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Purpose: To assess the performance of FLIS in predicting adverse outcomes, namely post-hepatectomy liver failure (PHLF) and death, in patients who underwent liver surgery for malignancies., Methods: All consecutive patients who underwent liver resection and 1.5 T gadoxetic acid MR were enrolled. PHLF and overall survival (OS) were collected. Two radiologists with 18 and 8 years of experience in abdominal imaging, blinded to clinical data, evaluated all images. Radiologists evaluated liver parenchymal enhancement (EnQS), biliary contrast excretion (ExQS), and signal intensity of the portal vein relative to the liver parenchyma (PVsQs). Reliability analysis was computed with Cohen's Kappa. Cox regression analysis was calculated to determine which factors are associated with PHLF and OS. Area Under the Receiver Operating Characteristic curve (AUROC) was computed., Results: 150 patients were enrolled, 58 (38.7 %) in the HCC group and 92 (61.3 %) in the non-HCC group. The reliability analysis between the two readers was almost perfect (κ = 0.998). The multivariate Cox analysis showed that only post-surgical blood transfusions and major resection were associated with adverse events [HR=8.96 (7.98-9.88), p = 0.034, and HR=0.99 (0.781-1.121), p = 0.032, respectively] in the whole population. In the HCC group, the multivariable Cox analysis showed that blood transfusions, major resection and FLIS were associated with adverse outcomes [HR=13.133 (2.988-55.142), p = 0.009, HR=0.987 (0.244-1.987), p = 0.021, and HR=1.891 (1.772-3.471), p = 0.039]. The FLIS AUROC to predict adverse outcomes was 0.660 (95 %CIs = 0.484-0.836), with 87 % sensitivity and 33.3 % specificity (81.1-94.4 and 22.1-42.1)., Conclusions: FLIS can be considered a promising tool to preoperative depict patients at risk of PHLF and death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Approximately 15% of patients experience post-hepatectomy liver failure after major hepatectomy. Poor hepatocyte uptake of gadoxetate disodium, a magnetic resonance imaging contrast agent, may be a predictor of post-hepatectomy liver failure., Methods: A retrospective cohort study of patients undergoing major hepatectomy (≥3 segments) with a preoperative gadoxetate disodium-enhanced magnetic resonance imaging was conducted. The liver signal intensity (standardized to the spleen) and the functional liver remnant was calculated to determine if this can predict post-hepatectomy liver failure after major hepatectomy., Results: In 134 patients, low signal intensity of the remnant liver standardized by signal intensity of the spleen in post-contrast images was associated with post-hepatectomy liver failure in multiple logistic regression analysis (Odds Ratio 0.112; 95% CI 0.023-0.551). In a subgroup of 33 patients with lower quartile of functional liver remnant, area under the curve analysis demonstrated a diagnostic accuracy of functional liver remnant to predict post-hepatectomy liver failure of 0.857 with a cut-off value for functional liver remnant of 1.4985 with 80.0% sensitivity and 89.3% specificity., Conclusion: Functional liver remnant determined by gadoxetate disodium-enhanced magnetic resonance imaging is a predictor of post-hepatectomy liver failure which may help identify patients for resection, reducing morbidity and mortality., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Objectives: Sarcopenia is a morbi-mortality risk factor in digestive surgery, though its impact after major hepatectomy (MH) remains unknown. This prospective pilot study investigated whether volume and function of a regenerating liver is influenced by body composition., Methods: From 2011 to 2016, 125 consecutive patients had computed tomography and 99mTc-labelled-mebrofenin SPECT-scintigraphy before and after MH at day 7 and 1 month for measurements of liver volumes and functions. L3 vertebra muscle mass identified sarcopenia. Primary endpoint was the impact of sarcopenia on regeneration capacities (i.e. volume/function changes and post-hepatectomy liver failure (PHLF) rate). Secondary endpoint was 3-month morbi-mortality., Results: Sarcopenic patients (SP; N = 69) were significantly older than non-sarcopenic (NSP), with lower BMI and more malignancies, but with comparable liver function/volume at baseline. Postoperatively, SP showed higher rates of ISGLS_PHLF (24.6 % vs 10.9 %; p = 0.05) but with comparable rates of severe morbidity (23.2 % vs 16.4 %; p = 0.35), overall (8.7 % vs 3.6 %; p = 0.3) and PHLF-related mortality (8,7 % vs 1.8 %; p = 0.075). After matching on the extent of resection or using propensity score, regeneration and PHLF rates were similar., Conclusion: This prospective study using first sequential SPECT-scintigraphy showed that sarcopenia by itself does not affect liver regeneration capacities and short-term postoperative course after MH., Competing Interests: Declaration of competing interest No conflict of interest to disclose, (Copyright © 2024. Published by Elsevier Masson SAS.)

Introduction: The usefulness of gadolinium-ethoxybenzyl diethylenetriamine pentaacetate acid-enhanced magnetic resonance imaging (EOB-MRI) in assessing the functional future remnant liver volume (fFRLV) to predict post-hepatectomy liver failure (PHLF) has been previously reported. Herein, we evaluated the efficacy of this technique in patients with hepatocellular carcinoma (HCC) with a major portal vein tumor thrombus (PVTT)., Methods: This study included 21 patients with PVTT in the ipsilateral first-order branch (Vp3) and 30 patients with PVTT in the main trunk/contralateral branch (Vp4). To evaluate fFRLV, the signal intensity (SI) of the remnant liver was determined on T1-weighted images, using both conventional and newly developed methods. The fFRLV was calculated using the SI of the remnant liver and muscle, remnant liver volume, and body surface area. Preoperative factors predicting PHLF (≥grade B) in HCC patients with Vp3/4 PVTT were evaluated., Results: In the Vp3 group, we found fFRLV area under the receiver-operating characteristic curves (AUCs) above 0.70 (AUC = 0.875, 0.750) using EOB-MRI results calculated using either the plot or whole method. None of the parameters in the Vp4 group had an AUC greater than 0.70., Conclusion: The fFRLV calculated by EOB-MRI using the whole method can be as useful as the conventional method in predicting PHLF (≥grade B) for HCC patients with Vp3 PVTT., (© 2024 S. Karger AG, Basel.)

