirubin level of &gt;200 &#x3bc;mol/L based on expert consensus in China and the research reported by Laurent (<xref ref-type="bibr" rid="B20">20</xref>). The liver regeneration volume and ratio in PBD group were both significantly higher than that in non-PBD group (<italic>P</italic>=0.012, <italic>P</italic>=0.016). During the early postoperative period, the rate of liver growth was significantly higher in the PBD than non-PBD group within 4 or 8 weeks (&#x2264;4 weeks, <italic>P</italic>=0.003; &#x2264;8 weeks, <italic>P</italic>=0.006). Notably, among patients with a preoperative bilirubin level of &gt;200 &#x3bc;mol/L, the probability of postoperative liver insufficiency was significantly higher in the non-PBD than PBD group (<italic>P</italic>=0.012). For patients with HC who have severe jaundice (200 &#x3bc;mol/L) and are candidates for hepatectomy, preoperative jaundice palliation may improve liver function and maintain a better liver regeneration potential after the operation, thus enhancing liver regeneration in the early postoperative period. In patients who do not undergo PBD, however, poor liver function caused by severe jaundice may increase the risk of postoperative liver insufficiency.</p>
<p>The recommended optimal preoperative bilirubin level for patients with HC after jaundice palliation widely ranges among recent studies (<xref ref-type="bibr" rid="B51">51</xref>&#x2013;<xref ref-type="bibr" rid="B54">54</xref>). Some studies suggest that PBD should be performed to reduce the bilirubin level to 34.2 to 53.1 &#x3bc;mol/L before hepatectomy (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B45">45</xref>, <xref ref-type="bibr" rid="B53">53</xref>). In a study from Hong Kong, She et&#xa0;al. retrospectively analyzed 90 patients with HC and found that a preoperative bilirubin level of &lt;75 &#x3bc;mol/L can significantly reduce the blood transfusion volume required during the operation and significantly improve patients&#x2019; postoperative survival rate (<xref ref-type="bibr" rid="B55">55</xref>). Cannon et&#xa0;al. advocated three-segment hepatic drainage to reduce the serum bilirubin level to &lt;171.0 &#x3bc;mol/L to improve remnant liver function (<xref ref-type="bibr" rid="B52">52</xref>). The rate of liver regeneration reflects not only changes in liver morphology but also liver function to a certain extent. To our knowledge, no other studies have explored the cut-off value of preoperative bilirubin using the rate of liver regeneration as an outcome. Our study indicated that the preoperative bilirubin cut-off value affecting the liver regeneration rate was 103.15 &#x3bc;mol/L. Patients with preoperative bilirubin &#x2264;103.15 &#x3bc;mol/L exhibited better liver regeneration rate (<italic>P</italic>&lt;0.01), regeneration volume and ratio (<italic>P</italic>&lt;0.01, <italic>P</italic>=0.02), compared to patients with preoperative bilirubin greater than that. Interestingly, we further verified its influence on postoperative hepatic insufficiency and found that the probability of postoperative liver insufficiency in patients with HC was higher in those with a preoperative bilirubin level of &gt;103.15 &#x3bc;mol/L than &#x2264;103.15 &#x3bc;mol/L (<italic>P</italic>=0.011). When we examined the effect of a preoperative bilirubin level of &#x2264;103.15 &#x3bc;mol/L on the liver regeneration rate in the PBD subgroup, we found that the postoperative liver regeneration rate was significantly higher in patients with a bilirubin level of &#x2264;103.15 &#x3bc;mol/L than &gt;103.15 &#x3bc;mol/L (<italic>P</italic>=0.015). These results may help to select the optimal operative time for hepatectomy in patients with HC. Better postoperative liver regeneration and a lower incidence of liver insufficiency may be obtained when the preoperative bilirubin level is &#x2264;103.15 &#x3bc;mol/L. With the goal of prioritizing postoperative safety, earlier surgical treatment can prevent tumor progression and reduce the impact of bile loss on patients&#x2019; overall health.</p>
<p>This study had several limitations. First, because it was a retrospective study, it had a certain selection bias, and our sample size was too small to perform a more detailed subgroup comparison. Second, the method by which the liver volume was drawn in this study was semi-automatic, and certain manual delineation errors seem unavoidable. At the same time, the V<sub>FLR</sub> was obtained by dividing the V<sub>BLV</sub> along the middle hepatic vein, which deviated from the real postoperative residual liver volume to a certain degree.</p>
</sec>
<sec id="s5" sec-type="conclusions">
<label>5</label>
<title>Conclusion</title>
<p>Patients with HC usually develop an increase in liver volume after hepatectomy. The rate of liver regeneration may be an effective index to evaluate postoperative liver function. The preoperative bilirubin level may be an independent risk factor affecting the liver regeneration rate and postoperative liver insufficiency. For patients whose initial bilirubin is &gt;200 &#x3bc;mol/L, PBD may enhance liver regeneration and reduce the incidence of liver insufficiency after surgery. Preoperative bilirubin levels &#x2264;103.15 maybe recommended for leading to a better liver regeneration and lower incidence of postoperative hepatic insufficiency.</p>
</sec>
<sec id="s6" sec-type="data-availability">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="supplementary-material" rid="SM1">
<bold>Supplementary Material</bold>
</xref>. Further inquiries can be directed to the corresponding authors.</p>
</sec>
<sec id="s7" sec-type="author-contributions">
<title>Author contributions</title>
<p>HZ: Data curation, Methodology, Validation, Visualization, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. JZ: Conceptualization, Resources, Supervision, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. BL: Project administration, Supervision, Writing &#x2013; review &amp; editing. XhL: Conceptualization, Data curation, Writing &#x2013; review &amp; editing. XnL: Validation, Visualization, Writing &#x2013; review &amp; editing. CZ: Supervision, Validation, Visualization, Writing &#x2013; review &amp; editing. TG: Data curation, Formal analysis, Writing &#x2013; review &amp; editing. ZD: Data curation, Formal analysis, Writing &#x2013; review &amp; editing.</p>
