Predicting post-hepatectomy liver failure based on future remnant liver function combined with future remnant liver volume using magnetic resonance imaging

Predicting post-hepatectomy liver failure based on future remnant liver function combined with future remnant liver volume using magnetic resonance imaging | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predicting post-hepatectomy liver failure based on future remnant liver function combined with future remnant liver volume using magnetic resonance imaging Masashi Kudo, Naoto Gotohda, Motokazu Sugimoto, Shin Kobayashi, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6532051/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jun, 2025 Read the published version in Langenbeck's Archives of Surgery → Version 1 posted 12 You are reading this latest preprint version Abstract Purpose Significant advances have been made in image-based determinations of future remnant liver function, in attempts to better predict post-hepatectomy liver failure (PHLF). We have reported time-associated liver functional assessments using magnetic resonance imaging with liver-to-spleen signal intensity ratio increasing rate (LSRi) and LSRi of the future remnant liver region (LSRi-rem) to predict PHLF. This study aimed to investigate the predictability of PHLF by a preoperative liver function assessment index that combined LSRi-rem and future remnant liver volume (FRLV). Methods Participants comprised 333 patients who underwent EOB-MRI for the diagnosis of liver tumor before major hepatectomy between 2009 and 2024. LSRi-rem was evaluated by three-dimensional volumetric analysis, and the volume adjusted LSRi-rem (vaLSRi-rem) was calculated using the following formula: LSRi-rem × (FRLV / whole-liver volume). The vaLSRi-rem and clinical variables were then analyzed to assess the risk of PHLF. Results In patients with vaLSRi-rem < 0.147, right hepatectomy, operation time ≥ 400 min, and estimated blood loss ≥ 1495 mL were associated with clinically relevant PHLF ( P < 0.05 each) in multivariable analysis. Multivariable analysis showed the highest odds ratio (OR) for vaLSRi-rem (OR 9.12; P < 0.01). Of the 333 patients, 114 (34%) underwent portal vein embolization before major hepatectomy. The OR of vaLSRi-rem from multivariable analysis in this patient cohort was particularly high (OR 21.04; P < 0.01). Conclusions Strong associations were identified between vaLSRi-rem and clinically relevant PHLF after major hepatectomy, particularly among portal vein embolization patients. hepatectomy liver failure magnetic resonance imaging liver function Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Recent reports indicate that post-hepatectomy liver failure (PHLF) after major hepatectomy occurs in 8–12% of patients and represents a key cause of prolonged hospitalization and perioperative mortality. 1 Precise preoperative assessments of liver function, extent of resection, and estimated remnant liver volume are thus important to minimize the risks associated with liver surgery. Intraoperative factors involved in PHLF reportedly include prolonged operative time, increased blood loss, need for blood transfusion, and prolonged ischemia (from hypotension or hepatic in-flow occlusion). Otherwise, two important preoperative factors, future remnant liver volume (FRLV) and liver functional assessment, have been used as predictors of PHLF. 1,2 FRLV is defined as the percentage of the liver volume remaining functional postoperatively compared with the preoperative functional whole-liver volume, and has been considered the most important modifiable predictor of PHLF. 2,3 Assessments of liver function such as indocyanine green (ICG) clearance test, Child–Pugh score, and albumin-bilirubin (ALBI) grade have been also reported as predictors of PHLF. 1 These traditional assessments of liver function, obtained from blood tests and clinical evaluations, reflect whole-liver function, but not future remnant liver function after hepatectomy. As a result, many researchers have reported on image-based assessments of liver function, such as molecular nuclear imaging techniques and magnetic resonance imaging (MRI), that may be applicable to more precisely assessing future remnant liver function. 4,5 Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a liver-specific contrast medium, and MRI using Gd-EOB-DTPA (EOB-MRI) is widely used in the preoperative diagnosis of liver tumors. EOB-MRI allows much clearer extraction of the liver parenchyma, liver tumors, and blood vessels than molecular nuclear imaging techniques. 5 EOB-MRI is thus expected to prove useful as an image-based liver functional assessment that can accurately determine the liver dissection line before surgery. 5 However, the quantification of liver signal intensity in EOB-MRI requires standardization against other organs such as the spleen and iliopsoas muscle because MRI signal intensity is defined on an arbitrary scale and varies greatly with calibration. 6 We reported that the liver-to-spleen signal intensity ratio (LSR) in the hepatobiliary phase of EOB-MRI as evaluated using a three-dimensional volumetric analysis system correlated with conventional assessments of liver function. 7 We also reported that the LSR of the future remnant liver region (LSR-rem) offers a stronger predictor of PHLF than traditional whole-liver functional assessments such as ICG clearance test, Child–Pugh score, and ALBI grade. 8 However, those single-center investigations of image-based liver functional assessments using EOB-MRI were not easily applicable to other institutions, because doses of Gd-EOB-DTPA and timings of the hepatobiliary phase after Gd-EOB-DTPA injection vary between institutions. 8-10 The plasma disappearance rate of ICG (KICG) is widely used as a preoperative liver functional assessment in high-volume centers in Japan. 11 The KICG is calculated from serum ICG concentrations at multiple time points, reflecting time-associated changes in ICG concentration over time without the dose bias of ICG or the timing bias of blood sampling. 12,13 Based on this idea, we developed a time-associated image-based liver functional assessment, termed the LSR increasing rate (LSRi), that can exclude limitations such as the dose bias of contrast medium or the timing bias of the hepatobiliary phase. 14 Along with the FRLV as a strong predictor of PHLF, this time-associated image-based determination of future remnant liver function is also expected to provide a strong predictor of PHLF. The combination of these two strong predictors is thus expected to provide a more accurate preoperative prediction of PHLF. The purpose of this study was to investigate the relationship between PHLF after major hepatectomy and a novel liver function assessment that combines FRLV and time-associated image-based future remnant liver function. MATERIALS AND METHODS Patients Between January 2009 and December 2024, a total of 414 consecutive patients underwent major hepatectomy for tumors of the liver or biliary system at the National Cancer Center Hospital East, Kashiwa, Japan. Of these 414 patients, 81 were excluded from analyses for the following reasons: jaundice with total bilirubin >1.5 mg/dL on MRI examination (n = 46); contrast-enhanced MRI not performed (n = 27); interval from MRI examination to surgery > 90 days (n = 5); ICG intolerance (n = 2); and prior splenectomy (n = 1). The remaining 333 patients who underwent standardized EOB-MRI as part of the diagnostic procedures before major hepatectomy were evaluated for risk factors for PHLF. Among these, 114 patients who underwent preoperative portal vein embolization (PVE) were also evaluated for risk factors for PHLF. Definition of PHLF PHLF was defined as an increased prothrombin time-international normalized ratio and concomitant hyperbilirubinemia on or after postoperative day 5, as per the definition of the International Study Group for Liver Surgery (ISGLS). 15 Cut-off values for increased prothrombin time-international normalized ratio and serum bilirubin concentration at our institute were set as 1.15 and 1.30 mg/dL, respectively. According to the ISGLS definition, grade B PHLF involves deviation from the regular course without requiring invasive therapy, and grade C PHLF requires invasive treatment. In this study, clinically relevant PHLF was defined as grade B or C. Differences in the postoperative course were examined based on the presence or absence of PHLF grade B and C. Preoperative evaluation ICG retention rate at 15 min (ICGR15) and computed tomography were performed within a month before surgery, and surgical indications were evaluated using the Takasaki criteria 16 and/or Makuuchi criteria 17,18 . The Takasaki criteria determine the safe limit of FRLV using the following formula: {1 - [log(40) – log(ICGR15) ] / [log(100) – log(ICGR15) ] } ´100 (%). 16 Estimated FRLV was calculated using images from 10-mm-slice computed tomography (CT), as reported in a previous study, and was compared to the safe limit of FRLV as calculated using the Takasaki criteria. 16 According to the Makuuchi criteria, the extent of hepatectomy was determined based on the presence of ascites, serum total bilirubin level and ICGR15. 17,18 Major hepatectomy was scheduled for patients those satisfying the Takasaki and/or Makuuchi criteria. PVE to increase FRLV was performed if a patient did not fulfill these criteria. FRLV and ICGR15 were then re-evaluated four weeks after PVE. The Child–Pugh score was calculated based on the following five variables: serum bilirubin level, serum albumin level, prothrombin activity, ascites status, and degree of encephalopathy. ALBI grade was calculated according to the following equation: -0.085 ´ (serum albumin level, g/L) + 0.66 ´ log(serum total bilirubin level, µmol/L). ALBI score was categorized into the following three grades: 1, £ -2.60; 2; > -2.06 to £ -1.39; and 3, > -1.39. MRI protocol MRI was performed within 90 days before surgery. For patients who underwent PVE, CT and MRI were performed every four weeks after PVE, and indications for surgery were discussed each time. All MRI studies were performed using 3.0-T scanners at our institute (Achieva or Ingenia, Philips Medical Systems, Amsterdam, the Netherlands). Contrast-enhanced three-dimensional fat-suppressed T1-weighted images were obtained 20 min after intravenous administration of Gd-EOB-DTPA for the hepatobiliary phase, using either of the following parameters: repetition time, 4 ms; echo time, 2 ms; flip angle, 10°; slice thickness, 4.6 mm; and matrix size, 512 ´ 512 for Achieva, or repetition time, 3 ms; echo time, 2 ms; flip angle, 10°; slice thickness, 4.6 mm; and matrix size, 480 ´ 480 for Ingenia. Gd-EOB-DTPA was administered at a dose of about 0.1 mL/kg body weight, by rapid intravenous bolus injection using a power injector (Sonic Shot GX; Nemoto Kyorindo Co., Tokyo, Japan), at a rate of 2 mL/s. MRI was performed prior to injection and at 20 s, 1, 3, 10, and 15–20 min after intravenous Gd-EOB-DTPA injection. The hepatobiliary phase was taken to be between 15 and 20 min. Image-based liver functional assessment using MRI Figure 1 shows image analyses for a patient who underwent hepatectomy. The indicated parenchyma of the liver and spleen was semi-automatically extracted from a small operator-defined