Despite improvements in operative techniques and perioperative care, post-hepatectomy liver failure (PHLF) remains the most serious cause of morbidity and mortality after surgery, and several risk factors have been identified to predict PHLF. Although volumetric assessment using imaging contributes to surgical simulation by estimating the function of future liver remnants in predicting PHLF, liver function is assumed to be homogeneous throughout the liver. The combination of volumetric and functional analyses may be more useful for an accurate evaluation of liver function and prediction of PHLF than only volumetric analysis. Gadoxetic acid is a hepatocyte-specific magnetic resonance (MR) contrast agent that is taken up by hepatocytes via the OATP1 transporter after intravenous administration. Gadoxetic acid-enhanced MR imaging (MRI) offers information regarding both global and regional functions, leading to a more precise evaluation even in cases with heterogeneous liver function. Various indices, including signal intensity-based methods and MR relaxometry, have been proposed for the estimation of liver function and prediction of PHLF using gadoxetic acid-enhanced MRI. Recent developments in MR techniques, including high-resolution hepatobiliary phase images using deep learning image reconstruction and whole-liver T1 map acquisition, have enabled a more detailed and accurate estimation of liver function in gadoxetic acid-enhanced MRI., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Background and Objectives: Assessment of liver function is paramount before hepatectomy. This study aimed to assess future liver remnant function (FLR-F) using hepatobiliary scintigraphy (HBS) and to compare it to FLR volume (FLR-V) in the prediction of posthepatectomy liver failure (PHLF). The impact of volume and function gains were also assessed in patients undergoing portal vein embolization (PVE) or liver venous deprivation (LVD)., Methods: All consecutive patients undergoing major hepatectomy between 02/2018 and 09/2021 with preoperative HBS were included. FLR-V was expressed as percentage of total liver volume and analyzed using preoperative computed tomography. FLR-V and FLR-F gains after embolization were expressed in percentage. Receiver operating characteristic analysis was performed to compare both methods in predicting PHLF., Results: Thirty-six patients were included. PVE and LVD were performed in 4 (11%) and 28 patients (78%), respectively. Overall, PHLF occurred in eight patients (22%). FLR-F gain after embolization showed significant ability to predict PHLF (area under the curve [AUC] = 0.789), with cut-off value of 150% showing a sensitivity of 1.00, a specificity of 0.42, and a negative predictive value of 1.00., Conclusion: Preoperative HBS shows a high sensitivity to predict PHLF when HBS is performed twice to measure the function gain after venous embolization., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Purpose: The risk of posthepatectomy liver failure (PHLF) remains an important concern following major liver resection. Assessment of future remnant liver function (FRLF) by hepatobiliary scintigraphy has shown its significance to prevent PHLF after major liver resection in adults with a threshold value of FRLF greater than 2.7%/min per m2. However, such data for pediatric patients were not published., Methods: A total of 77 pediatric patients with liver tumors who underwent 1-stage liver resection were included in this study. Assessment of FRLF, future remnant liver volume (FRLV), and the ratio of remnant liver volume to body weight (RLV-BWR) was performed before the surgery., Results: All patients had RLV-BWR values of more than 0.5%/kg. Future remnant liver volume values ranged from 19% to 89%, and FRLF values ranged from 1.8% to 31.8%/min per m2. Only 7 of 77 patients had FRLV values less than 25%, but their FRLF values exceeded 2.7%/min per m2. Two patients developed grade A and grade B PHLF., Conclusion: Future remnant liver volume and the RLV-BWR can be used in most pediatric patients for the assessment of liver before hepatectomy. According to our data, implementation of FRLF assessment using hepatobiliary scintigraphy can be most beneficial for children with FRLV of less than 25%. The cutoff value of FRLV greater than 25% can be slightly decreased with minimal risk of developing PHLF. However, to establish a new cutoff value for FRLV in children, further prospective studies including larger numbers of patients with FRLV of less than 25% are needed., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This study aimed to analyze the predictive value of Hepatobiliary scintigraphy (HBS) for posthepatectomy liver failure (PHLF) after major liver resection with a comparison to assessment of liver volume in a multicenter cohort., Methods: Patients who underwent liver resection after HBS were included from six centers. Remnant liver volume was calculated from CT images. PHLF was scored and graded according to the grade B/C ISGLS criteria., Results: In 547 patients PHLF incidence was 10% (56/547) and 90-day mortality rate 8% (42/547). Overall predictive value of remnant liver function was 0.66 (0.58-0.74) and similar to that of remnant volume (0.63 (0.72). For biliary tumors, a function cut-off of 2.7%/min/m2 and 30% volume cut-off resulted in a PHLF rate 12% and 13%, respectively. While an 8.5%/min (4.5%/min/m2) function cut-off resulted in 7% PHLF for those with a function above the cutoff while a 40% volume cutoff still resulted in 14% PHLF rate. In the multivariable analyses for PHLF, liver function was predictive but liver volume was not., Conclusion: The current study shows that preoperative liver function assessment using HBS is at least as predictive for PHLF as liver volume assessment, and likely has several advantages, particularly in the high-risk sub-group of biliary tumors., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Accurate preoperative diagnosis of post-hepatectomy liver failure (PHLF) is particularly important to improve the prognosis of patients., Purpose: To evaluate the predictive value of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) for post-hepatectomy liver failure., Material and Methods: A systematic search was performed in the PubMed, Embase, the Cochrane Library, and Web of Science databases to find relevant original articles published up to December 2021. The included studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The bivariate random-effects model was used to assess the diagnostic authenticity. Meta-regression analyses were performed to analyze the potential heterogeneity., Results: In total, 13 articles were included. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the summary receiver operating characteristic curves were 88% (95% confidence interval [CI] = 0.80-0.94), 80% (95% CI = 0.73-0.86), 4.4 (95% CI = 3.3-5.9), 0.14 (95% CI = 0.08-0.25), 31 (95% CI = 17-57), and 0.91 (95% CI = 0.89-0.94), respectively. There was no publication bias and threshold effect in our study., Conclusion: Gd-EOB-DTPA-enhanced MRI is a potentially useful for the prediction of PHLF after major hepatectomy.

Purpose: To assess and compare the value of liver stiffness measurement (LSM) by two-dimensional shear wave elastography (2D-SWE) with the diagnosis of clinically significant portal hypertension (CSPH) and pathological examination in predicting symptomatic posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC)., Method: A total of 130 patients who underwent liver resection for HCC between August 2018 and July 2021 were enrolled. Preoperative assessments for LSM and other clinicopathological tests were performed in all patients. The performance of LSM, CSPH and fibrosis stage in predicting symptomatic PHLF was assessed and compared. Univariate and multivariate analyses were conducted on the risk factors for symptomatic PHLF., Results: Symptomatic PHLF occurred in 40 patients (30.8%). The best LSM cutoff value for predicting symptomatic PHLF was 9.5 kPa. The areas under the receiver operating characteristic curve (AUCs) of LSM ≥ 9.5 kPa, fibrosis stage and CSPH for predicting symptomatic PHLF were 0.732 (95% CI: 0.638-0.826, p < 0.001), 0.655 (95% CI: 0.553-0.758, p = 0.005) and 0.594 (95% CI: 0.484-0.705, p = 0.086), respectively. The AUC of LSM ≥ 9.5 kPa was significantly higher than that of CSPH (p = 0.010), and was comparable to that of fibrosis stage (p = 0.073). Multivariate analysis identified LSM ≥ 9.5 kPa (p = 0.001), major hepatectomy (p = 0.007) and CSPH diagnosis (p = 0.040) as independent predictors of symptomatic PHLF., Conclusions: LSM by 2D-SWE was promising for predicting symptomatic PHLF in HCC patients. The predictive performance was higher than that of CSPH and comparable to that of pathological fibrosis stage., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Effective and non-invasive biomarkers to predict and avoid posthepatectomy liver failure (PHLF) are urgently needed. This systematic review aims to evaluate the efficacy of gadoxetic acid-enhanced MRI-derived parameters as an imaging biomarker in preoperative prediction of PHLF., Methods: A systematic literature search was performed in the databases of PubMed/Medline, Web of Science, Embase, and Cochrane Library up to 11 December 2020. Studies evaluating the incidence of PHLF on patients who underwent hepatectomy with preoperative liver function assessment using gadoxetic acid-enhanced MRI were included. Data was extracted using pre-designed tables. The Quality In Prognostic Studies (QUIPS) tool was adopted to evaluate the risk of bias., Results: A total of 15 studies were identified for qualitative synthesis and most studies were marked as low to moderate risk of bias in each domain of QUIPS. The most commonly used parameter was relative liver enhancement or its related parameters. The reported incidence of PHLF ranged from 3.9 to 40%. The predictive sensitivity and specificity of gadoxetic acid-enhanced MRI parameters varied from 75 to 100% and from 54 to 93% in ten reported studies. A majority of the studies revealed that the gadoxetic acid-enhanced MRI parameter was a predictor for PHLF., Conclusions: Gadoxetic acid-enhanced MRI showed a high predictive capacity for PHLF and represents a promising imaging biomarker in prediction of PHLF. Multicenter, prospective trials with large sample size and reliable, unified liver function parameters are required to validate the efficacy of individual liver function parameters., Key Points: • There is an obvious heterogeneity of the published studies, not only in variance of MRI liver function parameters but also in indication and extent of the liver resection. • Signal intensity (SI)-based parameters derived from gadoxetic acid-enhanced MRI are the commonly used method for PHLF prediction. • Gadoxetic acid-enhanced MRI-derived parameters showed high predictive efficacy for PHLF and can potentially serve as a predictor for the incidence of PHLF., (© 2021. The Author(s).)

Background: Despite increasing attention in the cardiac anesthesiology literature, continuous measurement of right ventricular pressure using a pulmonary artery catheter has not been described in orthotopic liver transplantation, despite similarities in the anesthetic approach to the two populations. We describe our preliminary experience with this technique in orthotopic liver transplantation, and by combining various derived measures with trans-esophageal echocardiography, make some early observations regarding the response of these measures of right ventricular function during the procedure., Methods: In this case series, ten patients (five men and five women) undergoing orthotopic liver transplantation in our institution had their surgeries performed while monitored with a pulmonary artery catheter with continuous right ventricular port transduction and trans-esophageal echocardiography. We recorded various right ventricular waveform (early-to-end diastolic pressure difference, right ventricular outflow tract gradient, right ventricular dP/dT and right ventricular end-diastolic pressure) and echocardiographic (right ventricular fractional area change, tricuspid annular plane systolic excursion, right ventricular lateral wall strain) and described their change relative to baseline at timepoints five minutes before and after portal vein reperfusion, immediately after hepatic artery reperfusion and on abdominal closure., Results: Except for tricuspid annular plane systolic excursion at five minutes prior to reperfusion (mean -0.8 cm; 95% CI-1.4, -0.3; p = 0.007), no echocardiographic metric was statistically significantly different at any timepoint relative to baseline. In contrast, changes in right ventricular outflow tract gradient and right ventricular dP/dt were highly significant at multiple timepoints, generally peaking immediately before or after reperfusion before reducing, but not returning to baseline in the neohepatic phase. Nine of 10 participants in this series demonstrated a degree of dynamic right ventricular outflow tract obstruction, which met criteria for hemodynamic significance (> 25 mmHg) in two participants. These changes were not materially affected by cardiac index., Conclusions: Dynamic right ventricular outflow tract obstruction of varying severity appears common in patients undergoing orthotopic liver transplantation. These results are hypothesis generating and will form the basis of future prospective research., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: The institution for which Lachlan F. Miles works has received financial support from Edwards LifeSciences, although he himself is not the recipient of any grants or funding. Cristhian Potes is an employee of Edwards LifeSciences. Laurence Weinberg is a member of the speaker bureau for Edwards LifeSciences and Masimo and has received financial support from both organizations. André Y. Denault reports grants from Edwards LifeSciences outside the submitted work. He is a member of the speaker bureau and a key opinion leader for CAE Healthcare and Masimo. This does not alter our adherence to PLOS ONE policies on sharing data and materials. No other authors have any conflicts of interest to report.