</sec>
</body>
<back>
<sec id="s8" sec-type="funding-information">
<title>Funding</title>
<p>The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.</p>
</sec>
<sec id="s9" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s10" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s11" sec-type="supplementary-material">
<title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fonc.2024.1375648/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fonc.2024.1375648/full#supplementary-material</ext-link>
</p>
<supplementary-material xlink:href="Table_1.docx" id="SM1" mimetype="application/vnd.openxmlformats-officedocument.wordprocessingml.document"/>
</sec>
<fn-group>
<title>Abbreviations</title>
<fn fn-type="abbr">
<p>ALBI, albumin-bilirubin ALT; Alanine aminotransferase; ALP, Alkaline phosphatase; AST, Aspartate aminotransferase; CT, computed tomography; GGT, Gamma glutamyl transpeptidase; HBV, hepatitis B virus; HC, hilar cholangiocarcinoma; PBD, preoperative biliary drainage; SLV, standard liver volume; V<sub>BLV</sub>, baseline liver volume; V<sub>FLR</sub>, future liver remnant volume; V<sub>PRO</sub>, postoperative liver volume.</p>
</fn>
</fn-group>
<ref-list>
<title>References</title>
<ref id="B1">
<label>1</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mansour</surname> <given-names>JC</given-names>
</name>
<name>
<surname>Aloia</surname> <given-names>TA</given-names>
</name>
<name>
<surname>Crane</surname> <given-names>CH</given-names>
</name>
<name>
<surname>Heimbach</surname> <given-names>JK</given-names>
</name>
<name>
<surname>Nagino</surname> <given-names>M</given-names>
</name>
<name>
<surname>Vauthey</surname> <given-names>JN</given-names>
</name>
</person-group>. <article-title>Hilar cholangiocarcinoma: expert consensus statement</article-title>. <source>HPB (Oxford)</source>. (<year>2015</year>) <volume>17</volume>:<page-range>691&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/hpb.12450</pub-id>
</citation>
</ref>
<ref id="B2">
<label>2</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Banales</surname> <given-names>JM</given-names>
</name>
<name>
<surname>Marin</surname> <given-names>JJG</given-names>
</name>
<name>
<surname>Lamarca</surname> <given-names>A</given-names>
</name>
<name>
<surname>Rodrigues</surname> <given-names>PM</given-names>
</name>
<name>
<surname>Khan</surname> <given-names>SA</given-names>
</name>
<name>
<surname>Roberts</surname> <given-names>LR</given-names>
</name>
<etal/>
</person-group>. <article-title>Cholangiocarcinoma 2020: the next horizon in mechanisms and management</article-title>. <source>Nat Rev Gastroenterol Hepatol</source>. (<year>2020</year>) <volume>17</volume>:<page-range>557&#x2013;88</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1038/s41575-020-0310-z</pub-id>
</citation>
</ref>
<ref id="B3">
<label>3</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Lidsky</surname> <given-names>ME</given-names>
</name>
<name>
<surname>Jarnagin</surname> <given-names>WR</given-names>
</name>
</person-group>. <article-title>Surgical management of hilar cholangiocarcinoma at memorial sloan kettering cancer center</article-title>. <source>Ann Gastroenterol Surg</source>. (<year>2018</year>) <volume>2</volume>:<page-range>304&#x2013;12</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/ags3.12181</pub-id>
</citation>
</ref>
<ref id="B4">
<label>4</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Groot Koerkamp</surname> <given-names>B</given-names>
</name>
<name>
<surname>Wiggers</surname> <given-names>JK</given-names>
</name>
<name>
<surname>Allen</surname> <given-names>PJ</given-names>
</name>
<name>
<surname>Besselink</surname> <given-names>MG</given-names>
</name>
<name>
<surname>Blumgart</surname> <given-names>LH</given-names>
</name>
<name>
<surname>Busch</surname> <given-names>OR</given-names>
</name>
<etal/>
</person-group>. <article-title>Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection</article-title>. <source>J Am Coll Surg</source>. (<year>2015</year>) <volume>221</volume>:<page-range>1041&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.jamcollsurg.2015.09.005</pub-id>
</citation>
</ref>
<ref id="B5">
<label>5</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ribero</surname> <given-names>D</given-names>
</name>
<name>
<surname>Zimmitti</surname> <given-names>G</given-names>
</name>
<name>
<surname>Aloia</surname> <given-names>TA</given-names>
</name>
<name>
<surname>Shindoh</surname> <given-names>J</given-names>
</name>
<name>
<surname>Fabio</surname> <given-names>F</given-names>
</name>
<name>
<surname>Amisano</surname> <given-names>M</given-names>
</name>
<etal/>
</person-group>. <article-title>Preoperative cholangitis and future liver remnant volume determine the risk of liver failure in patients undergoing resection for hilar cholangiocarcinoma</article-title>. <source>J Am Coll Surg</source>. (<year>2016</year>) <volume>223</volume>:<fpage>87</fpage>&#x2013;<lpage>97</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.jamcollsurg.2016.01.060</pub-id>
</citation>
</ref>
<ref id="B6">
<label>6</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jarnagin</surname> <given-names>WR</given-names>
</name>
<name>
<surname>Fong</surname> <given-names>Y</given-names>
</name>
<name>
<surname>DeMatteo</surname> <given-names>RP</given-names>
</name>
<name>
<surname>Gonen</surname> <given-names>M</given-names>
</name>
<name>
<surname>Burke</surname> <given-names>EC</given-names>
</name>
<name>
<surname>Bodniewicz</surname> <given-names>BJ</given-names>
</name>
<etal/>
</person-group>. <article-title>Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma</article-title>. <source>Ann Surg</source>. (<year>2001</year>) <volume>234</volume>:<fpage>507</fpage>&#x2013;<lpage>17; discussion 17-9</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/00000658-200110000-00010</pub-id>
</citation>
</ref>
<ref id="B7">
<label>7</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cillo</surname> <given-names>U</given-names>