volume of interest using the image-processing algorithm (Fig. 1a, b). An estimated liver resection line was then drawn on the operator-defined axial MRI, and the future remnant liver region was extracted (Fig. 1c, d). Finally, LSR-rem was calculated as the average signal intensity of the future remnant liver parenchyma divided by that of splenic parenchyma. The LSR (whole liver) and LSR-rem of all patients were calculated at the following time points: 1, 3, 10, and 15–20 min after intravenous administration of Gd-EOB-DTPA. The relationship between LSR-rem and time after injection was then semi-logarithmically converted to be straightened, and LSR-rem at the four time points (1, 3, 10, and 15–20 min after injection) were plotted on a semi-logarithmic graph using a non-logarithmic scale for LSR-rem (y-axis) and a logarithmic scale for minutes after injection (x-axis) (Fig. 2a, b). Next, the approximate line of these four time points was created using the least-squares method (Fig. 2c). Finally, we defined the slope of the approximate line as the LSRi of the future remnant liver region (LSRi-rem). The LSR, LSRi, and LSRi-rem of EOB-MRI were calculated using the Synapse Vincent three-dimensional volumetric analysis system (Fujifilm Medical, Tokyo, Japan) by hepatobiliary and pancreatic surgeons with 5-14 years of clinical experience. Preoperative evaluation for PHLF using FRLV and LSRi-rem The volume-adjusted LSRi-rem is a novel index of preoperative liver function assessment that combines two important factors (liver volume and liver function) for predicting PHLF. The FRLV for this novel assessment was calculated simultaneously with LSRi-rem using the Synapse Vincent three-dimensional volumetric analysis system. Volume-adjusted LSRi-rem was calculated using the following formula: LSRi-rem ´ (FRLV / whole-liver volume). Statistical analyses Categorical variables are presented as the number and percentage, and continuous variables are presented as the median and range. Pre- and intraoperative variables were evaluated using logistic regression analysis for the risk of clinically relevant PHLF, and the odds ratio (OR) and 95% confidence interval (95%CI) are presented. Variables identified as significant in univariable analyses were included in the multivariable analysis. However, to avoid considering variables that varied with each other (confounding variables), correlations between variables were evaluated using the chi-square test. Analysis of the receiver operating characteristic curve was performed to determine cut-off values for continuous variables such as age, ICGR15, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, operation time, and estimated blood loss in association with clinically relevant PHLF. Categorical variables were evaluated using the chi-square test and continuous variables were evaluated using the Mann–Whitney test. Two-sided P -values less than 0.05 were considered significant. Statistical analysis was performed using JMP version 12.0.10 software (SAS Institute, Cary, NC). Results Patient demographics Patient characteristics are shown in Table 1. Diagnoses included metastatic liver tumor in 111 patients (33%), perihilar cholangiocarcinoma in 78 patients (23%), intrahepatic cholangiocarcinoma in 57 patients (17%), hepatocellular carcinoma in 57 patients (17%), and intraductal papillary neoplasm of the bile duct in nine patients (3%). Surgical procedures performed included right hepatectomy in 163 patients (49%), left hepatectomy in 153 patients (46%), left trisectionectomy in nine patients (3%), and central bisectionectomy in seven patients (2%). Clinically relevant PHLF was identified in 35 patients (11%), of whom 21 patients (6%) had grade B and two patients (1%) had grade C PHLF. Of the 333 patients, three patients developed mortality. Risk analysis for clinically relevant PHLF after major hepatectomy Cut-offs for age, ICGR15, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, operation time, and estimated blood loss in association with clinically relevant PHLF were identified as 64 years, 13.3%, 43.7%, 1.95, 1.87, 0.354, 0.147, 400 min, and 1495 mL, respectively. Risk analyses for clinically relevant PHLF in the entire cohort of 333 patients undergoing major hepatectomy are shown in Table 2. In univariable analysis, male sex, preoperative biliary drainage, preoperative portal embolization, perihilar cholangiocarcinoma, Child–Pugh score, ALBI grade, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, right hepatectomy, biliary reconstruction, operation time, estimated blood loss, and blood transfusion were found to be significant risk factors for PHLF. Among the variables identified as significant in univariable analyses, preoperative biliary drainage and perihilar cholangiocarcinoma were confounders with biliary reconstruction. PVE was confounded by right hepatectomy. Child–Pugh score, ALBI grade, estimated FRLV, LSR (whole liver), LSR-rem, and LSRi-rem were confounders with volume-adjusted LSRi-rem. Blood transfusion was confounded by estimated blood loss. Based on these findings, male sex, volume-adjusted LSRi-rem, right hepatectomy, biliary reconstruction, operation time, and estimated blood loss were included in the multivariable analysis. Subsequent multivariable analysis identified volume-adjusted LSRi-rem < 0.147, right hepatectomy, operation time ≥ 400 min, and estimated blood loss ≥ 1495 mL as independent risk factors for clinically relevant PHLF. In particular, the highest OR in the multivariable analysis for this patient cohort was for volume-adjusted LSRi-rem (OR 9.12, 95%CI 2.71–38.00; P < 0.01) (Table 2). Risk analysis for clinically relevant PHLF after PVE and major hepatectomy Of the 333 patients, 114 (34%) underwent PVE before major hepatectomy. In this patient cohort, cut-offs for age, ICGR15, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, operation time, and estimated blood loss in association with clinically relevant PHLF were determined to be 64 years, 11.7%, 43.7%, 1.66, 1.75, 0.355, 0.147, 406 min, and 967 mL, respectively. Risk analysis for clinically relevant PHLF in this patient cohort is shown in Table 3. In univariable analysis, preoperative biliary drainage, perihilar cholangiocarcinoma, Child–Pugh score, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, biliary reconstruction, operation time, estimated blood loss, and blood transfusion were found to be significant risk factors for PHLF. Among the significant variables in univariable analyses, preoperative biliary drainage and perihilar cholangiocarcinoma were confounders with biliary reconstruction. Child–Pugh score, estimated FRLV, LSR (whole liver), LSR-rem, and LSRi-rem were confounders with volume-adjusted LSRi-rem. Blood transfusion was confounded by estimated blood loss. As a result, volume-adjusted LSRi-rem, biliary reconstruction, operation time, and estimated blood loss were included in the multivariable analysis. This multivariable analysis then showed that volume-adjusted LSRi-rem < 0.147, operation time ≥ 406 min, and estimated blood loss ≥ 967 mL were independent risk factors for clinically relevant PHLF. In particular, the highest OR in the multivariable analysis of this patient cohort was for volume-adjusted LSRi-rem (OR 21.04, 95%CI 3.61–403.35; P < 0.01) (Table 3). Relationship between PHLF and short-term outcomes Differences in postoperative course with or without PHLF grade B or C are shown in Table 4. Patients with PHLF showed a significantly longer postoperative hospital stay (24 days) than those without PHLF (11 days, P < 0.01). The incidence of all complications of Clavien–Dindo grade ≥ IIIa was significantly higher in patients with PHLF than in patients without PHLF. Discussion In this study, we proposed a novel preoperative liver functional assessment that combines FRLV and time-associated, image-based future remnant liver function. In the cohort of 333 patients, volume-adjusted LSRi-rem was the strongest predictor of PHLF, showing the highest OR in multivariable analysis (OR 9.12, 95%CI 2.71–38.00). The present study revealed volume-adjusted LSRi-rem as a better predictor of PHLF than traditional liver functional assessments such as ICGR15, Child–Pugh score, or ALBI grade. Further, a subgroup analysis of patients who underwent PVE showed that volume-adjusted LSRi-rem to PHLF showed the highest OR in multivariable analysis (OR 21.04, 95%CI 3.61–403.35). This result suggests that this novel assessment of liver function can be expected to provide a useful predictor of PHLF, particularly among patients with PVE, because future remnant liver function is reflected rather than whole-liver function. In this study, patients who developed clinically relevant PHLF displayed a higher overall complication ratio and a longer postoperative hospital stay, suggesting the importance of accurate preoperative evaluation using volume-adjusted LSRi-rem. The ICG clearance test has been shown to offer one of the most reliable whole-liver functional assessments for predicting PHLF. However, the ICG clearance test has potential for human error because of the need for injections and multiple blood collections, and ICG is also known to have dose-dependent and cumulative hepatotoxic effects. 13,19 Further, since the whole liver region does not remain after hepatectomy, image-based assessment of liver function limited to the region of the future remnant liver is expected to prove more useful and less prone to human error in assessments predicting PHLF. Previous investigators have thus reported the relationship between PHLF and image-based assessments of future remnant liver function. 9,20,21 We have likewise reported that LSR-rem calculated using a three-dimensional volumetric analysis system represents a stronger risk factor for clinically relevant PHLF compared to traditional whole-liver functional assessments, particularly in PVE patients. 8 In the subgroup of patients who underwent PVE in the present study (Table 3), ORs in univariable analyses of LSR-rem (OR 4.67, 95%CI 1.46–14.69) and LSRi-rem (OR 5.70, 95%CI 1.49–37.56) were higher than those from whole-liver functional assessments such as ICGR15 (OR 0.60, 95%CI 0.19–1.75), Child–Pugh score (OR 3.71, 95%CI 1.18–11.39), ALBI grade (OR 2.05, 95%CI 0.70–6.43), and LSR (whole liver) (OR 3.71, 95%CI 1.18–11.39). These results suggest that the signal intensity of the future remnant liver on EOB-MRI, particularly in PVE patients, is more strongly associated with PHLF than whole-liver functional assessments. This indicates that signal intensity in the future remnant liver reflects future remnant liver function and might be a useful tool for preoperative liver functional assessment. As well as liver functional assessment, most hepatobiliary surgeons consider FRLV to be another important factor for predicting PHLF. The indication criteria for liver surgery proposed by Makuuchi et al., Takasaki et al., and Nagino et al., which are used in many Japanese hospitals, suggest an acceptable liver resection volume based on ICG values reflecting whole-liver function, not future remnant liver function. 