Objectives: To evaluate the ability of liver stiffness (LS) measured by two-dimensional shear wave elastography (2D SWE) to predict symptomatic post-hepatectomy liver failure (SPHLF) in patients with hepatocellular carcinoma (HCC)., Methods: A total of 119 patients who underwent hepatectomy for HCC between August 2018 and July 2019 were enrolled. Preoperative assessments for LS and other clinicopathological tests were performed in all patients. Univariate and multivariate analyses were conducted for the risk factors of SPHLF. Further subgroup analysis was performed according to multivariate analysis results., Results: SPHLF occurred in 38 patients (31.9%). The best cutoff value of LS for predicting SPHLF was 9.5 kPa. Multivariate analysis identified LS ≥ 9.5 kPa, greater Child-Turcotte-Pugh (CTP) grade, and major hepatectomy as independent predictors of SPHLF. Based on the extent of hepatectomy, CTP grade could stratify the risk of SPHLF in the minor hepatectomy group (12.2% vs. 100.0%, p = 0.001), whereas LS was superior in predicting SPHLF in the major hepatectomy group (18.9% vs. 72.4%, p < 0.001). In patients with CTP grade A, LS could further stratify the risks of SPHLF in both the minor and major hepatectomy groups (3.7% vs. 22.7%, p = 0.043; 17.6% vs. 70.4%, p < 0.001, respectively)., Conclusions: LS measured using 2D SWE could predict SPHLF using the best cutoff value of 9.5 kPa. CTP grade was a stronger indicator of SPHLF in minor hepatectomy, whereas LS was more effective in selecting candidates for major hepatectomy. LS could further stratify the risk of SPHLF in CTP grade A patients, regardless of the extent of hepatectomy., (© 2021. Society of Surgical Oncology.)

Background: The aim of the current study is to investigate the variations of anatomical (LV Rem %) and functional remnant volumes (fLV Rem %) and the dynamic uptake of Technetium-Mebrofinate (FRLF) measured from 99 m Technetium-Mebrofinate SPECT-CT scan (TMSCT) in patients at high risk of post-hepatectomy liver failure (PHLF)., Methods: Variations in the measures of LV Rem % and fLV Rem % were assessed. The predictive accuracies of LV Rem %, fLV Rem % and FRLF with respect to PHLF were reported., Results: From the N = 92 scans performed, LV Rem % and fLV Rem % returned identical results in 15% of cases, and ±10 percentage points in 79% of cases. Some patients had larger discrepancies, with difference of >10 percentage points in 21% of cases. The difference was significant in those with primary liver cancers (-4.4 ± 9.2, p = 0.002). For the N = 29 patients that underwent surgery as planned on TMSCT, FRLF was a strong predictor of PHLF, with an AUROC of 0.83 (p = 0.005)., Conclusion: TMSCT is emerging as a useful modality in pre-operative assessment of patients undergoing major liver resection. For those with primary liver cancer, there is a significant variation in the anatomical and functional distributions that needs considered in surgical planning. Reduced FRLF, measured as the dynamic uptake in the future liver remnant, is a strong predictor of PHLF., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

99m Tc-mebrofenin hepatobiliary scintigraphy with SPECT/CT (HBS-M) has become an important quantitative method to evaluate global liver function and future liver remnant (FLR) function in patients who are candidates for resective liver surgery. The purpose of this work was to describe the method in the prediction of post-surgical liver failure. The overall liver function and that of the FLR are obtained by analysis of the initial dynamic phase of the scan. Liver volume to be preserved is expressed as a percentage of the total liver volume measured in both CT sections. HBS-M is able to accurately gauge regional liver function abnormalities that could be represented as normal liver tissue parenchyma in the CT study. This technique can provide very valuable prognostic information for the estimation of the postoperative risk of liver failure in all patients who are candidates for resective liver surgery., (Copyright © 2021 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

BACKGROUND. Drug-eluting bead transarterial chemoembolization (DEB-TACE) has emerged as an alternative to conventional TACE (cTACE) for treatment of hepatocellular carcinoma (HCC), although selection between the approaches remains controversial. OBJECTIVE. The purpose of this study was to compare DEB-TACE and cTACE in the treatment of patients with unresectable HCC in terms of hepatobiliary changes on imaging and clinical complications. METHODS. This retrospective study included 1002 patients (871 men, 131 women; mean age, 59 ± 12 years) from three centers who had previously untreated unresectable HCC and underwent DEB-TACE with epirubicin (780 procedures in 394 patients) or cTACE with ethiodized oil mixed with doxorubicin and oxaliplatin (1187 procedures in 608 patients) between May 2016 and November 2018. Among these patients 83.4% had hepatitis B-related liver disease, 57.6% had Barcelona Clinic Liver Cancer (BCLC) stage A or B HCC, and 42.4% had three or more nodules. Mean tumor size was 6.3 ± 4.2 cm. Hepatobiliary changes and tumor response were evaluated with CT or MRI 1 month after TACE. Clinical records were reviewed for adverse events. RESULTS. Bile duct dilatation ( p < .001) and portal vein narrowing ( p = .006) on imaging and liver failure ( p = .03) and grade 3 abdominal pain ( p < .001) in clinical follow-up occurred at higher frequency in the DEB-TACE group (15.5%, 4.6%, 2.3%, and 6.1%) than in the cTACE (7.4%, 1.6%, 0.7%, and 2.1%) group. Higher frequency of bile duct dilation in patients who underwent DEB-TACE was observed in subgroup analyses that included patients with BCLC stage A or B HCC ( p = .001), with cirrhosis ( p < .001), without cirrhosis ( p = .04), and without main portal vein tumor thrombus ( p = .002). Total bilirubin level 1 month after treatment was 1.5 ± 2.4 mg/dL (95% CI, 1.2-1.8 mg/dL) for DEB-TACE versus 1.3 ± 2.0 mg/dL (95% CI, 1.1-1.5 mg/dL) for cTACE ( p = .02). The cTACE and DEB-TACE groups did not differ in other manifestations of postembolization syndrome or systemic toxicity ( p > .05). Local tumor disease control rates did not differ between the cTACE and DEB-TACE groups (1 month, 96.7% vs 98.5%, p = .06; 3 months, 81.8% vs 82.4%, p = .87), but overall DCR was significantly higher in the cTACE than in the DEB-TACE group (1 month, 87.5% vs 80.0%, p = .001; 3 months, 78.5% vs 72.1%, p = .02). CONCLUSION. Compared with cTACE, DEB-TACE was associated with greater frequency of hepatobiliary injury and severe abdominal pain. CLINICAL IMPACT. Greater caution and closer follow-up are warranted for patients who undergo DEB-TACE for unresectable HCC than for those who undergo cTACE.

Objectives: Post-hepatectomy liver failure (PHLF) can occur as a major complication after hepatic resection (HR) in patients with hepatocellular carcinoma (HCC) and negatively affects the prognosis. We aimed to retrospectively assess whether the spleen volume (SV) measured from preoperative CT images would be associated with the development of PHLF and overall survival (OS) after HR in patients with HCC., Methods: We enrolled 317 consecutive patients with very early/early stage HCC who underwent a preoperative CT and HR between January 2010 and December 2016. The SV was obtained from preoperative CT images using semi-automated volumetric software and was divided by body surface area to yield SV BSA . Receiver operating characteristic (ROC) curves and logistic regression analyses were performed to identify factors affecting the development of PHLF. The Cox proportional hazard model was used to identify prognostic factors for OS., Results: PHLF was observed in 72 patients (22.7% [72/317]). SV BSA was associated with the development of PHLF (odds ratio, 2.321; 95% CI, 1.347-4.001; p = 0.002) with the area under the ROC curve of 0.663 using the cutoff value of 107.5 cm 3 (p < 0.001). SV BSA was also an influencing factor for OS (hazard ratio, 3.935; 95% CI 1.520-10.184; p = 0.005), with the optimal cutoff of 146 cm 3 . The 5-year OS rate was higher in 245 patients with a SV BSA ≤ 146 cm 3 than in 72 patients with a SV BSA > 146 cm 3 (95.0% vs. 78.7%, p < 0.001)., Conclusions: In patients with HCC, a larger SV BSA was associated with a higher rate of PHLF and worse OS after HR. The SV BSA may be useful in selecting good surgical candidates., Key Points: • A significantly higher spleen volume divided by body surface area was observed in patients who experienced post-hepatectomy liver failure than in patients who did not (148 cm 3 vs. 112 cm 3 , p < 0.001). • The area under the receiver operating characteristic curve of spleen volume divided by body surface area to predict the development of post-hepatectomy liver failure was 0.663 (p < 0.001). • Spleen volume divided by body surface area was a significant influencing factor for overall survival (hazard ratio, 3.935; 95% CI, 1.520-10.184; p < 0.001), with the optimal cutoff of 146 cm 3 .