</name>
<name>
<surname>Fondevila</surname> <given-names>C</given-names>
</name>
<name>
<surname>Donadon</surname> <given-names>M</given-names>
</name>
<name>
<surname>Gringeri</surname> <given-names>E</given-names>
</name>
<name>
<surname>Mocchegiani</surname> <given-names>F</given-names>
</name>
<name>
<surname>Schlitt</surname> <given-names>HJ</given-names>
</name>
<etal/>
</person-group>. <article-title>Surgery for cholangiocarcinoma</article-title>. <source>Liver Int Off J Int Assoc Study Liver</source>. (<year>2019</year>) <volume>39 Suppl 1</volume>:<page-range>143&#x2013;55</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/liv.14089</pub-id>
</citation>
</ref>
<ref id="B8">
<label>8</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yamanaka</surname> <given-names>N</given-names>
</name>
<name>
<surname>Okamoto</surname> <given-names>E</given-names>
</name>
<name>
<surname>Kawamura</surname> <given-names>E</given-names>
</name>
<name>
<surname>Kato</surname> <given-names>T</given-names>
</name>
<name>
<surname>Oriyama</surname> <given-names>T</given-names>
</name>
<name>
<surname>Fujimoto</surname> <given-names>J</given-names>
</name>
<etal/>
</person-group>. <article-title>Dynamics of normal and injured human liver regeneration after hepatectomy as assessed on the basis of computed tomography and liver function</article-title>. <source>Hepatology</source>. (<year>1993</year>) <volume>18</volume>:<fpage>79</fpage>&#x2013;<lpage>85</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/(ISSN)1527-3350</pub-id>
</citation>
</ref>
<ref id="B9">
<label>9</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Halpern</surname> <given-names>A</given-names>
</name>
<name>
<surname>Bircher</surname> <given-names>J</given-names>
</name>
<name>
<surname>Tauber</surname> <given-names>J</given-names>
</name>
<name>
<surname>Blankart</surname> <given-names>R</given-names>
</name>
<name>
<surname>R&#xf6;sler</surname> <given-names>H</given-names>
</name>
<name>
<surname>Preisig</surname> <given-names>R</given-names>
</name>
</person-group>. <article-title>[Specific liver function: liver volume as reference parameter of the function]</article-title>. <source>Schweiz Med Wochenschr</source>. (<year>1971</year>) <volume>101</volume>:<page-range>736&#x2013;7</page-range>.</citation>
</ref>
<ref id="B10">
<label>10</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Lee</surname> <given-names>CH</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>SH</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>IH</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>SW</given-names>
</name>
<name>
<surname>Lee</surname> <given-names>ST</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>DG</given-names>
</name>
<etal/>
</person-group>. <article-title>Endoscopic stenting in bile duct cancer increases liver volume</article-title>. <source>Gastrointest Endosc</source>. (<year>2014</year>) <volume>80</volume>:<page-range>447&#x2013;55</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.gie.2014.01.051</pub-id>
</citation>
</ref>
<ref id="B11">
<label>11</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Otao</surname> <given-names>R</given-names>
</name>
<name>
<surname>Beppu</surname> <given-names>T</given-names>
</name>
<name>
<surname>Isiko</surname> <given-names>T</given-names>
</name>
<name>
<surname>Mima</surname> <given-names>K</given-names>
</name>
<name>
<surname>Okabe</surname> <given-names>H</given-names>
</name>
<name>
<surname>Hayashi</surname> <given-names>H</given-names>
</name>
<etal/>
</person-group>. <article-title>External biliary drainage and liver regeneration after major hepatectomy</article-title>. <source>Br J Surg</source>. (<year>2012</year>) <volume>99</volume>:<page-range>1569&#x2013;74</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/bjs.8906</pub-id>
</citation>
</ref>
<ref id="B12">
<label>12</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sakata</surname> <given-names>J</given-names>
</name>
<name>
<surname>Shirai</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Tsuchiya</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Wakai</surname> <given-names>T</given-names>
</name>
<name>
<surname>Nomura</surname> <given-names>T</given-names>
</name>
<name>
<surname>Hatakeyama</surname> <given-names>K</given-names>
</name>
</person-group>. <article-title>Preoperative Cholangitis Independently Increases in-Hospital Mortality after Combined Major Hepatic and Bile Duct Resection for Hilar Cholangiocarcinoma</article-title>. <source>Langenbeck's Arch Surg</source>. (<year>2009</year>) <volume>394</volume>:<page-range>1065&#x2013;72</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s00423-009-0464-1</pub-id>
</citation>
</ref>
<ref id="B13">
<label>13</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chaudhary</surname> <given-names>RJ</given-names>
</name>
<name>
<surname>Higuchi</surname> <given-names>R</given-names>
</name>
<name>
<surname>Nagino</surname> <given-names>M</given-names>
</name>
<name>
<surname>Unno</surname> <given-names>M</given-names>
</name>
<name>
<surname>Ohtsuka</surname> <given-names>M</given-names>
</name>
<name>
<surname>Endo</surname> <given-names>I</given-names>
</name>
<etal/>
</person-group>. <article-title>Survey of preoperative management protocol for perihilar cholangiocarcinoma at 10 Japanese high-volume centers with a combined experience of 2,778 cases</article-title>. <source>J hepato-biliary-pancreatic Sci</source>. (<year>2019</year>) <volume>26</volume>:<fpage>490</fpage>&#x2013;<lpage>502</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/jhbp.668</pub-id>
</citation>
</ref>
<ref id="B14">
<label>14</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Soares</surname> <given-names>KC</given-names>
</name>
<name>
<surname>Jarnagin</surname> <given-names>WR</given-names>
</name>
</person-group>. <article-title>The landmark series: hilar cholangiocarcinoma</article-title>. <source>Ann Surg Oncol</source>. (<year>2021</year>) <volume>28</volume>:<page-range>4158&#x2013;70</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1245/s10434-021-09871-6</pub-id>
</citation>
</ref>
<ref id="B15">