11,16,17 The volume-adjusted LSRi-rem proposed in this study is thus expected to be more useful as an indication criterion for liver surgery that combines future remnant liver function and FRLV. LSRi-rem is a time-associated assessment of liver function using dynamic information from multiple time points after contrast injection, and is not an assessment using data from the hepatobiliary phase alone. There are two reasons why LSRi-rem uses dynamic (time-associated) information. First, dynamic quantitative liver function assessments provide a more accurate assessment of specific aspects of liver function than passive (non-time-associated) assessments such as albumin, prothrombin, ICG clearance test, Child–Pugh grade, and ALBI grade. 4,22,23 Dynamic (time-associated) quantitative assessments of liver function, such as KICG, are calculated from ICG concentrations at multiple time points and can accurately assess liver function using time-related ICG uptake and metabolic capacity. 11,23 In this study cohort (Table 2), LSRi-rem, which uses dynamic information, showed a higher OR for PHLF (OR 4.75, 95%CI 1.59–20.46) than LSR-rem (OR 4.38, 95%CI 1.84–11.20), which uses only hepatobiliary-phase information from EOB-MRI. This result was similar to the findings from a subgroup analysis of patients who underwent PVE (Table 3). To the best of our knowledge, no previous reports have investigated associations between PHLF and time-associated changes in image-based assessments of liver function. Second, time-associated assessments of liver function are expected to overcome limitations such as the dose bias of contrast media or the timing bias of the hepatobiliary phase. Aono et al. reported that the KICG with a 0.5-mg/dL dose of ICG was almost the same as that with a 0.1-mg/dL dose. 13 That findings suggests that the speed at which ICG is cleared from plasma (i.e., the change in ICG over time) offers a universal quantitative assessment regardless of the ICG dose. Considering the similar metabolic pathways for ICG and Gd-EOB-DTPA, the LSRi reflecting changes in Gd-EOB-DTPA uptake over time is expected to provide a universal quantitative assessment of liver function regardless of Gd-EOB-DTPA dose. As for the timing bias of the hepatobiliary phase, we have previously reported considerably high correlations between LSRi calculated using four time points (1, 3, 10, and 15 min) and that calculated using three time points, indicating minimal timing bias. 14 We also suggested that LSRi carries less biases from MRI equipment and slice thickness. 14 Given those previous reports, volume-adjusted LSRi-rem can be expected to provide a universal elaborate image-based assessment of liver function that can be used at any institution. Finally, we propose novel surgical indications for major hepatectomy using volume-adjusted LSRi-rem. Figure 3 shows the presence or absence of PHLF and plots of volume-adjusted LSRi-rem values for all patients in this study. Considering these plots of volume-adjusted LSRi-rem values, surgical indications based on the three cut-offs can be proposed. First, the value with the highest volume-adjusted LSRi-rem in patients with PHLF (cut-off = 0.208) can be used. Since PHLF did not develop in all patients with volume-adjusted LSRi-rem > 0.208, liver surgery can be expected to be safely performed in this patient group. In the future, indications for liver surgery may be able to be determined in this patient group by EOB-MRI alone, without ICG clearance test before major hepatectomy. Second, the cut-off calculated as a predictor of PHLF in this study (cut-off = 0.147) can be used. This cut-off offered 83% sensitivity, 80% specificity, a positive predictive value of 24%, and a negative predictive value of 98% for PHLF. The negative predictive value was particularly high. Interestingly, three of the four patients with volume-adjusted LSRi-rem ≥ 0.147 and PHLF had experienced massive intraoperative bleeding (> 1000 mL) and required blood transfusions. Accordingly, if liver surgery can be performed without massive bleeding in cases with volume-adjusted LSRi-rem ≥ 0.147, PHLF may be avoidable. This may be useful information for high-risk patients in whom PHLF must be absolutely avoided. Finally, the value without the lowest volume-adjusted LSRi-rem in patients without PHLF (cut-off = 0.081) can be used. All three patients with volume-adjusted LSRi-rem < 0.081 developed PHLF, and one of them died due to liver failure. In this study, we encountered two patients who developed grade C PHLF with volume-adjusted LSRi-rem values of 0.123 and 0.070. Major hepatectomy may thus need to be aborted in patients showing volume-adjusted LSRi-rem < 0.081 before surgery. As a representative example, we present the case of a patient who might have benefited from assessment of future remnant liver function. The patient was a man in his 60s who had been diagnosed with hilar cholangiocarcinoma with invasion of right hepatic artery (Fig. 4a). Extended right hepatectomy with extrahepatic bile duct resection had been planned, but percutaneous right PVE was performed before surgery because the FRLV was < 30%. Contrast-enhanced CT at 3 weeks after PVE showed enlargement of future remnant left liver volume, with an FRLV of 41%, but residual blood flow in the right portal vein was observed (Fig. 4b). The ICGR15 was 7.8%, meeting both Makuuchi and Takasaki criteria. The patient therefore underwent extended right hepatectomy with extrahepatic bile duct resection one month after PVE. The operation time was 682 min and total blood loss was 2687 mL, requiring blood transfusion. After surgery, intensive care treatment with mechanical ventilation was performed for unstable circulatory dynamics due to severe dehydration and liver failure. The patient required intensive treatment due to PHLF grade C, renal failure, and sepsis, but his general condition gradually improved and he was discharged from the intensive care unit on postoperative day 33. On postoperative day 69, he was discharged from our hospital, but his physical condition had deteriorated considerably and he required a wheelchair. Retrospective evaluation showed his volume-adjusted LSRi-rem was 0.070 on preoperative MRI, corresponding to unresectable status according to our proposed surgical indications for major hepatectomy. After PVE, most cases show a distinct demarcation line between the future remnant liver and future resected liver region on hepatobiliary-phase MRI (Fig. 1a), whereas the demarcation line was unclear in this case (Fig. 4c). This MRI finding may indicate that PVE was inadequate. If the volume-adjusted LSRi-rem had been evaluated preoperatively and the patient had been assessed as high risk for PHLF, this patient might have instead undergone additional PVE. This novel surgical indication for major hepatectomy is determined by the volume-adjusted LSRi-rem value, which includes two important factors for predicting PHLF: LSRi-rem and FRLV. The present study indicated that LSRi-rem, representing future remnant liver function, offers a better predictor of PHLF than markers of whole-liver function such as ICG clearance test, Child–Pugh grade, or ALBI grade. FRLV is also considered the most important predictor of PHLF, particularly for patients scheduled for major hepatectomy requiring PVE. When considering indications for major hepatectomy, both LSRi-rem and FRLV appear to be essential factors for predicting PHLF. This study has several limitations. First, the three-dimensional volumetric analysis system sometimes automatically extracts extrahepatic parenchymal tissues such as portal veins, hepatic veins, small cysts and tumors. However, our previous report showed a high correlation between LSR and vascular subtraction LSR (LSR excluding extrahepatic parenchymal tissues) and demonstrated that the LSR adequately reflects contrast enhancement of the liver parenchyma. Our previous report suggested that liver function can be evaluated without subtracting vessels and vascular perfusion areas. Second, this was a retrospective, single-center investigation of patients who had undergone major hepatectomy, including a relatively small number of patients with PHLF, indicating a selection bias towards surgery. Our cut-offs for indicating surgery should thus be validated in future multicenter research. In conclusion, the present study revealed that the volume-adjusted LSRi-rem calculated using a three-dimensional volumetric analysis system on EOB-MRI offered an independent risk factor for clinically relevant PHLF in patients who underwent major hepatectomy, particularly those with preoperative PVE. The volume-adjusted LSRi-rem might provide a reliable preoperative assessment of liver function, enabling safe performance of major hepatectomy. Abbreviations ALBI, albumin-bilirubin; CT, computed tomography; EOB-MRI, magnetic resonance imaging using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; FRLV, future remnant liver volume; Gd-EOB-DTPA, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; ICG, indocyanine green; ICGR15, indocyanine green retention rate at 15 min; ISGLS, International Study Group for Liver Surgery; KICG, plasma disappearance rate of indocyanine green; LSR, liver-to-spleen signal intensity ratio; LSRi, liver-to-spleen signal intensity ratio increasing rate; LSRi-rem, liver-to-spleen signal intensity ratio increasing rate in the future remnant liver region; LSR-rem, liver-to-spleen signal intensity ratio in the future remnant liver region; MRI, magnetic resonance imaging; OR, odds ratio; PHLF, post-hepatectomy liver failure; PVE, portal vein embolization; 95%CI, 95% confidence interval. Declarations Funding information This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare that they have no conflicts of interest. This paper is not based on any previous communication to a society or meeting. Ethics statements This study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the institutional review board of the National Cancer Center, Japan (reference 2017-483). Due to the retrospective design and the absence of invasive interventions, a waiver of participant informed consent was granted by the institutional review board of the National Cancer Center, Japan. Consent to participate Not applicable. Consent to publication Not applicable. Availability of data and material The datasets generated and/or analyzed during the present study are available from the corresponding author upon reasonable request. Code availability Not applicable. Authors’ contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Masashi Kudo. The first draft of the manuscript was written by Masashi Kudo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank all participating patients and their families who made this study possible. References Soreide JA, Deshpande R. Post hepatectomy liver failure (PHLF) - recent advances in prevention and clinical management. Eur J Surg Oncol. 2021; 47(2): 216–24. Khan AS, Garcia-Aroz S, Ansari MA, et al. Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review. Int J Surg. 2018; 52: 74–81. Olthof PB, Aldrighetti L, Alikhanov R, et al. Portal vein embolization is associated with reduced liver failure and mortality in high-risk resections for perihilar cholangiocarcinoma. Ann Surg Oncol. 2020; 27(7): 2311–8. Hoekstra LT, de Graaf W, Nibourg GA, et al. Physiological and biochemical basis of clinical liver function tests: a review. Ann Surg. 2013; 257(1): 27–36. Utsunomiya T, Shimada M, Hanaoka J, et al. Possible utility of MRI using Gd-EOB-DTPA for estimating liver functional reserve. J Gastroenterol. 