Background: The preoperative prediction of post hepatectomy liver failure (PHLF) is essential, but there is no gold standard for the prediction at present, and the efficacy of different methods for the prediction has not been compared systematically. In this study, we aimed to compare the efficacy of preoperative two-dimensional shear wave elastography (2D-SWE), indocyanine green (ICG) clearance test and biomarkers for PHLF prediction in patients with hepatocellular carcinoma (HCC)., Methods: We retrospectively studied 215 patients with HCC, who had undergone major liver resection in our hospital. Preoperative data of each patient, including liver stiffness value (LSV) of underlying hepatic parenchyma measured by 2D-SWE, ICG retention rate at 15 min (ICG-R15) measured by ICG clearance test, albumin-bilirubin (ALBI) scores, aspartate aminotransferase-platelet ratio index (APRI), and Fibrosis-4 (FIB-4) were collected for analysis. Post hepatectomy outcomes of study patients were also recorded for assessment of PHLF. The study patients were divided into development cohort (133 patients without PHLF, and 17 patients with PHLF) and validation cohort (59 patients without PHLF, and 6 patients with PHLF) randomly., Results: In the development cohort, LSV, ICG-R15 and ALBI scores were significantly different between patients with and without PHLF, while no significant difference of APRI and FIB-4 scores was found. LSV had higher AUC (the area under the receiver operating characteristic curve) (AUC = 0.795) for PHLF prediction than ICG-R15 (AUC = 0.619) and ALBI scores (AUC = 0.686) (p < 0.05 for all comparisons). In the validation cohort, the cutoff value of LSV obtained from the development cohort, 10.35 kPa,  revealed higher specificity (76.3%) for PHLF prediction than ICG-R15 (specificity: 66.1%) and ALBI scores (specificity: 69.5%) (p < 0.0001)., Conclusions: Compared with ICG-R15, ALBI scores, APRI and FIB-4, LSV measured by 2D-SWE may demonstrate better efficacy for preoperative PHLF prediction in patients with HCC.

Background & Aims: Despite improvements in medical and surgical techniques, post-hepatectomy liver failure (PHLF) remains the leading cause of postoperative death. High postoperative portal vein pressure (P PV ) and portocaval gradient (PCG), which cannot be predicted by current tools, are the most important determinants of PHLF. Therefore, we aimed to evaluate a digital twin to predict the risk of postoperative portal hypertension (PHT)., Methods: We prospectively included 47 patients undergoing major hepatectomy. A mathematical (0D) model of the entire blood circulation was assessed and automatically calibrated from patient characteristics. Hepatic flows were obtained from preoperative flow MRI (n = 9), intraoperative flowmetry (n = 16), or estimated from cardiac output (n = 47). Resection was then simulated in these 3 groups and the computed P PV and PCG were compared to intraoperative data., Results: Simulated post-hepatectomy pressures did not differ between the 3 groups, comparing well with collected data (no significant differences). In the entire cohort, the correlation between measured and simulated P PV values was good (r = 0.66, no adjustment to intraoperative events) or excellent (r = 0.75) after adjustment, as well as for PCG (respectively r = 0.59 and r = 0.80). The difference between simulated and measured post-hepatectomy PCG was ≤3 mmHg in 96% of cases. Four patients suffered from lethal PHLF for whom the model satisfactorily predicted their postoperative pressures., Conclusions: We demonstrated that a 0D model could correctly anticipate postoperative PHT, even using estimated hepatic flow rates as input data. If this major conceptual step is confirmed, this algorithm could change our practice toward more tailor-made procedures, while ensuring satisfactory outcomes., Lay Summary: Post-hepatectomy portal hypertension is a major cause of liver failure and death, but no tool is available to accurately anticipate this potentially lethal complication for a given patient. Herein, we propose using a mathematical model to predict the portocaval gradient at the end of liver resection. We tested this model on a cohort of 47 patients undergoing major hepatectomy and demonstrated that it could modify current surgical decision-making algorithms., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

There is no gold standard indicator that is currently used to predict posthepatectomy liver failure (PHLF). A novel indicator of liver function, the LU15 index of 99mTc-galactosyl serum albumin (GSA) scintigraphy, refers to the liver uptake ratio over a 15-min interval. We aimed to evaluate the usefulness of the future liver remnant (FLR)-LU15 in predicting PHLF. The clinical data of 102 patients (70 males and 32 females; median age, 70 years) who underwent liver resection between January 2011 and August 2019 were analyzed. The FLR-LU15 was calculated by a fusion of simulated 3-dimensional images and 99mTc-GSA scintigraphy. PHLF was determined according to the definition of the International Study Group of Liver Surgery. The FLR-LU15 was an independent risk factor for PHLF ≥ Grade B according to multivariate analysis, and its value correlated with the PHLF grade. The area under the receiver operating characteristic curve of the FLR-LU15 for PHLF ≥ Grade B was 0.816 (95% confidence interval, 0.704-0.929), which was better than that of other indicators. When the cut-off value of FLR-LU15 was set at 16.7, the sensitivity was 86.7%, specificity was 74.7%, and odds ratio was 19.2 (95% confidence interval, 4.0-90.9), all of which were superior to other indicators. If the cut-off value was 13, the positive predictive value was 57.1%. The FLR-LU15 is a useful predictor of PHLF and may be more reliable than other predictors., Competing Interests: The authors have declared that no competing interests exist.

Hepatobiliary scintigraphy (HBS) has been demonstrated to predict post-hepatectomy liver failure (PHLF). However, existing cutoff values for future liver remnant function (FLR-F) were previously set according to the "50-50 criteria" PHLF definition. Methods of calculation and fields of application in liver surgery have changed in the meantime. The aim of this study was to demonstrate the role of HBS combined with single photon emission computed tomography (SPECT/CT) in predicting severity of PHLF, according to the International Study Group of Liver Surgery (ISGLS). All patients submitted to major hepatectomy with preoperative HBS-SPECT/CT between November 2016 and December 2019, were analyzed. Patients were resected according to hepatic volumetry. Receiver operating characteristic (ROC) curve analysis was performed to identify cutoffs of FLR function for predicting PHLF according to ISGLS definition and grading. Of the 38 patients enrolled, 26 were submitted to one-stage hepatectomy (living liver donors = 4) and 12 to two-stage procedures (portal vein embolization = 4, ALPPS = 8). Overall, 18 patients developed PHLF according to ISGLS criteria: 12 of grade A (no change in the patient's clinical management) and 6 of grade B (change in clinical management). ROC analysis established increasingly higher cutoffs of FLR-F for predicting PHLF according to the "50-50 criteria", ISGLS grade B and ISGLS grade A/B, respectively. HBS with SPECT/CT may help to assess severity of PHLF following major hepatectomy. Prospective multicenter trials are needed to confirm the effective role of HBS-SPECT/CT in liver surgery.

Post hepatectomy liver failure (PHLF) could occur even though an adequate liver volume is preserved. Liver function is not strictly related to the volume and the necessity to pre-operatively predict the future liver remnant (FLR) function is emerging, together with the wide spreading of techniques, aiming to optimize the FLR. The aim of this study was to systematically review all the available tests, to pre-operatively assess the liver function and to estimate the risk of PHLF. A systematic literature research of Medline, Embase, Scopus was performed in accordance to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, to identify all the studies available for pre-operative liver function tests to assess the risk of PHLF and/or complications. From the 1122 references retrieved, 79 were included in the review. Dynamic functional tests, such as indocyanine green test (ICG), could evaluate only global liver function, with no definition of functional capacity of the remnant. Magnetic resonance imaging (MRI) with liver-specific contrast agents enables both liver function and volume evaluation; the absence of ionizing radiation showed a better patient's compliance. Nuclear imaging studies as hepatobiliary scintigraphy (HBS) present the unique ability to allow a precise evaluation of the segmental liver function of the remnant liver. Liver volume could overestimate liver function. Several liver function tests are available to evaluate the risk of PHLF in the pre-operative setting. However, no single test alone could accurately predict PHLF. Pre-operative combination between a dynamic quantitative test, such as ICG, with MRI or HBS, should enable a more complete functional evaluation. Functional tests to predict PHLF should be chosen according to patient's characteristics, disease, and center experience.

Background: Our aim was to determine if end-stage liver disease (ESLD) is associated with an attenuated response to vasodilator-stress or dobutamine-stress using 82 Rb-PET MPI with blood flow quantification., Methods and Results: Pre-liver transplant patients who had a normal dipyridamole-stress (n = 27) or dobutamine-stress (n = 26) 82 Rb PET/CT MPI study with no identifiable coronary artery calcium were identified retrospectively and compared to a prospectively identified low-risk of liver disease dipyridamole-stress control group (n = 20). The dipyridamole-stress liver disease group had a lower myocardial flow reserve (MFR) (1.89 ± 0.79) than the control group (2.79 ± 0.96, P < .05). The dobutamine-stress group had a higher MFR than both other groups (3.69 ± 1.49, P < .05). A moderate negative correlation between MELD score and MFR was demonstrated for the dipyridamole-stress liver disease group (r = - 0.473, P < .05). This correlation was not observed for the dobutamine-stress liver disease group (r = - 0.253, P = .21). The liver failure group as a whole (n = 53) had a higher resting myocardial blood flow (0.97 ± 0.33 mL/min/g) than the control group (0.82 ± 0.26, P < .05)., Conclusion: Dipyridamole demonstrates an attenuated vasodilatory response in ESLD patients compared to a non-ESLD control group related to higher resting blood flow and comparatively reduced stress blood flow. Dobutamine does not demonstrate this effect implying it may be the preferred pharmacologic MPI stress agent for ESLD patients.