<label>15</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Suzuki</surname> <given-names>H</given-names>
</name>
<name>
<surname>Iyomasa</surname> <given-names>S</given-names>
</name>
<name>
<surname>Nimura</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Yoshida</surname> <given-names>S</given-names>
</name>
</person-group>. <article-title>Internal biliary drainage, unlike external drainage, does not suppress the regeneration of cholestatic rat liver after partial hepatectomy</article-title>. <source>Hepatology</source>. (<year>1994</year>) <volume>20</volume>:<page-range>1318&#x2013;22</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/(ISSN)1527-3350</pub-id>
</citation>
</ref>
<ref id="B16">
<label>16</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sun</surname> <given-names>Q</given-names>
</name>
<name>
<surname>Fang</surname> <given-names>F</given-names>
</name>
<name>
<surname>Lu</surname> <given-names>GC</given-names>
</name>
<name>
<surname>Mao</surname> <given-names>HH</given-names>
</name>
<name>
<surname>Xu</surname> <given-names>JH</given-names>
</name>
<name>
<surname>Zhou</surname> <given-names>SK</given-names>
</name>
<etal/>
</person-group>. <article-title>Effects of different drainage methods on serum bile acid and hepatocyte apoptosis and regeneration after partial hepatectomy in rats with obstructive jaundice</article-title>. <source>J Biol Regul Homeostat Agents</source>. (<year>2019</year>) <volume>33</volume>:<page-range>571&#x2013;9</page-range>.</citation>
</ref>
<ref id="B17">
<label>17</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Li</surname> <given-names>CH</given-names>
</name>
<name>
<surname>Zhang</surname> <given-names>X</given-names>
</name>
<name>
<surname>Ge</surname> <given-names>XL</given-names>
</name>
<name>
<surname>Huang</surname> <given-names>X</given-names>
</name>
<name>
<surname>Zhang</surname> <given-names>AQ</given-names>
</name>
<name>
<surname>Gu</surname> <given-names>WQ</given-names>
</name>
</person-group>. <article-title>Effects of combined anisodamine and neostigmine treatment on the inflammatory response and liver regeneration of obstructive jaundice rats after hepatectomy</article-title>. <source>BioMed Res Int</source>. (<year>2014</year>) <volume>2014</volume>:<elocation-id>362024</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.1155/2014/362024</pub-id>
</citation>
</ref>
<ref id="B18">
<label>18</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ueda</surname> <given-names>J</given-names>
</name>
<name>
<surname>Chijiiwa</surname> <given-names>K</given-names>
</name>
<name>
<surname>Nakano</surname> <given-names>K</given-names>
</name>
<name>
<surname>Zhao</surname> <given-names>G</given-names>
</name>
<name>
<surname>Tanaka</surname> <given-names>M</given-names>
</name>
</person-group>. <article-title>Lack of intestinal bile results in delayed liver regeneration of normal rat liver after hepatectomy accompanied by impaired cyclin E-associated kinase activity</article-title>. <source>Surgery</source>. (<year>2002</year>) <volume>131</volume>:<page-range>564&#x2013;73</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1067/msy.2002.123008</pub-id>
</citation>
</ref>
<ref id="B19">
<label>19</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Iacono</surname> <given-names>C</given-names>
</name>
<name>
<surname>Ruzzenente</surname> <given-names>A</given-names>
</name>
<name>
<surname>Campagnaro</surname> <given-names>T</given-names>
</name>
<name>
<surname>Bortolasi</surname> <given-names>L</given-names>
</name>
<name>
<surname>Valdegamberi</surname> <given-names>A</given-names>
</name>
<name>
<surname>Guglielmi</surname> <given-names>A</given-names>
</name>
</person-group>. <article-title>Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection: highlights and drawbacks</article-title>. <source>Ann Surg</source>. (<year>2013</year>) <volume>257</volume>:<fpage>191</fpage>&#x2013;<lpage>204</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/SLA.0b013e31826f4b0e</pub-id>
</citation>
</ref>
<ref id="B20">
<label>20</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Laurent</surname> <given-names>A</given-names>
</name>
<name>
<surname>Tayar</surname> <given-names>C</given-names>
</name>
<name>
<surname>Cherqui</surname> <given-names>D</given-names>
</name>
</person-group>. <article-title>Cholangiocarcinoma: preoperative biliary drainage (Con)</article-title>. <source>HPB (Oxford)</source>. (<year>2008</year>) <volume>10</volume>:<page-range>126&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1080/13651820802007472</pub-id>
</citation>
</ref>
<ref id="B21">
<label>21</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Nimura</surname> <given-names>Y</given-names>
</name>
</person-group>. <article-title>Preoperative biliary drainage before resection for cholangiocarcinoma (Pro)</article-title>. <source>HPB (Oxford)</source>. (<year>2008</year>) <volume>10</volume>:<page-range>130&#x2013;3</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1080/13651820801992666</pub-id>
</citation>
</ref>
<ref id="B22">
<label>22</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Nimura</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Hayakawa</surname> <given-names>N</given-names>
</name>
<name>
<surname>Kamiya</surname> <given-names>J</given-names>
</name>
<name>
<surname>Kondo</surname> <given-names>S</given-names>
</name>
<name>
<surname>Shionoya</surname> <given-names>S</given-names>
</name>
</person-group>. <article-title>Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus</article-title>. <source>World J Surg</source>. (<year>1990</year>) <volume>14</volume>:<fpage>535</fpage>&#x2013;<lpage>43; discussion 44</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/bf01658686</pub-id>
</citation>
</ref>
<ref id="B23">
<label>23</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bismuth</surname> <given-names>H</given-names>
</name>
<name>
<surname>Corlette</surname> <given-names>MB</given-names>
</name>
</person-group>. <article-title>Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver</article-title>. <source>Surgery gynecology obstetrics</source>. (<year>1975</year>) <volume>140</volume>:<page-range>170&#x2013;8</page-range>.</citation>