2012; 47(4): 470–6. Onoda M, Hyodo T, Murakami T, et al. Optimizing signal intensity correction during evaluation of hepatic parenchymal enhancement on gadoxetate disodium-enhanced MRI: comparison of three methods. Eur J Radiol. 2015; 84(3): 339–45. Kudo M, Gotohda N, Sugimoto M, et al. Evaluation of liver function using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging based on a three-dimensional volumetric analysis system. Hepatol Int. 2018; 12(4): 368–76. Kudo M, Gotohda N, Sugimoto M, et al. The assessment of regional liver function before major hepatectomy using magnetic resonance imaging. Am Surg. 2022; 88(9): 2353–60. Wang Y, Zhang L, Ning J, et al. Preoperative remnant liver function evaluation using a routine clinical dynamic Gd-EOB-DTPA-enhanced MRI protocol in patients with hepatocellular carcinoma. Ann Surg Oncol. 2021; 28(7): 3672–82. Imai Y, Katayam K, Hori M, Yakushijin T, Fujimoto K, Itoh T, et al. Erratum: Prospective comparison of Gd-EOB-DPTA-enhanced MRI with dynamic CT for detecting recurrence of HCC after radiofrequency ablation. Liver Cancer. 2018; 7(3): 294. Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg. 2006; 243(3): 364–72. Kumazawa K, Kikuchi T, Oishi T, et al. Variations in the disappearance rate of indocyanine green. Jpn J Surg. 1988; 18(1): 1–6. Aono T, Tsukada K, Sakaguchi T, Ishiduka D, Suzuki T, Hatakeyama K. Utilization of low dose indocyanine green test for evaluating liver function. Acta Med Biol. 1994; 42(4): 165–9. Kudo M, Gotohda N, Sugimoto M, Kobayashi S, Konishi M, Kobayashi T. Liver functional assessment using time-associated change in the liver-to-spleen signal intensity ratio on enhanced magnetic resonance imaging: a retrospective study. BMC Surg. 2023; 23(1): 179. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011; 149(5): 713–24. Takasaki T, Kobayashi S, Suzuki S, et al. Predetermining postoperative hepatic function for hepatectomies. Int Surg. 1980; 65(4): 309–13. Makuuchi M, Kosuge T, Takayama T, et al. Surgery for small liver cancers. Semin Surg Oncol. 1993; 9(4): 298–304. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology. 1997; 26(5): 1176–81. Laperche Y, Oudea MC, Lostanlen D. Toxic effects of indocyanine green on rat liver mitochondria. Toxicol Appl Pharmacol. 1977; 41(2): 377–87. Araki K, Harimoto N, Kubo N, et al. Functional remnant liver volumetry using Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) predicts post-hepatectomy liver failure in resection of more than one segment. HPB (Oxford). 2020; 22(2): 318–27. Smet H, Martin D, Uldry E, et al. Tc-99m mebrofenin hepatobiliary scintigraphy to assess future liver remnant function before major liver surgery. J Surg Oncol. 2023; 128(8): 1312–9. Yokoyama Y, Ebata T, Igami T, et al. The predictive value of indocyanine green clearance in future liver remnant for posthepatectomy liver failure following hepatectomy with extrahepatic bile duct resection. World J Surg. 2016; 40(6): 1440–7. Halle BM, Poulsen TD, Pedersen HP. Indocyanine green plasma disappearance rate as dynamic liver function test in critically ill patients. Acta Anaesthesiol Scand. 2014; 58(10): 1214–9. Tables Table 1,2,3 are available in the Supplementary Files section. Table 4. Differences in postoperative course with or without post-hepatectomy liver failure PHLF (grade B/C) No (n=310) Yes (n=23) P Postoperative hospital stay, days 11 [3-125] 24 [7-88] < 0.01 Complications, grade ≥ IIIa 40 (13) 13 (57) < 0.01 PHLF, post-hepatectomy liver failure. Categorical variables were evaluated using the chi-square test and continuous variables were evaluated using the Mann–Whitney test. Categorical variables are presented as number and percentage, whereas continuous variables are presented as median and range. Additional Declarations No competing interests reported. Supplementary Files Table1to3.docx Cite Share Download PDF Status: Published Journal Publication published 06 Jun, 2025 Read the published version in Langenbeck's Archives of Surgery → Version 1 posted Editorial decision: Revision requested 25 May, 2025 Reviews received at journal 18 May, 2025 Reviewers agreed at journal 18 May, 2025 Reviewers agreed at journal 18 May, 2025 Reviews received at journal 15 May, 2025 Reviewers agreed at journal 08 May, 2025 Reviewers agreed at journal 07 May, 2025 Reviewers agreed at journal 06 May, 2025 Reviewers invited by journal 06 May, 2025 Editor assigned by journal 29 Apr, 2025 Submission checks completed at journal 29 Apr, 2025 First submitted to journal 25 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6532051","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":453006753,"identity":"ec1ce105-cc9e-47ad-a92a-11b6705f10f8","order_by":0,"name":"Masashi Kudo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYJACxgYGZgZ+VDEeIrRINgBZB0jSYnAARQseoNt+/OHHmW3WcsbHmx9//sBwR56/gf3iAwaZOzi1mJ3JMZbc2JZubHbmmJnEAYZnhjMO8BQbMPA8w63lQA6D5MO2w4nbbiSYAR12OAGoPE2Cgecwbi3nnz/+CdKyef7zzx+I0wI0HOiww4kbJHgMJCBa2I8R0PLGzHLGuXRjiTM5ZRJnDA4bzjjMw2yQgM8v59Mf3+wps5bjbz+++UNFxWF5/vb2hw8+9uAOMTRgAMTMPAYMiT0HiNUCBuwPGBh+kKZlFIyCUTAKhjUAAP+kW0ZyT+2aAAAAAElFTkSuQmCC","orcid":"","institution":"National Cancer Center Hospital East","correspondingAuthor":true,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Kudo","suffix":""},{"id":453006754,"identity":"2686582b-4bc4-48c4-978e-e210d802ea8c","order_by":1,"name":"Naoto Gotohda","email":"","orcid":"","institution":"National Cancer Center Hospital East","correspondingAuthor":false,"prefix":"","firstName":"Naoto","middleName":"","lastName":"Gotohda","suffix":""},{"id":453006755,"identity":"ee4785d3-a6a4-483b-845d-a5115f210917","order_by":2,"name":"Motokazu Sugimoto","email":"","orcid":"","institution":"National Cancer Center Hospital East","correspondingAuthor":false,"prefix":"","firstName":"Motokazu","middleName":"","lastName":"Sugimoto","suffix":""},{"id":453006756,"identity":"42729155-823f-440a-8a22-563b08e7e940","order_by":3,"name":"Shin Kobayashi","email":"","orcid":"","institution":"National Cancer Center Hospital East","correspondingAuthor":false,"prefix":"","firstName":"Shin","middleName":"","lastName":"Kobayashi","suffix":""},{"id":453006757,"identity":"39d93d7d-db49-4b85-92c6-b5fe18726d89","order_by":4,"name":"Tatsushi Kobayashi","email":"","orcid":"","institution":"National Cancer Center Hospital East","correspondingAuthor":false,"prefix":"","firstName":"Tatsushi","middleName":"","lastName":"Kobayashi","suffix":""}],"badges":[],"createdAt":"2025-04-26 01:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6532051/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6532051/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00423-025-03764-y","type":"published","date":"2025-06-06T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82359756,"identity":"762d4d7b-2d95-4be3-bf42-17e885e6f25d","added_by":"auto","created_at":"2025-05-09 11:32:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":7145450,"visible":true,"origin":"","legend":"\u003cp\u003eImage analysis using the three-dimensional volumetric system\u003c/p\u003e\n\u003cp\u003ea) The investigator defines a small volume of interest (VOI) in the liver parenchyma.\u003c/p\u003e\n\u003cp\u003eb) All liver parenchyma are semi-automatically extracted from the initial VOI seed.\u003c/p\u003e\n\u003cp\u003ec) The investigator draws the estimated resection line.\u003c/p\u003e\n\u003cp\u003ed) The three-dimensional future remnant liver parenchyma is extracted. The future remnant liver volume and liver-to-spleen signal intensity ratio of the future remnant liver region are calculated automatically (yellow arrow).\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-6532051/v1/0d4796751bb7f18e00dcb034.png"},{"id":82358417,"identity":"80b5897a-fac7-48a7-98ec-ea38c9728688","added_by":"auto","created_at":"2025-05-09 11:24:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1152961,"visible":true,"origin":"","legend":"\u003cp\u003eDefinition of the liver-to-spleen signal intensity ratio (LSR) increasing rate (LSRi) in the future remnant liver region (LSRi-rem)\u003c/p\u003e\n\u003cp\u003ea) Dynamic information on the LSR-rem. Values of LSR-rem calculated using four time points (1, 3, 10, and 15–20 min after injection) are selected (black plot).\u003c/p\u003e\n\u003cp\u003eb) Information from these four time points is plotted on a semi-logarithmic graph using a non-logarithmic scale for LSR-rem (y axis) and a logarithmic scale for time after injection (x axis).\u003c/p\u003e\n\u003cp\u003ec) Approximate line of information from these four time points is created using the least-squares methods, and the slope of the approximate line is defined as LSRi-rem (in this case, 0.2927).\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-6532051/v1/9f1071aef7b16d48453971cc.png"},{"id":82359757,"identity":"fc38b3c2-35f1-4de8-a1b6-27ab8be52075","added_by":"auto","created_at":"2025-05-09 11:32:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1307190,"visible":true,"origin":"","legend":"\u003cp\u003eIndications for major hepatectomy using volume-adjusted LSRi-rem\u003c/p\u003e\n\u003cp\u003eThe cut-off for the volume-adjusted LSRi-rem for safe resection is 0.208. The cut-off for the volume-adjusted LSRi-rem for predicting post-hepatectomy liver failure is 0.147. The cut-off for unresectable liver is 0.081.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-6532051/v1/2eed3fae329b5a224ccdb6b3.png"},{"id":82358424,"identity":"844b21e1-af26-4943-898b-d1c62e8962d1","added_by":"auto","created_at":"2025-05-09 11:24:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":5618268,"visible":true,"origin":"","legend":"\u003cp\u003eCase presentation\u003c/p\u003e\n\u003cp\u003ea) A male patient in his 60s diagnosed with hilar cholangiocarcinoma (arrow) shows invasion of the right hepatic artery.\u003c/p\u003e\n\u003cp\u003eb) Residual blood flow in the right portal vein (arrowhead) is observed 3 weeks after percutaneous embolization of the right portal vein.\u003c/p\u003e\n\u003cp\u003ec) Despite percutaneous embolization of the portal vein, hepatobiliary-phase MRI shows an indistinct demarcation line.\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-6532051/v1/1a91f4256a7d68f0db165736.png"},{"id":84242594,"identity":"3a96e0a3-5184-4812-b81d-42ddbbf228cc","added_by":"auto","created_at":"2025-06-09 16:10:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":13609066,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6532051/v1/887ab72e-cd67-4cb8-a144-93c150bc17d3.pdf"},{"id":82358416,"identity":"56ca998c-8275-4adf-b3b7-ae12f27f2afb","added_by":"auto","created_at":"2025-05-09 11:24:10","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":47748,"visible":true,"origin":"","legend":"","description":"","filename":"Table1to3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6532051/v1/5aeef3f4e5cdd0fe232829d5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predicting post-hepatectomy liver failure based on future remnant liver function combined with future remnant liver volume using magnetic resonance imaging","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRecent reports indicate that post-hepatectomy liver failure (PHLF) after major hepatectomy occurs in 8\u0026ndash;12% of patients and represents a key cause of prolonged hospitalization and perioperative mortality.