Objective: To investigate the value of two-dimensional shear wave elastography (2D SWE) combined with clinical biochemical data in predicting posthepatoectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). Methods: A total of 274 HCC patients who underwent hepatectomy in Zhongshan Hospital Fudan University from January 2015 to January 2016 were retrospectively collected, including 235 males and 39 females, age 19-80 (56±11) years. All patients were confirmed to be HCC by postoperative pathology. The preoperative 2D SWE examination, laboratory examination results and intraoperative indicators were analyzed. According to the occurrence of PHLF after surgery, single factor analysis and multiple logistic regression analysis were performed on the above indicators to obtain a binary logistic regression model, and evaluate the diagnostic effect of the model on PHLF. In addition, 103 HCC patients from October 2019 to January 2020 were retrospectively collected as an external validation set, including 89 males and 14 females, age 23-80 (55±11) years old. Results: The liver stiffness measurement (LSM) obtained from 2D SWE, INR and Laminin (LN) were independent predictors of PHLF. The formula of prediction model PM=-15.451+0.095×LSM+11.7×INR+0.012×LN was obtained by combining above three factors. The area under the curve (AUC) of PHLF was 0.82, which was higher than that of end-stage liver disease model (MELD) score and Child-Pugh grading diagnosis of PHLF. The AUC of PHLF predicted by PM in the external validation group was 0.81. Conclusion: 2D SWE is helpful for clinicians to evaluate liver reserve function preoperatively and to predict the occurrence of PHLF in patients with HCC.

Background: Post hepatectomy liver failure (PHLF) after ALPPS has been related to the discrepancy between liver volume and function. Pre-operative hepatobiliary scintigraphy (HBS) can predict post-operative liver function and guide when it is safe to proceed with major hepatectomy. Aim of this study was to evaluate the role of HBS in predicting PHLF after ALPPS, defining a safe cut-off., Methods: A multicenter retrospective study was approved by the ALPPS Registry. All patients selected for ALPPS between 2012 and 2018, were evaluated. Every patient underwent HBS during ALPPS evaluation. PHLF was reported according to ISGLS definition, considering grade B or C as clinically significant., Results: 98 patients were included. Thirteen patients experienced PHLF grade B or C (14%) following ALPPS-2. The HBS and the daily gain in volume (KGR FLR ) of the future liver remnant (FLR) were significantly lower in PHLF B and C (p = .004 and .041 respectively). ROC curves indicated safe cut-offs of 4.1%/day (AUC = 0.68) for KGR FLR , and of 2.7 %/min/m 2 (AUC = 0.75) for HBS FLR . Multivariate analysis confirmed these cut-offs as variables predicting PHLF after ALPPS-2., Conclusion: Patients presenting a KGR FLR ≤4.1%/day and a HBS FLR ≤2.7%/min/m 2 are at high risk of PHLF and their second stage should be re-discussed., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Accurate prediction of post-hepatectomy liver failure (PHLF) is important in advanced hepatocellular carcinoma (HCC). We aimed to retrospectively evaluate the utility of gadoxetic acid-enhanced MRI for predicting PHLF in patients who underwent anatomic hepatectomy for HCC with portal vein invasion., Methods: Forty-one patients (32 men, 9 women) were included. Hepatobiliary-phase MR images were acquired 20 min after injection of gadoxetic acid using a 3D fat-suppressed T1-weighted spoiled gradient-echo sequence. Liver-spleen ratio (LSR), remnant hepatocellular uptake index (rHUI), and HUI were calculated. The severity of PHLF was defined according to the International Study Group of Liver Surgery. Differences in LSR between the resected liver and the remnant liver, and HUI and rHUI/HUI between no/mild and severe PHLF were compared using the Wilcoxon signed-rank test and Wilcoxon rank-sum test, respectively. Univariate and multivariate logistic regression analyses were performed to identify predictors of severe PHLF. Areas under the receiver operating characteristic curves (AUCs) of rHUI and rHUI/HUI were calculated for predicting severe PHLF., Results: Nine patients developed severe PHLF. LSR of the remnant liver was significantly higher than that of the resected liver (P < 0.001). Severe PHLF demonstrated significantly lower rHUI (P < 0.001) and rHUI/HUI (P < 0.001) compared with no/mild PHLF. Multivariate logistic regression analysis showed that decreased rHUI (P = 0.012, AUC=0.885) and rHUI/HUI (P = 0.002, AUC=0.852) were independent predictors of severe PHLF., Conclusion: Gadoxetic acid-enhanced MRI can be a promising noninvasive examination for assessing global and regional liver function, allowing estimation of the functional liver remnant and accurate prediction of severe PHLF before hepatic resection., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: We assessed the usefulness of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging for the prediction of posthepatectomy liver failure (PHLF) after a major hepatectomy., Methods: We reviewed 140 cases involving a hepatectomy of two or more sections between 2010 and 2016 (study cohort). We used the standardized remnant hepatocellular uptake index (SrHUI) which was calculated by: SrHUI = future remnant liver volume × [(signal intensity of remnant liver on hepatobiliary phase images/signal intensity of spleen on hepatobiliary phase images) - 1]/body surface area. Validation of the SrHUI was performed in another cohort of 52 major hepatectomy cases between 2017 and 2018 (validation cohort)., Results: The SrHUI of patients with PHLF was significantly lower than that of non-PHLF cases. Receiver operating characteristic analysis and the Youden index revealed that the SrHUI cutoff value for the prediction of PHLF and PHLF grade ≥ B were 0.313 L/m 2 and 0.257 L/m 2 , respectively. In the validation cohort, the cutoff value of SrHUI for the prediction of PHLF or PHLF grade ≥ B had a sensitivity of 75.0% or 88.8%, and specificity of 78.1% or 91.6%, respectively., Conclusions: The SrHUI value is a predictor for PHLF after a major hepatectomy., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

There is a growing interest in assessment of future remnant liver function with Tc-mebrofenin hepatobiliary scintigraphy before major hepatectomy to estimate the risk of posthepatectomy liver failure. We illustrate the case of a 42-year-old woman with liver metastasis from colorectal cancer who performed hepatobiliary scintigraphy. Tc-mebrofenin clearance rate of the total liver was considerably low. The patient recently started a treatment for active hepatitis C with a combination of 2 new direct-acting antiviral agents (grazoprevir, elbasvir). Apart from hypoalbuminemia or hyperbilirubinemia, physicians must be aware that drug interactions can interfere with Tc-mebrofenin liver uptake, thereby resulting in a dramatic underestimation of liver function.

Background: The optimal cardiovascular evaluation prior to liver transplantation remains controversial and includes stress echocardiography, stress MPI, cardiac CTA, and coronary angiography. This study summarizes our experience of the past decade using SPECT MPI in patients with end-stage liver disease, including patient characteristics, stress testing protocols, test results, the need for repeat testing, and downstream testing., Methods: All patients who underwent a clinically indicated stress SPECT MPI study as part of their pre-liver transplant evaluation from 2004 to 2014 were reviewed from the Nuclear Cardiology database. Results of perfusion imaging, repeat testing, subsequent angiography, and need for revascularization were reviewed., Results: A total of 2500 patients were referred for SPECT MPI, of those 111 had known CAD and 271 underwent more than one MPI study. Compared to other patients undergoing stress MPI, pre-liver transplant patients were younger, had fewer cardiac risk factors and lower prevalence of prior cardiac history, and used pharmacologic stress more often. During the study decade, patient age increased, prevalence of hypertension increased and smoking decreased, prevalence of known CAD increased, and the number of abnormal studies decreased. Abnormal perfusion results were present in 7.8% of pre-liver transplant patients compared to 34.3% of all other patients. In a multivariate model, age and lower ejection fraction were associated with an abnormal MPI result. Of the 64 patients who underwent subsequent invasive or non-invasive coronary angiography after an abnormal MPI, obstructive CAD was diagnosed in 25 patients (1.0%), non-obstructive CAD was diagnosed in 23 patients (0.9%), and normal coronaries found in 16 patients (0.6%); a total of 18 (0.7%) of these underwent coronary revascularization. The average time to repeat testing was 27.2 ± 17.9 months. In a multivariate model, younger age and exercise stress were associated with repeat testing. In only 17 patients out of 271 with a normal initial perfusion, the repeat study became abnormal. The use of stress-first imaging was successful in 80% of patients with a reduction in Tc-99m dose from 39.1 to 18.3 mCi., Conclusion: Abnormal SPECT MPI results in candidates for liver transplantation are infrequent compared to non-liver transplant patients and the incidence of obstructive CAD on subsequent angiography even less. Repeat testing in those on the transplant waiting list after initial normal test results appears to be of limited value. Stress-first protocols may be considered for the majority of these patients to reduce testing time and radiation exposure.