</ref>
<ref id="B24">
<label>24</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Skrzypczyk</surname> <given-names>C</given-names>
</name>
<name>
<surname>Truant</surname> <given-names>S</given-names>
</name>
<name>
<surname>Duhamel</surname> <given-names>A</given-names>
</name>
<name>
<surname>Langlois</surname> <given-names>C</given-names>
</name>
<name>
<surname>Boleslawski</surname> <given-names>E</given-names>
</name>
<name>
<surname>Koriche</surname> <given-names>D</given-names>
</name>
<etal/>
</person-group>. <article-title>Relevance of the isgls definition of posthepatectomy liver failure in early prediction of poor outcome after liver resection: study on 680 hepatectomies</article-title>. <source>Ann Surg</source>. (<year>2014</year>) <volume>260</volume>:<fpage>865</fpage>&#x2013;<lpage>70; discussion 70</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/sla.0000000000000944</pub-id>
</citation>
</ref>
<ref id="B25">
<label>25</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mullen</surname> <given-names>JT</given-names>
</name>
<name>
<surname>Ribero</surname> <given-names>D</given-names>
</name>
<name>
<surname>Reddy</surname> <given-names>SK</given-names>
</name>
<name>
<surname>Donadon</surname> <given-names>M</given-names>
</name>
<name>
<surname>Zorzi</surname> <given-names>D</given-names>
</name>
<name>
<surname>Gautam</surname> <given-names>S</given-names>
</name>
<etal/>
</person-group>. <article-title>Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy</article-title>. <source>J Am Coll Surg</source>. (<year>2007</year>) <volume>204</volume>:<fpage>854</fpage>&#x2013;<lpage>62; discussion 62-4</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.jamcollsurg.2006.12.032</pub-id>
</citation>
</ref>
<ref id="B26">
<label>26</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Shi</surname> <given-names>ZR</given-names>
</name>
<name>
<surname>Yan</surname> <given-names>LN</given-names>
</name>
<name>
<surname>Li</surname> <given-names>B</given-names>
</name>
<name>
<surname>Wen</surname> <given-names>TF</given-names>
</name>
</person-group>. <article-title>Evaluation of standard liver volume formulae for chinese adults</article-title>. <source>World J Gastroenterol</source>. (<year>2009</year>) <volume>15</volume>:<page-range>4062&#x2013;6</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3748/wjg.15.4062</pub-id>
</citation>
</ref>
<ref id="B27">
<label>27</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Fong</surname> <given-names>ZV</given-names>
</name>
<name>
<surname>Brownlee</surname> <given-names>SA</given-names>
</name>
<name>
<surname>Qadan</surname> <given-names>M</given-names>
</name>
<name>
<surname>Tanabe</surname> <given-names>KK</given-names>
</name>
</person-group>. <article-title>The clinical management of cholangiocarcinoma in the United States and europe: A comprehensive and evidence-based comparison of guidelines</article-title>. <source>Ann Surg Oncol</source>. (<year>2021</year>) <volume>28</volume>:<page-range>2660&#x2013;74</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1245/s10434-021-09671-y</pub-id>
</citation>
</ref>
<ref id="B28">
<label>28</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ellis</surname> <given-names>RJ</given-names>
</name>
<name>
<surname>Soares</surname> <given-names>KC</given-names>
</name>
<name>
<surname>Jarnagin</surname> <given-names>WR</given-names>
</name>
</person-group>. <article-title>Preoperative management of perihilar cholangiocarcinoma</article-title>. <source>Cancers</source>. (<year>2022</year>) <volume>14</volume>:<fpage>2119</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.3390/cancers14092119</pub-id>
</citation>
</ref>
<ref id="B29">
<label>29</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Xiong</surname> <given-names>JJ</given-names>
</name>
<name>
<surname>Nunes</surname> <given-names>QM</given-names>
</name>
<name>
<surname>Huang</surname> <given-names>W</given-names>
</name>
<name>
<surname>Pathak</surname> <given-names>S</given-names>
</name>
<name>
<surname>Wei</surname> <given-names>AL</given-names>
</name>
<name>
<surname>Tan</surname> <given-names>CL</given-names>
</name>
<etal/>
</person-group>. <article-title>Preoperative biliary drainage in patients with hilar cholangiocarcinoma undergoing major hepatectomy</article-title>. <source>World J Gastroenterol</source>. (<year>2013</year>) <volume>19</volume>:<page-range>8731&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3748/wjg.v19.i46.8731</pub-id>
</citation>
</ref>
<ref id="B30">
<label>30</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Farges</surname> <given-names>O</given-names>
</name>
<name>
<surname>Regimbeau</surname> <given-names>JM</given-names>
</name>
<name>
<surname>Fuks</surname> <given-names>D</given-names>
</name>
<name>
<surname>Le Treut</surname> <given-names>YP</given-names>
</name>
<name>
<surname>Cherqui</surname> <given-names>D</given-names>
</name>
<name>
<surname>Bachellier</surname> <given-names>P</given-names>
</name>
<etal/>
</person-group>. <article-title>Multicentre european study of preoperative biliary drainage for hilar cholangiocarcinoma</article-title>. <source>Br J Surg</source>. (<year>2013</year>) <volume>100</volume>:<page-range>274&#x2013;83</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/bjs.8950</pub-id>
</citation>
</ref>
<ref id="B31">
<label>31</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tong</surname> <given-names>C</given-names>
</name>
<name>
<surname>Xu</surname> <given-names>X</given-names>
</name>
<name>
<surname>Liu</surname> <given-names>C</given-names>
</name>
<name>
<surname>Zhang</surname> <given-names>T</given-names>
</name>
<name>
<surname>Qu</surname> <given-names>K</given-names>
</name>
</person-group>. <article-title>Assessment of liver volume variation to evaluate liver function</article-title>. <source>Front Med</source>. (<year>2012</year>) <volume>6</volume>:<page-range>421&#x2013;7</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s11684-012-0223-5</pub-id>
</citation>
</ref>
<ref id="B32">