\u003csup\u003e1\u003c/sup\u003e Precise preoperative assessments of liver function, extent of resection, and estimated remnant liver volume are thus important to minimize the risks associated with liver surgery.\u003c/p\u003e\n\u003cp\u003eIntraoperative factors involved in PHLF reportedly include prolonged operative time, increased blood loss, need for blood transfusion, and prolonged ischemia (from hypotension or hepatic in-flow occlusion). Otherwise, two important preoperative factors, future remnant liver volume (FRLV) and liver functional assessment, have been used as predictors of PHLF.\u003csup\u003e1,2\u003c/sup\u003e FRLV is defined as the percentage of the liver volume remaining functional postoperatively compared with the preoperative functional whole-liver volume, and has been considered the most important modifiable predictor of PHLF.\u003csup\u003e2,3\u003c/sup\u003e Assessments of liver function such as indocyanine green (ICG) clearance test, Child\u0026ndash;Pugh score, and albumin-bilirubin (ALBI) grade have been also reported as predictors of PHLF.\u003csup\u003e1\u003c/sup\u003e These traditional assessments of liver function, obtained from blood tests and clinical evaluations, reflect whole-liver function, but not future remnant liver function after hepatectomy. As a result, many researchers have reported on image-based assessments of liver function, such as molecular nuclear imaging techniques and magnetic resonance imaging (MRI), that may be applicable to more precisely assessing future remnant liver function.\u003csup\u003e4,5\u003c/sup\u003e Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a liver-specific contrast medium, and MRI using Gd-EOB-DTPA (EOB-MRI) is widely used in the preoperative diagnosis of liver tumors. EOB-MRI allows much clearer extraction of the liver parenchyma, liver tumors, and blood vessels than molecular nuclear imaging techniques.\u003csup\u003e5\u003c/sup\u003e EOB-MRI is thus expected to prove useful as an image-based liver functional assessment that can accurately determine the liver dissection line before surgery.\u003csup\u003e5\u003c/sup\u003e However, the quantification of liver signal intensity in EOB-MRI requires standardization against other organs such as the spleen and iliopsoas muscle because MRI signal intensity is defined on an arbitrary scale and varies greatly with calibration.\u003csup\u003e6\u003c/sup\u003e We reported that the liver-to-spleen signal intensity ratio (LSR) in the hepatobiliary phase of EOB-MRI as evaluated using a three-dimensional volumetric analysis system correlated with conventional assessments of liver function.\u003csup\u003e7\u003c/sup\u003e We also reported that the LSR of the future remnant liver region (LSR-rem) offers a stronger predictor of PHLF than traditional whole-liver functional assessments such as ICG clearance test, Child\u0026ndash;Pugh score, and ALBI grade.\u003csup\u003e8\u003c/sup\u003e However,\u0026nbsp;those single-center investigations of image-based liver functional assessments using EOB-MRI were not easily applicable to other institutions, because doses of\u0026nbsp;Gd-EOB-DTPA\u0026nbsp;and timings of the hepatobiliary phase after Gd-EOB-DTPA injection vary between institutions.\u003csup\u003e8-10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe plasma\u0026nbsp;disappearance rate of ICG (KICG) is widely used as a preoperative liver functional assessment in high-volume centers in Japan.\u003csup\u003e11\u003c/sup\u003e The KICG is calculated from serum ICG concentrations at multiple time points, reflecting time-associated changes in ICG concentration over time without the dose bias of ICG or the timing bias of blood sampling.\u003csup\u003e12,13\u003c/sup\u003e Based on this idea, we developed a time-associated image-based liver functional assessment, termed the LSR increasing rate (LSRi), that can exclude limitations such as the dose bias of contrast medium or the timing bias of the hepatobiliary phase.\u003csup\u003e14\u003c/sup\u003e Along with the FRLV as a strong predictor of PHLF, this time-associated image-based determination of future remnant liver function is also expected to provide a strong predictor of PHLF. The combination of these two strong predictors is thus expected to provide a more accurate preoperative prediction of PHLF. The purpose of this study was to investigate the relationship between PHLF after major hepatectomy and a novel liver function assessment that combines FRLV and time-associated image-based future remnant liver function.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween January 2009 and December 2024, a total of 414 consecutive patients underwent major hepatectomy for tumors of the liver or biliary system at the National Cancer Center Hospital East, Kashiwa, Japan. Of these 414 patients, 81 were excluded from analyses for the following reasons: jaundice with total bilirubin \u0026gt;1.5 mg/dL on MRI examination (n = 46); contrast-enhanced MRI not performed (n = 27); interval from MRI examination to surgery \u0026gt; 90 days (n = 5); ICG intolerance (n = 2); and prior splenectomy (n = 1). The remaining 333 patients who underwent standardized EOB-MRI as part of the diagnostic procedures before major hepatectomy were evaluated for risk factors for PHLF. Among these, 114 patients who underwent preoperative portal vein embolization (PVE) were also evaluated for risk factors for PHLF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of PHLF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePHLF was defined as an increased prothrombin time-international normalized ratio and concomitant hyperbilirubinemia on or after postoperative\u003csup\u003e\u0026nbsp;\u003c/sup\u003eday 5, as per the definition of the International Study Group for Liver Surgery (ISGLS).\u003csup\u003e15\u003c/sup\u003e Cut-off values for increased prothrombin time-international normalized ratio and serum bilirubin concentration at our institute were set as 1.15 and 1.30 mg/dL, respectively. According to the ISGLS definition, grade B PHLF involves deviation from the regular course without requiring invasive therapy, and grade C PHLF requires invasive treatment. In this study, clinically relevant PHLF was defined as grade B or C. Differences in the postoperative course were examined based on the presence or absence of PHLF grade B and C.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreoperative evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eICG retention rate at 15 min (ICGR15) and computed tomography were performed within a month before surgery, and surgical indications were evaluated using the Takasaki criteria\u003csup\u003e16\u003c/sup\u003e and/or Makuuchi criteria\u003csup\u003e17,18\u003c/sup\u003e. The Takasaki criteria determine the safe limit of FRLV using the following formula: {1 - [log(40) – log(ICGR15) ] / [log(100) – log(ICGR15) ] }\u0026nbsp;´100 (%).\u003csup\u003e16\u003c/sup\u003e Estimated FRLV was calculated using images from 10-mm-slice computed tomography (CT), as reported in a previous study, and was compared to the safe limit of FRLV as calculated using the Takasaki criteria.\u003csup\u003e16\u003c/sup\u003e According to the Makuuchi criteria, the extent of hepatectomy was determined based on the presence of ascites, serum total bilirubin level and ICGR15.\u003csup\u003e17,18\u003c/sup\u003e Major hepatectomy was scheduled for patients those satisfying the Takasaki and/or Makuuchi criteria. PVE to increase FRLV was performed if a patient did not fulfill these criteria. FRLV and ICGR15 were then re-evaluated four weeks after PVE.\u003c/p\u003e\n\u003cp\u003eThe Child–Pugh score was calculated based on the following five variables: serum bilirubin level, serum albumin level, prothrombin activity, ascites status, and degree of encephalopathy. ALBI grade was calculated according to the following equation: -0.085\u0026nbsp;´\u0026nbsp;(serum albumin level, g/L) + 0.66\u0026nbsp;´\u0026nbsp;log(serum total bilirubin level, µmol/L). ALBI score was categorized into the following three grades: 1,\u0026nbsp;£\u0026nbsp;-2.60; 2; \u0026gt; -2.06 to\u0026nbsp;£\u0026nbsp;-1.39; and 3, \u0026gt; -1.39.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMRI was performed within 90 days before surgery. For patients who underwent PVE, CT and MRI were performed every four weeks after PVE, and indications for surgery were discussed each time. All MRI studies were performed using 3.0-T scanners at our institute (Achieva or Ingenia, Philips Medical Systems, Amsterdam, the Netherlands). Contrast-enhanced three-dimensional fat-suppressed T1-weighted images were obtained 20 min after intravenous administration of Gd-EOB-DTPA for the hepatobiliary phase, using either of the following parameters: repetition time, 4 ms; echo time, 2 ms; flip angle, 10°; slice thickness, 4.6 mm; and matrix size, 512\u0026nbsp;´\u0026nbsp;512 for Achieva, or repetition time, 3 ms; echo time, 2 ms; flip angle, 10°; slice thickness, 4.6 mm; and matrix size, 480\u0026nbsp;´\u0026nbsp;480 for Ingenia. Gd-EOB-DTPA was administered at a dose of about 0.1 mL/kg body weight, by rapid intravenous bolus injection using a power injector (Sonic Shot GX; Nemoto Kyorindo Co., Tokyo, Japan), at a rate of 2 mL/s. MRI was performed prior to injection and at 20 s, 1, 3, 10, and 15–20 min after intravenous Gd-EOB-DTPA injection. The hepatobiliary phase was taken to be between 15 and 20 min.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage-based liver functional assessment using MRI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 shows image analyses for a patient who underwent hepatectomy. The indicated parenchyma of the liver and spleen was semi-automatically extracted from a small operator-defined volume of interest using the image-processing algorithm (Fig. 1a, b). An estimated liver resection line was then drawn on the operator-defined axial MRI, and the future remnant liver region was extracted (Fig. 1c, d). Finally, LSR-rem was calculated as the average signal intensity of the future remnant liver parenchyma divided by that of splenic parenchyma. The LSR (whole liver) and LSR-rem of all patients were calculated at the following time points: 1, 3, 10, and 15–20 min after intravenous administration of Gd-EOB-DTPA. The relationship between LSR-rem and time after injection was then semi-logarithmically converted to be straightened, and LSR-rem at the four time points (1, 3, 10, and 15–20 min after injection) were plotted on a semi-logarithmic graph using a non-logarithmic scale for LSR-rem (y-axis) and a logarithmic scale for minutes after injection (x-axis) (Fig. 2a, b). Next, the approximate line of these four time points was created using the least-squares method (Fig. 2c). Finally, we defined the slope of the approximate line as the LSRi of the future remnant liver region (LSRi-rem). The LSR, LSRi, and LSRi-rem of EOB-MRI were calculated using the Synapse Vincent three-dimensional volumetric analysis system (Fujifilm Medical, Tokyo, Japan) by hepatobiliary and pancreatic surgeons with 5-14 years of clinical experience.