Objectives: To develop and validate a radiomics-based nomogram for the preoperative prediction of posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC)., Methods: One hundred twelve consecutive HCC patients who underwent hepatectomy were included in the study pool (training cohort: n = 80, validation cohort: n = 32), and another 13 patients were included in a pilot prospective analysis. A total of 713 radiomics features were extracted from portal-phase computed tomography (CT) images. A logistic regression was used to construct a radiomics score (Rad-score). Then a nomogram, including Rad-score and other risk factors, was built with a multivariate logistic regression model. The discrimination, calibration and clinical utility of nomogram were evaluated., Results: The Rad-score could predict PHLF with an AUC of 0.822 (95% CI, 0.726-0.917) in the training cohort and of 0.762 (95% CI, 0.576-0.948) in the validation cohort; however, the approach could not completely outmatch the existing methods (CP [Child-Pugh], MELD [Model of End Stage Liver Disease], ALBI [albumin-bilirubin]). The individual predictive nomogram that included the Rad-score, MELD and performance status (PS) showed better discrimination with an AUC of 0.864 (95% CI, 0.786-0.942), which was higher than the AUCs of the conventional methods (nomogram vs CP, MELD, and ALBI at P < 0.001, P < 0.005, and P < 0.005, respectively). In the validation cohort, the nomogram discrimination was also superior to those of the other three methods (AUC: 0.896; 95% CI, 0.774-1.000). The calibration curves showed good agreement in both cohorts, and the decision curve analysis of the entire cohort revealed that the nomogram was clinically useful. A pilot prospective analysis showed that the radiomics nomogram could predict PHLF with an AUC of 0.833 (95% CI, 0.591-1.000)., Conclusions: A nomogram based on the Rad-score, MELD, and PS can predict PHLF., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In living donor liver transplantation (LDLT), a thorough preoperative evaluation of the donor is imperative to minimize the risk of the donors and improve the outcome of the recipients. In order to select the best candidate, knowledge of the liver volume, degree of steatosis, and anatomic variations in the vascular and biliary system in potential donors is crucial. With recent technical advances, magnetic resonance imaging (MRI) is increasingly replacing the need for computed tomography (CT) examination in essential steps of donor evaluation. Along with the introduction of higher gradient strength, novel pulse sequences, and innovative contrast media, MRI has a potential to serve as an "all-in-one" imaging package. In this review, we provide an overview of clinical and radiologic considerations related to LDLT and highlight the basics and up-to-date knowledge of MRI techniques for a comprehensive donor evaluation. Level of Evidence: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;48:1453-1467., (© 2018 International Society for Magnetic Resonance in Medicine.)

Argininemia is a rare hereditary disease due to a deficiency of hepatic arginase, which is the last enzyme of the urea cycle and hydrolyzes arginine to ornithine and urea. Herein we report a patient with arginase I (ARG1) deficiency who presented with recurrent nonconvulsive status epilepticus and liver failure. A novel homozygous frameshift mutation c.703&#95;707delGGACTinsAGACTGGACC (p.G235Rfs*20) was detected.

Rationale and Objectives: Posthepatectomy liver failure (PHLF) remains challenging to diagnose and difficult to treat. The extent of transient regeneration-associated steatosis (TRAS) differs between successful liver regeneration and PHLF. This study aims to quantify TRAS by magnetic resonance imaging (MRI) after hepatectomy in mice., Materials and Methods: Mice (C57BL/6) underwent either extended hepatectomy (EH) or standard hepatectomy (SH). Serial MRI on postoperative days 1-7 was used to compare TRAS and liver remnant growth between groups. Survival was also assessed., Results: EH was associated with decreased survival and impaired proliferation when compared to SH (p = 0.02 and p = 0.03). MRI showed increased TRAS 48 h after EH compared to SH (11.8 ± 6% vs. 4.3 ± 2%, p < 0.001). Compared to EH survivors, death after EH was associated with increased TRAS 48 h postoperatively (16.4 ± 6% vs. 9.2 ± 5%, p = 0.02)., Conclusions: EH is associated with increased TRAS and inferior outcomes when compared to SH. MRI may help to predict PHLF after hepatectomy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To correlate point-shear wave elastography (SWE) with liver hypertrophy after right portal vein embolization (RPVE) and to determine its usefulness in predicting postoperative liver failure in patients undergoing partial liver resection., Patients and Methods: Point-SWE was performed the day before RPVE in 56 patients (41 men) with a median age of 66 years. The percentage (%) of future remnant liver (FRL) volume increase was defined as: %FRL post -%FRL pre %FRL pre ×100 and assessed on computed tomography performed 4 weeks after RPVE., Results: Median (range) %FRL pre and %FRL post was respectively, 31.5% (12-48%) and 41% (23-61%) (P<0.001), with a median %FRL volume increase of 25.6% (-8; 123%). SWE correlated with %FRL volume increase (P=-0.510; P<0.001). SWV (P=0.003) and %FRL pre (P<0.001) were associated with %FRL volume increase at multivariate regression analysis. Forty-three patients (77%) were operated. Postoperative liver failure occurred in 14 patients (32.5%). Median SWE was different between the group with (1.68m/s) and without liver failure (1.07m/s) (P=0.018). The AUROC of SWE predicting liver failure was 0.724 with a best cut-off of 1.31m/s, corresponding to a sensitivity of 21%, specificity of 96%, positive predictive value 75% and negative predictive value of 72%. SWE was the single independent preoperative variable associated with liver failure., Conclusions: SWE assessed by point-SWE is a simple and useful tool to predict the FRL volume increase and postoperative liver failure in a population of patients with liver tumor., (Copyright © 2018 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: The objective of this study was to assess the accuracy of gadoxetic acid hepatic enhancement indices in predicting posthepatectomy liver failure (PHLF) and other major complications (OMCs)., Methods: Sixty-five patients underwent prehepatectomy gadoxetic acid-enhanced magnetic resonance imaging. Enhancement indices were calculated by obtaining regions of interest on magnetic resonance images and segmented volumes of the liver and spleen. Multivariate regression analysis was performed to predict PHLF and OMC as a function of the indices, and areas under the receiver operator characteristic (AUROC) curves were calculated., Results: Areas under the receiver operator characteristic values varied from 0.412 to 0.681 and 0.462 to 0.738 in predicting PHLF and OMC, respectively. The most accurate indices in predicting PHLF were the region of interest-based, fat-normalized relative liver enhancement and liver enhancement index (AUROC, 0.681). The most accurate index in predicting OMC was the volumetric least-squares regression slope of a pharmacokinetic model (Khep&#95;V, AUROC, 0.738)., Conclusions: Indices of gadoxetic acid liver enhancement demonstrate variable performance in predicting PHLF and OMC.

Background & Aims: To assess the efficacy of functional MR image with volumetric, liver function test and indocyanine green clearance (ICG) in identifying the patients who are at risk of post-hepatectomy liver failure (PHLF)., Methods: We retrospectively included 115 patients undergoing gadoxetic acid-enhanced MR imaging before hepatectomy at one medical centre from January 2013 to December 2015. Contrast enhancement ratio (CER) between transitional and hepatobiliary phases (3 and 30 minutes post-contrast) was calculated. Total liver volume (TLV) and spleen volume (Sp) were measured. Post-operatively, the histological Ishak fibrosis score was collected. Potential risk factors for liver failure were analysed, and the performance was examined by receiver operating characteristic curve., Results: Post-hepatectomy liver failure (PHLF) occurred in 16 patients (13.9%). TLV/SLV, ADC value, CER HBP/TP and total liver contrast enhancement ratio (tCER) were associated with PHLF (P < .05). Between PHLF and non-PHLF groups, remnant liver volume (RLV), RLV/SLV, Sp/RLV, remnant liver contrast enhancement ratio (rCER) and Ishak fibrosis score showed statistical difference. rCER showed superiority in diagnostic performance (AUC = 0.78) with the optimal cut-off value of 1.23., Conclusions: Gadoxetic acid-enhanced MR imaging with volumetric is a reliable method for evaluating functional liver volume and determining the risk of PHLF., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study aimed to monitor the course of liver regeneration by multiparametric magnetic-resonance imaging (MRI) after partial liver resection characterizing Small-for-Size Syndrome (SFSS), which frequently leads to fatal post-hepatectomy liver failure (PLF). Twenty-two C57BL/6 mice underwent either conventional 70% partial hepatectomy (cPH), extended 86% partial hepatectomy (ePH) or SHAM operation. Subsequent MRI scans on days 0, 1, 2, 3, 5 and 7 in a 4.7T MR Scanner quantified longitudinal and transverse relaxation times, apparent diffusion coefficient (ADC) and the magnetization-transfer ratio (MTR) of the regenerating liver parenchyma. Histological examination was performed by hematoxylin-eosin staining. After hepatectomy, an increase of T1 time was detected being larger for ePH on day 1: 18% for cPH vs. 40% for ePH and on day 2: 24% for cPH vs. 49% for ePH. An increase in T2 time, again greater in ePH was most pronounced on day 5: 21% for cPH vs. 41% for ePH. ADC and MTR showed a decrease on day 1: 21% for ePH vs. 13% for cPH for ADC, 15% for ePH vs. 11% for cPH for MTR. Subsequently, all MR parameters converged towards initial values in surviving animals. Dying PLF animals exhibited the strongest increase of T1 relaxation time and most prominent decreases of ADC and MTR. The retrieved MRI biomarkers indicate SFSS and potentially developing PLF at an early stage, likely reflecting cellular hypertrophy with extended water content and concomitantly diluted cellular components as features of liver regeneration, appearing more intense in ePH as compared to cPH.