<label>32</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kalkmann</surname> <given-names>J</given-names>
</name>
<name>
<surname>Forsting</surname> <given-names>M</given-names>
</name>
<name>
<surname>Stattaus</surname> <given-names>J</given-names>
</name>
</person-group>. <article-title>Liver volume variations as a parameter to assess therapy response in advanced metastatic liver disease</article-title>. <source>Onkologie</source>. (<year>2011</year>) <volume>34</volume>:<page-range>30&#x2013;4</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1159/000323373</pub-id>
</citation>
</ref>
<ref id="B33">
<label>33</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Michalopoulos</surname> <given-names>GK</given-names>
</name>
</person-group>. <article-title>Liver regeneration after partial hepatectomy: critical analysis&#xa0;of mechanistic dilemmas</article-title>. <source>Am J Pathol</source>. (<year>2010</year>) <volume>176</volume>:<fpage>2</fpage>&#x2013;<lpage>13</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.2353/ajpath.2010.090675</pub-id>
</citation>
</ref>
<ref id="B34">
<label>34</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Khalaf</surname> <given-names>H</given-names>
</name>
<name>
<surname>Shoukri</surname> <given-names>M</given-names>
</name>
<name>
<surname>Al-Kadhi</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Neimatallah</surname> <given-names>M</given-names>
</name>
<name>
<surname>Al-Sebayel</surname> <given-names>M</given-names>
</name>
</person-group>. <article-title>Accurate method for preoperative estimation of the right graft volume in adult-to-adult living donor liver transplantation</article-title>. <source>Transplant Proc</source>. (<year>2007</year>) <volume>39</volume>:<page-range>1491&#x2013;5</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.transproceed.2007.03.021</pub-id>
</citation>
</ref>
<ref id="B35">
<label>35</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Schindl</surname> <given-names>MJ</given-names>
</name>
<name>
<surname>Redhead</surname> <given-names>DN</given-names>
</name>
<name>
<surname>Fearon</surname> <given-names>KC</given-names>
</name>
<name>
<surname>Garden</surname> <given-names>OJ</given-names>
</name>
<name>
<surname>Wigmore</surname> <given-names>SJ</given-names>
</name>
</person-group>. <article-title>The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection</article-title>. <source>Gut</source>. (<year>2005</year>) <volume>54</volume>:<page-range>289&#x2013;96</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1136/gut.2004.046524</pub-id>
</citation>
</ref>
<ref id="B36">
<label>36</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wiggers</surname> <given-names>JK</given-names>
</name>
<name>
<surname>Groot Koerkamp</surname> <given-names>B</given-names>
</name>
<name>
<surname>Cieslak</surname> <given-names>KP</given-names>
</name>
<name>
<surname>Doussot</surname> <given-names>A</given-names>
</name>
<name>
<surname>van Klaveren</surname> <given-names>D</given-names>
</name>
<name>
<surname>Allen</surname> <given-names>PJ</given-names>
</name>
<etal/>
</person-group>. <article-title>Postoperative Mortality after Liver Resection for Perihilar Cholangiocarcinoma: Development of a Risk Score and Importance of Biliary Drainage Of the future Liver Remnant</article-title>. <source>J Am Coll Surg</source>. (<year>2016</year>) <volume>223</volume>:<fpage>321</fpage>&#x2013;<lpage>31.e1</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.jamcollsurg.2016.03.035</pub-id>
</citation>
</ref>
<ref id="B37">
<label>37</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zhang</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Li</surname> <given-names>B</given-names>
</name>
<name>
<surname>He</surname> <given-names>Q</given-names>
</name>
<name>
<surname>Chu</surname> <given-names>Z</given-names>
</name>
<name>
<surname>Ji</surname> <given-names>Q</given-names>
</name>
</person-group>. <article-title>Comparison of liver regeneration between donors and recipients after adult right lobe living-donor liver transplantation</article-title>. <source>Quantitative Imaging Med Surg</source>. (<year>2022</year>) <volume>12</volume>:<page-range>3184&#x2013;92</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.21037/qims-21-1077</pub-id>
</citation>
</ref>
<ref id="B38">
<label>38</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Gong</surname> <given-names>WF</given-names>
</name>
<name>
<surname>Zhong</surname> <given-names>JH</given-names>
</name>
<name>
<surname>Lu</surname> <given-names>Z</given-names>
</name>
<name>
<surname>Zhang</surname> <given-names>QM</given-names>
</name>
<name>
<surname>Zhang</surname> <given-names>ZY</given-names>
</name>
<name>
<surname>Chen</surname> <given-names>CZ</given-names>
</name>
<etal/>
</person-group>. <article-title>Evaluation of liver regeneration and post-hepatectomy liver failure after hemihepatectomy in patients with hepatocellular carcinoma</article-title>. <source>Bioscience Rep</source>. (<year>2019</year>) <volume>39</volume>. doi:&#xa0;<pub-id pub-id-type="doi">10.1042/bsr20190088</pub-id>
</citation>
</ref>
<ref id="B39">
<label>39</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Deneme</surname> <given-names>MA</given-names>
</name>
<name>
<surname>Ok</surname> <given-names>E</given-names>
</name>
<name>
<surname>Akcan</surname> <given-names>A</given-names>
</name>
<name>
<surname>Akyildiz</surname> <given-names>H</given-names>
</name>
<name>
<surname>Soyuer</surname> <given-names>I</given-names>
</name>
<name>
<surname>Muhtaroglu</surname> <given-names>S</given-names>
</name>
</person-group>. <article-title>Single dose of anti-transforming growth factor-beta1 monoclonal antibody enhances liver regeneration after partial hepatectomy in biliary-obstructed rats</article-title>. <source>J Surg Res</source>. (<year>2006</year>) <volume>136</volume>:<page-range>280&#x2013;7</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.jss.2006.08.020</pub-id>
</citation>
</ref>
<ref id="B40">
<label>40</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Pagano</surname> <given-names>D</given-names>
</name>
<name>
<surname>Gruttadauria</surname> <given-names>S</given-names>
</name>