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreoperative evaluation for PHLF using FRLV and LSRi-rem\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe volume-adjusted LSRi-rem is a novel index of preoperative liver function assessment that combines two important factors (liver volume and liver function) for predicting PHLF. The FRLV for this novel assessment was calculated simultaneously with LSRi-rem using the Synapse Vincent three-dimensional volumetric analysis system. Volume-adjusted LSRi-rem was calculated using the following formula: LSRi-rem\u0026nbsp;´\u0026nbsp;(FRLV / whole-liver volume).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCategorical variables are presented as the number and percentage, and continuous variables are presented as the median and range. Pre- and intraoperative variables were evaluated using logistic regression analysis for the risk of clinically relevant PHLF, and the odds ratio (OR) and 95% confidence interval (95%CI) are presented. Variables identified as significant in univariable analyses were included in the multivariable analysis. However, to avoid considering variables that varied with each other (confounding variables), correlations between variables were evaluated using the chi-square test. Analysis of the receiver operating characteristic curve was performed to determine cut-off values for continuous variables such as age, ICGR15, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, operation time, and estimated blood loss in association with clinically relevant PHLF. Categorical variables were evaluated using the chi-square test and continuous variables were evaluated using the Mann–Whitney test. Two-sided \u003cem\u003eP\u003c/em\u003e-values less than 0.05 were considered significant. Statistical analysis was performed using JMP version 12.0.10 software (SAS Institute, Cary, NC).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient demographics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics are shown in Table 1. Diagnoses included metastatic liver tumor in 111 patients (33%), perihilar cholangiocarcinoma in 78 patients (23%), intrahepatic cholangiocarcinoma in 57 patients (17%), hepatocellular carcinoma in 57 patients (17%), and intraductal papillary neoplasm of the bile duct in nine patients (3%). Surgical procedures performed included right hepatectomy in 163 patients (49%), left hepatectomy in 153 patients (46%), left trisectionectomy in nine patients (3%), and central bisectionectomy in seven patients (2%). Clinically relevant PHLF was identified in 35 patients (11%), of whom 21 patients (6%) had grade B and two patients (1%) had grade C PHLF. Of the 333 patients, three patients developed mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk analysis for clinically relevant PHLF after major hepatectomy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCut-offs for age, ICGR15, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, operation time, and estimated blood loss in association with clinically relevant PHLF were identified as 64 years, 13.3%, 43.7%, 1.95, 1.87, 0.354, 0.147, 400 min, and 1495 mL, respectively.\u003c/p\u003e\n\u003cp\u003eRisk analyses for clinically relevant PHLF in the entire cohort of 333 patients undergoing major hepatectomy are shown in Table 2. In univariable analysis, male sex, preoperative biliary drainage, preoperative portal embolization, perihilar cholangiocarcinoma, Child–Pugh score, ALBI grade, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, right hepatectomy, biliary reconstruction, operation time, estimated blood loss, and blood transfusion were found to be significant risk factors for PHLF.\u003c/p\u003e\n\u003cp\u003eAmong the variables identified as significant in univariable analyses, preoperative biliary drainage and perihilar cholangiocarcinoma were confounders with biliary reconstruction. PVE was confounded by right hepatectomy. Child–Pugh score, ALBI grade, estimated FRLV, LSR (whole liver), LSR-rem, and LSRi-rem were confounders with volume-adjusted LSRi-rem. Blood transfusion was confounded by estimated blood loss. Based on these findings, male sex, volume-adjusted LSRi-rem, right hepatectomy, biliary reconstruction, operation time, and estimated blood loss were included in the multivariable analysis. Subsequent multivariable analysis identified volume-adjusted LSRi-rem \u0026lt; 0.147, right hepatectomy, operation time ≥ 400 min, and estimated blood loss ≥ 1495 mL as independent risk factors for clinically relevant PHLF. In particular, the highest OR in the multivariable analysis for this patient cohort was for volume-adjusted LSRi-rem (OR 9.12, 95%CI 2.71–38.00; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01) (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk analysis for clinically relevant PHLF after PVE and major hepatectomy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 333 patients, 114 (34%) underwent PVE before major hepatectomy. In this patient cohort, cut-offs for age, ICGR15, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, operation time, and estimated blood loss in association with clinically relevant PHLF were determined to be 64 years, 11.7%, 43.7%, 1.66, 1.75, 0.355, 0.147, 406 min, and 967 mL, respectively.\u003c/p\u003e\n\u003cp\u003eRisk analysis for clinically relevant PHLF in this patient cohort is shown in Table 3. In univariable analysis, preoperative biliary drainage, perihilar cholangiocarcinoma, Child–Pugh score, estimated FRLV, LSR (whole liver), LSR-rem, LSRi-rem, volume-adjusted LSRi-rem, biliary reconstruction, operation time, estimated blood loss, and blood transfusion were found to be significant risk factors for PHLF.\u003c/p\u003e\n\u003cp\u003eAmong the significant variables in univariable analyses, preoperative biliary drainage and perihilar cholangiocarcinoma were confounders with biliary reconstruction. Child–Pugh score, estimated FRLV, LSR (whole liver), LSR-rem, and LSRi-rem were confounders with volume-adjusted LSRi-rem. Blood transfusion was confounded by estimated blood loss. As a result, volume-adjusted LSRi-rem, biliary reconstruction, operation time, and estimated blood loss were included in the multivariable analysis. This multivariable analysis then showed that volume-adjusted LSRi-rem \u0026lt; 0.147, operation time ≥ 406 min, and estimated blood loss ≥ 967 mL were independent risk factors for clinically relevant PHLF. In particular, the highest OR in the multivariable analysis of this patient cohort was for volume-adjusted LSRi-rem (OR 21.04, 95%CI 3.61–403.35; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01) (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelationship between PHLF and short-term outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDifferences in postoperative course with or without PHLF grade B or C are shown in Table 4. Patients with PHLF showed a significantly longer postoperative hospital stay (24 days) than those without PHLF (11 days, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01). The incidence of all complications of Clavien–Dindo grade ≥ IIIa was significantly higher in patients with PHLF than in patients without PHLF.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we proposed a novel preoperative liver functional assessment that combines FRLV and time-associated, image-based future remnant liver function. In the cohort of 333 patients, volume-adjusted LSRi-rem was the strongest predictor of PHLF, showing the highest OR in multivariable analysis (OR 9.12, 95%CI 2.71\u0026ndash;38.00). The present study revealed volume-adjusted LSRi-rem as a better predictor of PHLF than traditional liver functional assessments such as ICGR15, Child\u0026ndash;Pugh score, or ALBI grade. Further, a subgroup analysis of patients who underwent PVE showed that volume-adjusted LSRi-rem to PHLF showed the highest OR in multivariable analysis (OR 21.04, 95%CI 3.61\u0026ndash;403.35). This result suggests that this novel assessment of liver function can be expected to provide a useful predictor of PHLF, particularly among patients with PVE, because future remnant liver function is reflected rather than whole-liver function. In this study, patients who developed clinically relevant PHLF displayed a higher overall complication ratio and a longer postoperative hospital stay, suggesting the importance of accurate preoperative evaluation using volume-adjusted LSRi-rem.\u003c/p\u003e\n\u003cp\u003eThe ICG clearance test has been shown to offer one of the most reliable whole-liver functional assessments for predicting PHLF. However, the ICG clearance test has potential for human error because of the need for injections and multiple blood collections, and ICG is also known to have dose-dependent and cumulative hepatotoxic effects.\u003csup\u003e13,19\u003c/sup\u003e Further, since the whole liver region does not remain after hepatectomy, image-based assessment of liver function limited to the region of the future remnant liver is expected to prove more useful and less prone to human error in assessments predicting PHLF.\u0026nbsp;Previous investigators have thus reported the relationship between PHLF and image-based assessments of future remnant liver function.\u003csup\u003e9,20,21\u003c/sup\u003e We have likewise reported that LSR-rem calculated using a three-dimensional volumetric analysis system represents a stronger risk factor for clinically relevant PHLF compared to traditional whole-liver functional assessments, particularly in PVE patients.\u003csup\u003e8\u003c/sup\u003e In the subgroup of patients who underwent PVE in the present study (Table 3), ORs in univariable analyses of LSR-rem (OR 4.67, 95%CI 1.46\u0026ndash;14.69) and LSRi-rem (OR 5.70, 95%CI 1.49\u0026ndash;37.56) were higher than those from whole-liver functional assessments such as ICGR15 (OR 0.60, 95%CI 0.19\u0026ndash;1.75), Child\u0026ndash;Pugh score (OR 3.71, 95%CI 1.18\u0026ndash;11.39), ALBI grade (OR 2.05, 95%CI 0.70\u0026ndash;6.43), and LSR (whole liver) (OR 3.71, 95%CI 1.18\u0026ndash;11.39). These results suggest that the signal intensity of the future remnant liver on EOB-MRI, particularly in PVE patients, is more strongly associated with PHLF than whole-liver functional assessments. This indicates that signal intensity in the future remnant liver reflects future remnant liver function and might be a useful tool for preoperative liver functional assessment. As well as liver functional assessment, most hepatobiliary surgeons consider FRLV to be another important factor for predicting PHLF. The indication criteria for liver surgery proposed by Makuuchi et al., Takasaki et al., and Nagino et al., which are used in many Japanese hospitals, suggest an acceptable liver resection volume based on ICG values reflecting whole-liver function, not future remnant liver function.\u003csup\u003e11,16,17\u003c/sup\u003e The volume-adjusted LSRi-rem proposed in this study is thus expected to be more useful as an indication criterion for liver surgery that combines future remnant liver function and FRLV.\u003c/p\u003e\n\u003cp\u003eLSRi-rem is a time-associated assessment of liver function using dynamic information from multiple time points after contrast injection, and is not an assessment using data from the hepatobiliary phase alone. There are two reasons why LSRi-rem uses dynamic (time-associated) information. First, dynamic quantitative liver function assessments provide a more accurate assessment of specific aspects of liver function than passive (non-time-associated) assessments such as albumin, prothrombin, ICG clearance test, Child\u0026ndash;Pugh grade, and ALBI grade.