Purpose: The International Study Group of Liver Surgery (ISGLS) proposed a definition and grading system for posthepatectomy liver failure (PHLF). We evaluated the usefulness of residual liver function estimation using Tc-galactosyl human serum albumin (Tc-GSA) for the prediction of PHLF., Methods: Patients with liver tumors (n = 136) and scheduled for hepatectomy underwent Tc-GSA scintigraphy. Based on their imaging data, the maximal GSA removal rate (GSA-Rmax)was calculated using multicompartment analysis. We also calculated GSA-Rmax in the predicted residual liver (GSA-RL) whose volume was determined on computed tomography (CT) scans. We compared the age, sex, 15-minute indocyanine green retention rate; albumin, bilirubin, hyaluronic acid, and type 4 collagen levels; the Child-Pugh classification; residual liver volume; residual liver percentage; GSA-Rmax; and GSA-RL in patients with and without PHLF. Univariate and multivariate logistic analyses were used for statistical assessments., Results: Of 136 patients, 17 (12.5%) met the ISGLS criteria for PHLF (ISGLS-PHLF). There was a statistically significant difference in the age, albumin level, Child-Pugh classification, residual liver volume, residual liver percentage, GSA-Rmax, and GSA-RL between patients with and without PHLF. Based on multivariate analysis, GSA-RL and the residual liver volume were significant independent predictors of ISGLS-PHLF (P = 0.004 and P = 0.038, respectively). The odds ratio was 149423 for GSA-RL and 1.003 for the residual liver volume., Conclusions: GSA-RL calculated using Tc-GSA scintigraphy was the most useful independent predictor for ISGLS-PHLF.

Objective: The purpose of this study is to investigate the long-term safety and efficacy of a small-diameter expandable transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension., Materials and Methods: This single-center retrospective study included 28 patients (12 women and 16 men; mean age, 56.9 years) who underwent small-diameter expandable TIPS creation between 2008 and 2010 for refractory ascites (n = 15; mean [± SD] model for end-stage liver disease [MELD] score, 15.5 ± 5.3) or gastrointestinal variceal bleeding (n = 13; mean MELD score, 15.2 ± 8.4). An expandable TIPS was created by deploying a covered stent inside a balloon expandable stent. For patients with recurrent symptoms, TIPS adjustment was made by balloon expandable stent balloon dilation. The TIPS diameter was defined as the diameter of the final angioplasty balloon. TIPS patency and efficacy and the rate of post-TIPS hepatic encephalopathy were evaluated., Results: The median diameter of the initial TIPS was 8 mm in the group with variceal bleeding compared with 6 mm in the group with ascites (p = 0.003). The primary patency rate at 1 and 5 years was 90.8% and 73.3%, respectively. Eighty percent of patients with ascites required no or less-frequent large-volume paracentesis. The clinical success rate for patients with acute variceal bleeding was 92.3%. Six patients with ascites (initial TIPS diameter, 6 mm) and two patients with variceal bleeding (initial diameter, 6 mm and 8 mm) required subsequent TIPS adjustment. Of the 22 patients with no prior history of enecphalophy, seven patients (31.8%) experienced new hepatic encephalopathy within 90 days., Conclusion: A small-diameter expandable TIPS is technically feasible and safe, with efficacy falling within the range of that of conventional TIPS. This technique offers the possibility of individualizing the degree of portal decompression.

Objective: Posthepatectomy liver failure (PHLF) is one of the most serious complications after hepatectomy. The objective of the present study is to assess the potential diagnostic ability of 99m Tc-galactosyl human serum albumin (GSA) scintigraphy to predict PHLF as defined by the International Study Group of Liver Surgery (ISGLS)., Materials and Methods: Data from 100 patients who underwent 99m Tc-GSA scintigraphy and subsequent hepatectomy were retrospectively analyzed. The blood clearance ratio (HH15), hepatic uptake ratio (LHL15), and maximal removal rate (Rmax) of 99m Tc-GSA (GSA-Rmax) were calculated as scintigraphic parameters for the total liver. In addition to the ratio of preoperatively estimated remnant liver (ERL) counts to total liver counts (rERL-GSA), the ratio of actual remnant liver (ARL) counts to total liver counts (rARL-GSA), determined by applying a more accurate resection line with reference to both pre- and postoperative CT, was obtained from SPECT images. Functional remnant liver parameters of ERL-LHL15 (LHL15 of the estimated remnant liver), ERL-Rmax (maximal removal rate of estimated remnant liver counts), ARL-LHL15 (LHL15 of the actual remnant liver), and ARL-Rmax (maximal removal rate of actual remnant liver counts) were calculated using these values. ROC analysis was performed to evaluate the ability of these parameters to predict PHLF. Multivariate analysis was performed to identify independent predictors of PHLF., Results: PHLF occurred in 33 patients. Each of the ARL parameters had a significantly higher diagnostic performance compared with the corresponding ERL parameter (AUC values: for rARL-GSA vs rERL-GSA, 0.77 vs 0.62 [p = 0.0004]; for ARL-LHL15 vs ERL-LHL15, 0.79 vs 0.64 [p = 0.0005]; and for ARL-Rmax vs ERL-Rmax, 0.78 vs 0.66 [p = 0.0003]). According to multivariate analysis, each of three ARL parameters was identified as an independent predictor of PHLF (p < 0.0001 for all)., Conclusion: Technetium-99m-labeled GSA scintigraphy is useful for predicting PHLF, particularly for applying an accurate resection line on GSA-SPECT images.

Background: Posthepatectomy liver failure (PHLF) was recently defined with the corresponding recommendations as follows: grade A, no change in clinical management; grade B, clinical management with noninvasive treatment; and grade C, clinical management with invasive treatment. In this study, we identified the risk factors for grade B and C PHLF in patients with hepatocellular carcinoma (HCC)., Methods: Of 339 HCC patients who underwent curative hepatic resection, 218 were included for analysis. The LHL15 index (uptake ratio of the liver to that of the liver and heart at 15 min) was measured by 99m Tc-GSA (99m technetium-labelled galactosyl human serum albumin); remnant LHL15 was calculated as LHL15 × [1 - (resected liver weight - tumor volume)/whole liver volume without tumor]., Results: A total of 163 patients were classified as having no PHLF, whereas 17, 37, and 1 patient had PHLF grade A, B, and C, respectively. There were significant differences in indocyanine green R15, serum albumin, prothrombin time, Child-Pugh classification, LHL15 and remnant LHL15 between patients with grades B/C PHLF and patients with grade A or no PHLF. Only remnant LHL15 was identified as an independent risk factor for grades B/C PHLF (p = 0.023), with a cut-off value of 0.755., Conclusions: Remnant LHL15 was an independent risk factor for grades B/C PHLF. Patients with impaired remnant LHL15 value of <0.755 should be carefully monitored for PHLF., (© 2018 S. Karger AG, Basel.)

Stem-cell-based regenerative medicine holds great promise in clinical practices. However, the fate of stem cells after transplantation, including the distribution, viability, and the cell clearance, is not fully understood, which is critical to understand the process and the underlying mechanism of regeneration for better therapeutic effects. Herein, we develop a dual-labeling strategy to in situ visualize the fate of transplanted stem cells in vivo by combining the exogenous near-infrared fluorescence imaging in the second window (NIR-II) and endogenous red bioluminescence imaging (BLI). The NIR-II fluorescence of Ag 2 S quantum dots is employed to dynamically monitor the trafficking and distribution of all transplanted stem cells in vivo due to its deep tissue penetration and high spatiotemporal resolution, while BLI of red-emitting firefly luciferase (RfLuc) identifies the living stem cells after transplantation in vivo because only the living stem cells express RfLuc. This facile strategy allows for in situ visualization of the dynamic trafficking of stem cells in vivo and the quantitative evaluation of cell translocation and viability with high temporal and spatial resolution, and thus reports the fate of transplanted stem cells and how the living stem cells help, regeneration, for an instance, of a mouse with acute liver failure., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: It is essential to accurately predict Postoperative liver failure (PHLF) which is a life-threatening complication. Liver hardness measurement (LSM) is widely used in non-invasive assessment of liver fibrosis. The aims of this study were to explore the application of preoperative liver stiffness measurements (LSM) by transient elastography in predicting postoperative liver failure (PHLF) in patients with hepatitis B related hepatocellular carcinoma., Methods: The study included 247 consecutive patients with hepatitis B related hepatocellular carcinoma who underwent hepatectomy between May 2015 and September 2015. Detailed preoperative examinations including LSM were performed before hepatectomy. The endpoint was the development of PHLF., Results: All of the patients had chronic hepatitis B defined as the presence of hepatitis B surface antigen (HBsAg) for more than 6 months and 76 (30.8%) had cirrhosis. PHLF occurred in 37 (14.98%) patients. Preoperative LSM (odds ratio, OR, 1.21; 95% confidence interval, 95% CI: 1.13-1.29; P < 0.001) and international normalized ratio (INR) (OR, 1.07; 95% CI: 1.01-1.12; P < 0.05) were revealed to be independent risk factors for PHLF, and a new model was defined as LSM-INR index (LSM-INR index = 0.191*LSM + 6.317*INR-11.154). The optimal cutoff values of LSM and LSM-INR index for predicting PHLF were 14 kPa (AUC 0.86, 95% CI: 0.811-0.901, P < 0.001) and -1.92 (AUC 0.87, 95% CI: 0.822-0.909, P < 0.001), respectively., Conclusions: LSM can be helpful for surgeons to make therapeutic decisions in patients with hepatitis B related hepatocellular carcinoma.