</person-group>. <article-title>Impact of future remnant liver volume on post-hepatectomy regeneration in non-cirrhotic livers</article-title>. <source>Front Surg</source>. (<year>2014</year>) <volume>1</volume>:<elocation-id>10</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fsurg.2014.00010</pub-id>
</citation>
</ref>
<ref id="B41">
<label>41</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wronka</surname> <given-names>KM</given-names>
</name>
<name>
<surname>Gr&#x105;t</surname> <given-names>M</given-names>
</name>
<name>
<surname>Stypu&#x142;kowski</surname> <given-names>J</given-names>
</name>
<name>
<surname>Bik</surname> <given-names>E</given-names>
</name>
<name>
<surname>Patkowski</surname> <given-names>W</given-names>
</name>
<name>
<surname>Krawczyk</surname> <given-names>M</given-names>
</name>
<etal/>
</person-group>. <article-title>Relevance of preoperative hyperbilirubinemia in patients undergoing hepatobiliary resection for hilar cholangiocarcinoma</article-title>. <source>J Clin Med</source>. (<year>2019</year>) <volume>8</volume>:<fpage>458</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.3390/jcm8040458</pub-id>
</citation>
</ref>
<ref id="B42">
<label>42</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Makino</surname> <given-names>H</given-names>
</name>
<name>
<surname>Shimizu</surname> <given-names>H</given-names>
</name>
<name>
<surname>Ito</surname> <given-names>H</given-names>
</name>
<name>
<surname>Kimura</surname> <given-names>F</given-names>
</name>
<name>
<surname>Ambiru</surname> <given-names>S</given-names>
</name>
<name>
<surname>Togawa</surname> <given-names>A</given-names>
</name>
<etal/>
</person-group>. <article-title>Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy</article-title>. <source>World J Gastroenterol</source>. (<year>2006</year>) <volume>12</volume>:<page-range>2053&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3748/wjg.v12.i13.2053</pub-id>
</citation>
</ref>
<ref id="B43">
<label>43</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kim</surname> <given-names>JE</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>JH</given-names>
</name>
<name>
<surname>Park</surname> <given-names>SJ</given-names>
</name>
<name>
<surname>Choi</surname> <given-names>SY</given-names>
</name>
<name>
<surname>Yi</surname> <given-names>NJ</given-names>
</name>
<name>
<surname>Han</surname> <given-names>JK</given-names>
</name>
</person-group>. <article-title>Prediction of liver remnant regeneration after living donor liver transplantation using preoperative ct texture analysis</article-title>. <source>Abdominal Radiol (New York)</source>. (<year>2019</year>) <volume>44</volume>:<page-range>1785&#x2013;94</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s00261-018-01892-2</pub-id>
</citation>
</ref>
<ref id="B44">
<label>44</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Nagino</surname> <given-names>M</given-names>
</name>
<name>
<surname>Kamiya</surname> <given-names>J</given-names>
</name>
<name>
<surname>Arai</surname> <given-names>T</given-names>
</name>
<name>
<surname>Nishio</surname> <given-names>H</given-names>
</name>
<name>
<surname>Ebata</surname> <given-names>T</given-names>
</name>
<name>
<surname>Nimura</surname> <given-names>Y</given-names>
</name>
</person-group>. <article-title>One hundred consecutive hepatobiliary resections for biliary hilar Malignancy: preoperative blood donation, blood loss, transfusion, and outcome</article-title>. <source>Surgery</source>. (<year>2005</year>) <volume>137</volume>:<page-range>148&#x2013;55</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.surg.2004.06.006</pub-id>
</citation>
</ref>
<ref id="B45">
<label>45</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Nimura</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Kamiya</surname> <given-names>J</given-names>
</name>
<name>
<surname>Kondo</surname> <given-names>S</given-names>
</name>
<name>
<surname>Nagino</surname> <given-names>M</given-names>
</name>
<name>
<surname>Uesaka</surname> <given-names>K</given-names>
</name>
<name>
<surname>Oda</surname> <given-names>K</given-names>
</name>
<etal/>
</person-group>. <article-title>Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: nagoya experience</article-title>. <source>J Hepato-Biliary-Pancreatic Surg</source>. (<year>2000</year>) <volume>7</volume>:<page-range>155&#x2013;62</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s005340050170</pub-id>
</citation>
</ref>
<ref id="B46">
<label>46</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Lee</surname> <given-names>SG</given-names>
</name>
<name>
<surname>Song</surname> <given-names>GW</given-names>
</name>
<name>
<surname>Hwang</surname> <given-names>S</given-names>
</name>
<name>
<surname>Ha</surname> <given-names>TY</given-names>
</name>
<name>
<surname>Moon</surname> <given-names>DB</given-names>
</name>
<name>
<surname>Jung</surname> <given-names>DH</given-names>
</name>
<etal/>
</person-group>. <article-title>Surgical treatment of hilar cholangiocarcinoma in the new era: the asan experience</article-title>. <source>J hepato-biliary-pancreatic Sci</source>. (<year>2010</year>) <volume>17</volume>:<page-range>476&#x2013;89</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s00534-009-0204-5</pub-id>
</citation>
</ref>
<ref id="B47">
<label>47</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sakata</surname> <given-names>J</given-names>
</name>
<name>
<surname>Shirai</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Wakai</surname> <given-names>T</given-names>
</name>
<name>
<surname>Nomura</surname> <given-names>T</given-names>
</name>
<name>
<surname>Sakata</surname> <given-names>E</given-names>
</name>
<name>
<surname>Hatakeyama</surname> <given-names>K</given-names>
</name>
</person-group>. <article-title>Catheter tract implantation metastases associated with percutaneous biliary drainage for extrahepatic cholangiocarcinoma</article-title>. <source>World J Gastroenterol</source>. (<year>2005</year>) <volume>11</volume>:<page-range>7024&#x2013;7</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3748/wjg.v11.i44.7024</pub-id>
</citation>
</ref>
<ref id="B48">