\u003csup\u003e4,22,23\u003c/sup\u003e Dynamic (time-associated) quantitative assessments of liver function, such as KICG, are calculated from ICG concentrations at multiple time points and can accurately assess liver function using time-related ICG uptake and metabolic capacity.\u003csup\u003e11,23\u003c/sup\u003e In this study cohort (Table 2), LSRi-rem, which uses dynamic information, showed a higher OR for PHLF\u0026nbsp;(OR 4.75, 95%CI 1.59\u0026ndash;20.46) than LSR-rem (OR 4.38, 95%CI 1.84\u0026ndash;11.20), which uses only hepatobiliary-phase information from EOB-MRI. This result was similar to the findings from a subgroup analysis of patients who underwent PVE (Table 3). To the best of our knowledge, no previous reports have investigated associations between PHLF and time-associated changes in image-based assessments of liver function. Second, time-associated assessments of liver function are expected to overcome limitations such as the dose bias of contrast media or the timing bias of the hepatobiliary phase. Aono et al. reported that the KICG with a 0.5-mg/dL dose of ICG was almost the same as that with a 0.1-mg/dL dose.\u003csup\u003e13\u003c/sup\u003e That findings suggests that the speed at which ICG is cleared from plasma (i.e., the change in ICG over time) offers a universal quantitative assessment regardless of the ICG dose. Considering the similar metabolic pathways for ICG and Gd-EOB-DTPA, the LSRi reflecting changes in Gd-EOB-DTPA uptake over time is expected to provide a universal quantitative assessment of liver function regardless of Gd-EOB-DTPA dose. As for the timing bias of the hepatobiliary phase, we have previously reported considerably high correlations between LSRi calculated using four time points (1, 3, 10, and 15\u0026nbsp;min) and that calculated using three time points, indicating minimal timing bias.\u003csup\u003e14\u003c/sup\u003e We also suggested that LSRi carries less biases from MRI equipment and slice thickness.\u003csup\u003e14\u003c/sup\u003e Given those previous reports, volume-adjusted LSRi-rem can be expected\u0026nbsp;to provide a universal elaborate image-based assessment of liver function that can be used at any institution.\u003c/p\u003e\n\u003cp\u003eFinally, we propose novel surgical indications for major hepatectomy using volume-adjusted LSRi-rem. Figure 3 shows the presence or absence of PHLF and plots of volume-adjusted LSRi-rem values for all patients in this study. Considering these plots of volume-adjusted LSRi-rem values, surgical indications based on the three cut-offs can be proposed. First, the value with the highest volume-adjusted LSRi-rem in patients with PHLF (cut-off = 0.208) can be used. Since PHLF did not develop in all patients with volume-adjusted LSRi-rem \u0026gt; 0.208, liver surgery can be expected to be safely performed in this patient group. In the future, indications for liver surgery may be able to be determined in this patient group by EOB-MRI alone, without ICG clearance test before major hepatectomy. Second, the cut-off calculated as a predictor of PHLF in this study (cut-off = 0.147) can be used. This cut-off offered 83% sensitivity, 80% specificity, a positive predictive value of 24%, and a negative predictive value of 98% for PHLF. The negative predictive value was particularly high. Interestingly, three of the four patients with volume-adjusted LSRi-rem \u0026ge; 0.147 and PHLF had experienced massive intraoperative bleeding (\u0026gt; 1000 mL) and required blood transfusions. Accordingly, if liver surgery can be performed without massive bleeding in cases with volume-adjusted LSRi-rem \u0026ge; 0.147, PHLF may be avoidable. This may be useful information for high-risk patients in whom PHLF must be absolutely avoided. Finally, the value without the lowest volume-adjusted LSRi-rem in patients without PHLF (cut-off = 0.081) can be used. All three patients with volume-adjusted LSRi-rem \u0026lt; 0.081 developed PHLF, and one of them died due to liver failure. In this study, we encountered two patients who developed grade C PHLF with volume-adjusted LSRi-rem values of 0.123 and 0.070. Major hepatectomy may thus need to be aborted in patients showing volume-adjusted LSRi-rem \u0026lt; 0.081 before surgery.\u003c/p\u003e\n\u003cp\u003eAs a representative example, we present the case of a patient who might have benefited from assessment of future remnant liver function. The patient was a man in his 60s who had been diagnosed with hilar cholangiocarcinoma with invasion of right hepatic artery\u0026nbsp;(Fig. 4a). Extended right hepatectomy with extrahepatic bile duct resection had been planned, but percutaneous right PVE was performed before surgery because the FRLV was \u0026lt; 30%. Contrast-enhanced CT at 3 weeks after PVE showed enlargement of future remnant left liver volume, with an FRLV of 41%, but residual blood flow in the right portal vein was observed (Fig. 4b). The ICGR15 was 7.8%, meeting both Makuuchi and Takasaki criteria. The patient therefore underwent extended right hepatectomy with extrahepatic bile duct resection one month after PVE. The operation time was 682 min and total blood loss was 2687 mL, requiring blood transfusion. After surgery, intensive care treatment with mechanical ventilation was performed for unstable circulatory dynamics due to severe dehydration and liver failure. The patient required intensive treatment due to PHLF grade C, renal failure, and sepsis, but his general condition gradually improved and he was discharged from the intensive care unit on postoperative day 33. On postoperative day 69, he was discharged from our hospital, but his physical condition had deteriorated considerably and he required a wheelchair. Retrospective evaluation showed his volume-adjusted LSRi-rem was 0.070 on preoperative MRI, corresponding to unresectable status according to our proposed surgical indications for major hepatectomy. After PVE, most cases show a distinct demarcation line between the future remnant liver and future resected liver region on hepatobiliary-phase MRI (Fig. 1a), whereas the demarcation line was unclear in this case (Fig. 4c). This MRI finding may indicate that PVE was inadequate. If the volume-adjusted LSRi-rem had been evaluated preoperatively and the patient had been assessed as high risk for PHLF, this patient might have instead undergone additional PVE. This novel surgical indication for major hepatectomy is determined by the volume-adjusted LSRi-rem value, which includes two important factors for predicting PHLF: LSRi-rem and FRLV. The present study indicated that LSRi-rem, representing future remnant liver function, offers a better predictor of PHLF than markers of whole-liver function such as ICG clearance test, Child\u0026ndash;Pugh grade, or ALBI grade. FRLV is also considered the most important predictor of PHLF, particularly for patients scheduled for major hepatectomy requiring PVE. When considering indications for major hepatectomy, both LSRi-rem and FRLV appear to be essential factors for predicting PHLF.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the three-dimensional volumetric analysis system sometimes automatically extracts extrahepatic parenchymal tissues such as portal veins, hepatic veins, small cysts and tumors. However, our previous report showed a high correlation between LSR and vascular subtraction LSR (LSR excluding extrahepatic parenchymal tissues) and demonstrated that the LSR adequately reflects contrast enhancement of the liver parenchyma. Our previous report suggested that liver function can be evaluated without subtracting vessels and vascular perfusion areas. Second, this was a retrospective, single-center investigation of patients who had undergone major hepatectomy, including a relatively small number of patients with PHLF, indicating a selection bias towards surgery. Our cut-offs for indicating surgery should thus be validated in future multicenter research.\u003c/p\u003e\n\u003cp\u003eIn conclusion, the present study revealed that the volume-adjusted LSRi-rem calculated using a three-dimensional volumetric analysis system on EOB-MRI offered an independent risk factor for clinically relevant PHLF in patients who underwent major hepatectomy, particularly those with preoperative PVE. The volume-adjusted LSRi-rem might provide a reliable preoperative assessment of liver function, enabling safe performance of major hepatectomy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALBI, albumin-bilirubin; CT, computed tomography; EOB-MRI, magnetic resonance imaging using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; FRLV, future remnant liver volume; Gd-EOB-DTPA, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; ICG, indocyanine green; ICGR15, indocyanine green retention rate at 15 min; ISGLS, International Study Group for Liver Surgery; KICG, plasma disappearance rate of indocyanine green; LSR, liver-to-spleen signal intensity ratio; LSRi, liver-to-spleen signal intensity ratio increasing rate; LSRi-rem, liver-to-spleen signal intensity ratio increasing rate in the future remnant liver region; LSR-rem, liver-to-spleen signal intensity ratio in the future remnant liver region; MRI, magnetic resonance imaging; OR, odds ratio; PHLF, post-hepatectomy liver failure; PVE, portal vein embolization; 95%CI, 95% confidence interval.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest. This paper is not based on any previous communication to a society or meeting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the institutional review board of the National Cancer Center, Japan (reference 2017-483). Due to the retrospective design and the absence of invasive interventions, a waiver of participant informed consent was granted by the institutional review board of the National Cancer Center, Japan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the present study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Masashi Kudo. The first draft of the manuscript was written by Masashi Kudo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all participating patients and their families who made this study possible.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSoreide JA, Deshpande R. Post hepatectomy liver failure (PHLF) - recent advances in prevention and clinical management. Eur J Surg Oncol. 2021; 47(2): 216\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eKhan AS, Garcia-Aroz S, Ansari MA, et al. Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review. Int J Surg. 2018; 52: 74\u0026ndash;81.\u003c/li\u003e\n\u003cli\u003eOlthof PB, Aldrighetti L, Alikhanov R, et al. Portal vein embolization is associated with reduced liver failure and mortality in high-risk resections for perihilar cholangiocarcinoma. Ann Surg Oncol. 2020; 27(7): 2311\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eHoekstra LT, de Graaf W, Nibourg GA, et al. Physiological and biochemical basis of clinical liver function tests: a review. Ann Surg. 2013; 257(1): 27\u0026ndash;36.\u003c/li\u003e\n\u003cli\u003eUtsunomiya T, Shimada M, Hanaoka J, et al. Possible utility of MRI using Gd-EOB-DTPA for estimating liver functional reserve. J Gastroenterol. 