Introduction: Recently, there has been increasing interest in the preoperative prediction and prevention of post-hepatectomy liver failure (PHLF). This is a particular concern in colorectal liver metastases (CRLM), when surgery follows potentially hepatotoxic chemotherapy. Platelet-based liver scores (PBLS) such as APRI and FIB-4 are predictive of chemotherapy-associated liver injury (CALI) and PHLF. Estimation of the future liver remnant function (eFLRF) by combining 99m Tc-Mebrofenin Hepatobiliary Scintigraphy (HBS BSA ) with future liver remnant volume ratio (FLRV%), is predictive of PHLF and related mortality. We hypothesized that a HBS BSA based formula was a better predictor for PHLF than PBLS in chemotherapy-pretreated CRLM., Methods: Between 2012 and 2016, 140 patients underwent liver resection for CRLM following systemic therapy. HBS BSA , FLRV%, eFLRF and PBLS were calculated and compared for their value in predicting PHLF., Results: eFLRF and FLRV% had a better predictive value for PHLF than HBS BSA alone and APRI and FIB-4 (AUC = 0.800, 0.843 versus 0.652, 0.635 and 0.658 respectively). In a subgroup analysis (Oxaliplatin all, Oxaliplatin ≥ 6 cycles, Irinotecan all and Irinotecan ≥ 6 cycles), eFLRF was the only factor predictive for PHLF in all subgroups (all: p ≤ 0.05). Prediction of HBS BSA for chemotherapy associated steato-hepatitis (CASH) reached almost significance (p = 0.06). FIB-4 was predictive for sinusoidal obstruction syndrome (SOS) (p = 0.011). Only weak correlation was found between HBS BSA and PBLS., Conclusion: eFLRF is a better predictor of PHLF than PBLS or HBS BSA alone. PBLS seem to measure other aspects of liver function or damage than HBS BSA ., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces a rapid and extensive increase in liver volume. The functional quality of this hypertrophic response has been called into question because ALPPS is associated with a substantial incidence of liver failure and high perioperative mortality. This multicenter study aimed to evaluate functional liver regeneration in contrast to volumetric liver regeneration in ALPPS, using technetium-99m hepatobiliary scintigraphy and computed tomography volumetry, respectively., Methods: Patients who underwent ALPPS and hepatobiliary scintigraphy in 6 centers were included. Hepatobiliary scintigraphy data were analyzed centrally at the Academic Medical Center in Amsterdam according to established protocols. Increase in liver function as measured by hepatobiliary scintigraphy after stage 1 of ALPPS was compared with the increase in liver volume. In addition, we analyzed the impact of liver function and volume on postoperative outcomes including liver failure, morbidity, and mortality., Results: In 60 patients, future liver remnant volume increased by a median 78% (interquartile range 48-110) during a median 8 (interquartile range 6-14) days after stage 1, while function as measured by hepatobiliary scintigraphy increased by a median 29% (interquartile range 1-55) throughout 7 days (interquartile range 6-10) in the 27 patients with paired measurements. After stage 2 of ALPPS, liver failure occurred in 5/60 (8%) patients, severe complications in 24/60 (40%), and mortality occurred in 4/60 (7%)., Conclusion: In ALPPS, volumetry overestimates liver function as measured by hepatobiliary scintigraphy and may be responsible for the high rate of liver failure. Quantitative liver function tests are highly recommended to avoid post hepatectomy liver failure., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To determine whether a combination of clinical factors, the future liver remnant (FLR) ratio, and hepatic uptake of gadoxetic acid can be used to predict post-hepatectomy liver failure (PHLF) and other major complications (OMC)., Materials and Methods: Sixty-five consecutive patients who underwent pre-hepatectomy gadoxetic acid-enhanced magnetic resonance imaging (MRI) between October 2010 and December 2013 were included. The relative liver enhancement (RLE) of gadoxetic acid was calculated from regions of interest on MRI, and FLR ratios were obtained from computed tomography (CT). PHLF and OMC were defined by the International Study Group of Liver Surgery criteria and Clavien-Dindo grade of ≥3, respectively. Multivariate logistic regression modelling was performed to identify predictors of PHLF and OMC, including RLE, FLR ratio, age, sex, chemotherapy history, intra-operative blood loss, and intra-operative transfusion., Results: Nine patients experienced PHLF and another nine patients experienced OMC. RLE was comparable to the FLR ratio in predicting PHLF (areas under the receiver operating characteristic [AUROC] curves, 0.665 and 0.705), but performed poorly in predicting OMCs (AUROCs, 0.556 and 0.702). Combining all clinical and imaging parameters as predictors yielded the best performing predictive models (AUROCs, 0.875 and 0.742 for PHLF and OMC, respectively)., Conclusion: A model based on clinical parameters, the FLR ratio, and RLE of gadoxetic acid may improve pre-hepatectomy risk assessment., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate prognostic value of hepatic stiffness (HS) measurement using MR elastography (MRE) in patients with hepatocellular carcinoma (HCC) treated by hepatic resection (HR)., Methods: We enrolled 144 patients with Barcelona Clinic Liver Cancer stage A HCCs initially treated by HR who underwent preoperative liver MRE between January 2010 and June 2013. HS values were measured using MRE. Receiver operating characteristics (ROC) and multivariate logistic regression analyses were used to determine significant predictive factors for posthepatecomy liver failure (PHLF). Overall survival (OS) was analyzed by evaluating prognostic factors using the Kaplan-Meier method and Cox proportional hazard regression model., Results: After HR, 43 patients (29.9 %) experienced PHLF. HS values were significant predictive factors for PHLF. In ROC analysis, the area under the curve of HS was 0.740 (P = 0.001) for PHLF. Thirty-one patients had HS values ≥ 4.02 kPa; the estimated 1, 3, 5-year survival were 90.0 %, 74.7 % and 65.4 %, respectively, versus 98.1 %, 96.5 % and 96.5 % in 113 patients with HS values < 4.02 kPa (P = 0.015). An HS value ≥ 4.02 kPa was the only significant affecting factor for OS., Conclusion: HS values measured by MRE could predict PHLF development post-HR. Furthermore, an HS value ≥4.02 kPa was a significant predicting factor for poor OS post-HR., Key Points: • Hepatic stiffness value was a predictive factor for developing posthepatectomy liver failure • Hepatic stiffness value was a significant affecting factor for OS • Hepatic stiffness value ≥ 4.02 kPa was a predictive factor for poor OS.

Background and Aim: Liver stiffness measurement using transient elastography appears to be an excellent tool for detection of liver fibrosis and cirrhosis with high accuracy. The aim of this study is to evaluate the efficacy of preoperative liver stiffness measurement in predicting post-hepatectomy liver failure., Methods: A prospective cohort study of all consecutive patients undergoing hepatectomy for hepatocellular carcinoma from February 2010 to August 2014 was studied. All patients received detailed preoperative assessments including liver stiffness measurement. The primary outcome was post-hepatectomy liver failure according to the International Study Group of Liver Surgery definition., Results: A total of 255 patients were included. Liver stiffness measurement showed significant correlation with grade B or C post-hepatectomy liver failure. (P = 0.003) Using the cutoff at 12 kPa, liver stiffness measurement had a sensitivity of 52.4% and specificity of 73.3% in predication of high-grade (grade B or C) post-hepatectomy liver failure. Liver stiffness measurement > 12 kPa was also an independent prognostic factor for both high-grade post-hepatectomy liver failure and major postoperative complications by multivariate analysis. The diagnostic accuracy was better in patients without right lobe tumor with an area under the receiver operating characteristic of 0.83 compared with an area under the receiver operating characteristic of only 0.62 in patients with right lobe tumor., Conclusions: Liver stiffness measurement using Fibroscan is good to predict high-grade post-hepatectomy liver failure especially in patients without right lobe tumor., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)