<label>48</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ramanathan</surname> <given-names>R</given-names>
</name>
<name>
<surname>Borrebach</surname> <given-names>J</given-names>
</name>
<name>
<surname>Tohme</surname> <given-names>S</given-names>
</name>
<name>
<surname>Tsung</surname> <given-names>A</given-names>
</name>
</person-group>. <article-title>Preoperative biliary drainage is associated with increased complications after liver resection for proximal cholangiocarcinoma</article-title>. <source>J Gastrointest Surg Off J Soc Surg Alimentary Tract</source>. (<year>2018</year>) <volume>22</volume>:<page-range>1950&#x2013;7</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s11605-018-3861-3</pub-id>
</citation>
</ref>
<ref id="B49">
<label>49</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cai</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Tang</surname> <given-names>Q</given-names>
</name>
<name>
<surname>Xiong</surname> <given-names>X</given-names>
</name>
<name>
<surname>Li</surname> <given-names>F</given-names>
</name>
<name>
<surname>Ye</surname> <given-names>H</given-names>
</name>
<name>
<surname>Song</surname> <given-names>P</given-names>
</name>
<etal/>
</person-group>. <article-title>Preoperative biliary drainage versus direct surgery for perihilar cholangiocarcinoma: A retrospective study at a single center</article-title>. <source>Bioscience Trends</source>. (<year>2017</year>) <volume>11</volume>:<page-range>319&#x2013;25</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.5582/bst.2017.01107</pub-id>
</citation>
</ref>
<ref id="B50">
<label>50</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Su</surname> <given-names>CH</given-names>
</name>
<name>
<surname>Tsay</surname> <given-names>SH</given-names>
</name>
<name>
<surname>Wu</surname> <given-names>CC</given-names>
</name>
<name>
<surname>Shyr</surname> <given-names>YM</given-names>
</name>
<name>
<surname>King</surname> <given-names>KL</given-names>
</name>
<name>
<surname>Lee</surname> <given-names>CH</given-names>
</name>
<etal/>
</person-group>. <article-title>Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma</article-title>. <source>Ann Surg</source>. (<year>1996</year>) <volume>223</volume>:<page-range>384&#x2013;94</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/00000658-199604000-00007</pub-id>
</citation>
</ref>
<ref id="B51">
<label>51</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hemming</surname> <given-names>AW</given-names>
</name>
<name>
<surname>Reed</surname> <given-names>AI</given-names>
</name>
<name>
<surname>Fujita</surname> <given-names>S</given-names>
</name>
<name>
<surname>Foley</surname> <given-names>DP</given-names>
</name>
<name>
<surname>Howard</surname> <given-names>RJ</given-names>
</name>
</person-group>. <article-title>Surgical management of hilar cholangiocarcinoma</article-title>. <source>Ann Surg</source>. (<year>2005</year>) <volume>241</volume>:<fpage>693</fpage>&#x2013;<lpage>9; discussion 9-702</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/01.sla.0000160701.38945.82</pub-id>
</citation>
</ref>
<ref id="B52">
<label>52</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cannon</surname> <given-names>RM</given-names>
</name>
<name>
<surname>Brock</surname> <given-names>G</given-names>
</name>
<name>
<surname>Buell</surname> <given-names>JF</given-names>
</name>
</person-group>. <article-title>Surgical resection for hilar cholangiocarcinoma: experience improves resectability</article-title>. <source>HPB (Oxford)</source>. (<year>2012</year>) <volume>14</volume>:<page-range>142&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/j.1477-2574.2011.00419.x</pub-id>
</citation>
</ref>
<ref id="B53">
<label>53</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kawasaki</surname> <given-names>S</given-names>
</name>
<name>
<surname>Imamura</surname> <given-names>H</given-names>
</name>
<name>
<surname>Kobayashi</surname> <given-names>A</given-names>
</name>
<name>
<surname>Noike</surname> <given-names>T</given-names>
</name>
<name>
<surname>Miwa</surname> <given-names>S</given-names>
</name>
<name>
<surname>Miyagawa</surname> <given-names>S</given-names>
</name>
</person-group>. <article-title>Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization</article-title>. <source>Ann Surg</source>. (<year>2003</year>) <volume>238</volume>:<fpage>84</fpage>&#x2013;<lpage>92</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/01.Sla.0000074984.83031.02</pub-id>
</citation>
</ref>
<ref id="B54">
<label>54</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>She</surname> <given-names>WH</given-names>
</name>
<name>
<surname>Cheung</surname> <given-names>TT</given-names>
</name>
<name>
<surname>Ma</surname> <given-names>KW</given-names>
</name>
<name>
<surname>Yin Tsang</surname> <given-names>SH</given-names>
</name>
<name>
<surname>Dai</surname> <given-names>WC</given-names>
</name>
<name>
<surname>Yan Chan</surname> <given-names>AC</given-names>
</name>
<etal/>
</person-group>. <article-title>Impact of preoperative biliary drainage on postoperative outcomes in hilar cholangiocarcinoma</article-title>. <source>Asian J Surg</source>. (<year>2022</year>) <volume>45</volume>:<fpage>993</fpage>&#x2013;<lpage>1000</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.asjsur.2021.07.075</pub-id>
</citation>
</ref>
<ref id="B55">
<label>55</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>She</surname> <given-names>WH</given-names>
</name>
<name>
<surname>Cheung</surname> <given-names>TT</given-names>
</name>
<name>
<surname>Ma</surname> <given-names>KW</given-names>
</name>
<name>
<surname>Tsang</surname> <given-names>SHY</given-names>
</name>
<name>
<surname>Dai</surname> <given-names>WC</given-names>
</name>
<name>
<surname>Chan</surname> <given-names>ACY</given-names>
</name>
<etal/>
</person-group>. <article-title>Defining the optimal bilirubin level before hepatectomy for hilar cholangiocarcinoma</article-title>. <source>BMC Cancer</source>. (<year>2020</year>) <volume>20</volume>:<fpage>914</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1186/s12885-020-07385-0</pub-id>
</citation>
</ref>
</ref-list>
</back>
</article>