2012; 47(4): 470\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eOnoda M, Hyodo T, Murakami T, et al. Optimizing signal intensity correction during evaluation of hepatic parenchymal enhancement on gadoxetate disodium-enhanced MRI: comparison of three methods. Eur J Radiol. 2015; 84(3): 339\u0026ndash;45.\u003c/li\u003e\n\u003cli\u003eKudo M, Gotohda N, Sugimoto M, et al. Evaluation of liver function using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging based on a three-dimensional volumetric analysis system. Hepatol Int. 2018; 12(4): 368\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eKudo M, Gotohda N, Sugimoto M, et al. The assessment of regional liver function before major hepatectomy using magnetic resonance imaging. Am Surg. 2022; 88(9): 2353\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003eWang Y, Zhang L, Ning J, et al. Preoperative remnant liver function evaluation using a routine clinical dynamic Gd-EOB-DTPA-enhanced MRI protocol in patients with hepatocellular carcinoma. Ann Surg Oncol. 2021; 28(7): 3672\u0026ndash;82.\u003c/li\u003e\n\u003cli\u003eImai Y, Katayam K, Hori M, Yakushijin T, Fujimoto K, Itoh T, et al. Erratum: Prospective comparison of Gd-EOB-DPTA-enhanced MRI with dynamic CT for detecting recurrence of HCC after radiofrequency ablation. Liver Cancer. 2018; 7(3): 294.\u003c/li\u003e\n\u003cli\u003eNagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg. 2006; 243(3): 364\u0026ndash;72.\u003c/li\u003e\n\u003cli\u003eKumazawa K, Kikuchi T, Oishi T, et al. Variations in the disappearance rate of indocyanine green. Jpn J Surg. 1988; 18(1): 1\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eAono T, Tsukada K, Sakaguchi T, Ishiduka D, Suzuki T, Hatakeyama K. Utilization of low dose indocyanine green test for evaluating liver function. Acta Med Biol. 1994; 42(4): 165\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eKudo M, Gotohda N, Sugimoto M, Kobayashi S, Konishi M, Kobayashi T. Liver functional assessment using time-associated change in the liver-to-spleen signal intensity ratio on enhanced magnetic resonance imaging: a retrospective study. BMC Surg. 2023; 23(1): 179.\u003c/li\u003e\n\u003cli\u003eRahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011; 149(5): 713\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eTakasaki T, Kobayashi S, Suzuki S, et al. Predetermining postoperative hepatic function for hepatectomies. Int Surg. 1980; 65(4): 309\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eMakuuchi M, Kosuge T, Takayama T, et al. Surgery for small liver cancers. Semin Surg Oncol. 1993; 9(4): 298\u0026ndash;304.\u003c/li\u003e\n\u003cli\u003eKubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology. 1997; 26(5): 1176\u0026ndash;81.\u003c/li\u003e\n\u003cli\u003eLaperche Y, Oudea MC, Lostanlen D. Toxic effects of indocyanine green on rat liver mitochondria. Toxicol Appl Pharmacol. 1977; 41(2): 377\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eAraki K, Harimoto N, Kubo N, et al. Functional remnant liver volumetry using Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) predicts post-hepatectomy liver failure in resection of more than one segment. HPB (Oxford). 2020; 22(2): 318\u0026ndash;27.\u003c/li\u003e\n\u003cli\u003eSmet H, Martin D, Uldry E, et al. Tc-99m mebrofenin hepatobiliary scintigraphy to assess future liver remnant function before major liver surgery. J Surg Oncol. 2023; 128(8): 1312\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eYokoyama Y, Ebata T, Igami T, et al. The predictive value of indocyanine green clearance in future liver remnant for posthepatectomy liver failure following hepatectomy with extrahepatic bile duct resection. World J Surg. 2016; 40(6): 1440\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eHalle BM, Poulsen TD, Pedersen HP. Indocyanine green plasma disappearance rate as dynamic liver function test in critically ill patients. Acta Anaesthesiol Scand. 2014; 58(10): 1214\u0026ndash;9.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\n\u003cp\u003eTable 1,2,3 are available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Differences in postoperative course with or without post-hepatectomy liver failure\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"473\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd height=\"21\" style=\"width: 42.116%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" height=\"21\" style=\"width: 36.2157%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePHLF (grade B/C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 12.6144%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd height=\"21\" style=\"width: 42.116%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 19.1251%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo (n=310)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 17.0905%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYes (n=23)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 12.6144%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd height=\"21\" style=\"width: 42.116%;\"\u003e\n \u003cp\u003ePostoperative hospital stay, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 19.1251%;\"\u003e\n \u003cp\u003e11 [3-125]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 17.0905%;\"\u003e\n \u003cp\u003e24 [7-88]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 12.6144%;\"\u003e\n \u003cp\u003e\u0026lt; 0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd height=\"21\" style=\"width: 42.116%;\"\u003e\n \u003cp\u003eComplications, grade \u0026ge; IIIa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 19.1251%;\"\u003e\n \u003cp\u003e40 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 17.0905%;\"\u003e\n \u003cp\u003e13 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd height=\"21\" style=\"width: 12.6144%;\"\u003e\n \u003cp\u003e\u0026lt; 0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePHLF, post-hepatectomy liver failure. Categorical variables were evaluated using the chi-square test and continuous variables were evaluated using the Mann\u0026ndash;Whitney test. Categorical variables are presented as number and percentage, whereas continuous variables are presented as median and range.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"langenbecks-archives-of-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"laos","sideBox":"Learn more about [Langenbeck's Archives of Surgery](http://link.springer.com/journal/423)","snPcode":"423","submissionUrl":"https://submission.nature.com/new-submission/423/3","title":"Langenbeck's Archives of Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"hepatectomy, liver failure, magnetic resonance imaging, liver function","lastPublishedDoi":"10.21203/rs.3.rs-6532051/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6532051/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eSignificant advances have been made in image-based determinations of future remnant liver function, in attempts to better predict post-hepatectomy liver failure (PHLF). We have reported time-associated liver functional assessments using magnetic resonance imaging with liver-to-spleen signal intensity ratio increasing rate (LSRi) and LSRi of the future remnant liver region (LSRi-rem) to predict PHLF. This study aimed to investigate the predictability of PHLF by a preoperative liver function assessment index that combined LSRi-rem and future remnant liver volume (FRLV).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eParticipants comprised 333 patients who underwent EOB-MRI for the diagnosis of liver tumor before major hepatectomy between 2009 and 2024. LSRi-rem was evaluated by three-dimensional volumetric analysis, and the volume adjusted LSRi-rem (vaLSRi-rem) was calculated using the following formula: LSRi-rem \u0026times; (FRLV / whole-liver volume). The vaLSRi-rem and clinical variables were then analyzed to assess the risk of PHLF.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn patients with vaLSRi-rem\u0026thinsp;\u0026lt;\u0026thinsp;0.147, right hepatectomy, operation time\u0026thinsp;\u0026ge;\u0026thinsp;400 min, and estimated blood loss\u0026thinsp;\u0026ge;\u0026thinsp;1495 mL were associated with clinically relevant PHLF (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 each) in multivariable analysis. Multivariable analysis showed the highest odds ratio (OR) for vaLSRi-rem (OR 9.12; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Of the 333 patients, 114 (34%) underwent portal vein embolization before major hepatectomy. The OR of vaLSRi-rem from multivariable analysis in this patient cohort was particularly high (OR 21.04; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eStrong associations were identified between vaLSRi-rem and clinically relevant PHLF after major hepatectomy, particularly among portal vein embolization patients.\u003c/p\u003e","manuscriptTitle":"Predicting post-hepatectomy liver failure based on future remnant liver function combined with future remnant liver volume using magnetic resonance imaging","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 11:24:05","doi":"10.21203/rs.3.rs-6532051/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-25T11:40:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-18T13:46:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58859713893439775764452257240659758713","date":"2025-05-18T11:44:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"11829759716577239652242124163622380423","date":"2025-05-18T07:46:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-16T01:52:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"234078283610998678605760014537212439787","date":"2025-05-08T06:08:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"211239040627838089746818557364646467085","date":"2025-05-07T05:05:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"340078170793692578676410946956847084524","date":"2025-05-06T14:58:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-06T04:04:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-30T03:54:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-29T04:54:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Langenbeck's Archives of Surgery","date":"2025-04-26T01:34:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"langenbecks-archives-of-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"laos","sideBox":"Learn more about [Langenbeck's Archives of Surgery](http://link.springer.com/journal/423)","snPcode":"423","submissionUrl":"https://submission.nature.com/new-submission/423/3","title":"Langenbeck's Archives of Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a9b96875-7ee0-4c80-b4b5-be0e5dda76ca","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-09T16:02:35+00:00","versionOfRecord":{"articleIdentity":"rs-6532051","link":"https://doi.org/10.1007/s00423-025-03764-y","journal":{"identity":"langenbecks-archives-of-surgery","isVorOnly":false,"title":"Langenbeck's Archives of Surgery"},"publishedOn":"2025-06-06 15:57:34","publishedOnDateReadable":"June 6th, 2025"},"versionCreatedAt":"2025-05-09 11:24:05","video":"","vorDoi":"10.1007/s00423-025-03764-y","vorDoiUrl":"https://doi.org/10.1007/s00423-025-03764-y","workflowStages":[]},"version":"v1","identity":"rs-6532051","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6532051","identity":"rs-6532051","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}