Multi-organ Radiomics-Based Prediction of Future Remnant Liver Hypertrophy Following Portal Vein Embolization.

BACKGROUND: Portal vein embolization (PVE) is used to induce remnant liver hypertrophy prior to major hepatectomy. The purpose of this study was to evaluate the predictive value of baseline computed tomography (CT) data for future remnant liver (FRL) hypertrophy after PVE. METHODS: In this retrospective study, all consecutive patients undergoing right-sided PVE with or without hepatic vein embolization between 2018 and 2021 were included. CT volumetry was performed before and after PVE to assess standardized FRL volume (sFRLV). Radiomic features were extracted from baseline CT after segmenting liver (without tumor), spleen and bone marrow. For selecting features that allow classification of response (hypertrophy ≥ 1.33), a stepwise dimension reduction was performed. Logistic regression models were fitted and selected features were tested for their predictive value. Decision curve analysis was performed on the test dataset. RESULTS: A total of 53 patients with liver tumor were included in this study. sFRLV increased significantly after PVE, with a mean hypertrophy of FRL of 1.5 ± 0.3-fold. sFRLV hypertrophy ≥ 1.33 was reached in 35 (66%) patients. Three independent radiomic features, i.e. liver-, spleen- and bone marrow-associated, differentiated well between responders and non-responders. A logistic regression model revealed the highest accuracy (area under the curve 0.875) for the prediction of response, with sensitivity of 1.0 and specificity of 0.5. Decision curve analysis revealed a positive net benefit when applying the model. CONCLUSIONS: This proof-of-concept study provides first evidence of a potential predictive value of baseline multi-organ radiomics CT data for FRL hypertrophy after PVE.

Sequential Y90 liver radioembolization and portal vein embolization: an additional strategy to downstage liver tumors and to enhance liver hypertrophy before major hepatectomies.

BACKGROUND: Yttrium (Y)90 liver radioembolization (TARE) induces both tumor downsizing and contralateral liver hypertrophy. In this study, we report the preliminary results of a sequential strategy combining Y90 radioembolization and portal vein embolization (PVE) before major right liver resections. METHODS: We retrospectively reviewed clinical, radiological, and biological data of 5 consecutive patients undergoing Y90 TARE-PVE before major right liver resections. Comparison was made with patients undergoing PVE alone or liver venous deprivation (LVD) during the same period. RESULTS: Between January 2019 and September 2022, five patients underwent sequential TARE-PVE. Type of resection included the following: right hepatectomy (n = 1), right hepatectomy + 1 (n = 2), and right hepatectomy + 1 + 4 (n = 2) with no postoperative mortality. Volumetric data showed a mean hypertrophy ratio of 30.4% after TARE and an additional 37.4% after sequential PVE. Patients undergoing sequential TARE-PVE had higher hypertrophy ratio (p = 0.02; p = 0.004), hypertrophy degree (p = 0.02; p < 0.0001), shorter time to normalize bilirubin (p = 0.04), and prothrombin time (p = 0.003; p < 0.0001) compared with patients receiving LVD or PVE. Time from diagnosis to surgery was statistically significant longer in patients undergoing sequential TARE-PVE compared with LVD or PVE (293.4 ± 169.1 vs 54.18 ±18.26 vs 58.62±13.15; p = 0.0008; p = <0.0001). CONCLUSIONS: This preliminary report suggests that sequential PVE and TARE can represent a safe and an alternative strategy to downstage liver tumors and to enhance liver hypertrophy before major hepatectomies. When compared with PVE and LVD, sequential TARE/PVE takes longer times but achieves some advantages which warrant further evaluation in a larger setting.

Systematic Reviews and Meta-Analyses of Portal Vein Embolization, Associated Liver Partition and Portal Vein Ligation, and Radiation Lobectomy Outcomes in Hepatocellular Carcinoma Patients.

PURPOSE OF REVIEW: To understand portal vein embolization (PVE), associated liver partition and portal vein ligation (ALPPS) and radiation lobectomy (RL) outcomes in hepatocellular carcinoma (HCC) patients. Systematic reviews of future liver remnant (FLR) percent hypertrophy, proportion undergoing hepatectomy and proportion with major complications following PVE, ALPPS, and RL were performed by searching Ovid MEDLINE, Ovid EMBASE, The Cochrane Library, and Web of Science. Separate meta-analyses using random-effects models with assessment of study heterogeneity and publication bias were performed whenever allowable by available data. RECENT FINDINGS: Of the 10,616 articles screened, 21 articles with 636 subjects, 4 articles with 65 subjects, and 4 articles with 195 subjects met the inclusion criteria for systematic reviews and meta-analyses for PVE, ALPPS, and RL, respectively. The pooled estimate of mean percent FLR hypertrophy was 30.9% (95%CI: 22-39%, Q = 4034.8, p < 0.0001) over 40.3 +/- 26.3 days for PVE, 54.9% (95%CI: 36-74%, Q = 73.8, p < 0.0001) over 11.1 +/- 3.1 days for ALPPS, and 29.0% (95%CI: 23-35%, Q = 56.2, p < 0.0001) over 138.5 +/- 56.5 days for RL. The pooled proportion undergoing hepatectomy was 91% (95%CI: 83-95%, Q = 43.9, p = 0.002) following PVE and 98% (95%CI: 50-100%, Q = 0.0, p = 1.0) following ALPPS. The pooled proportion with major complications was 5% (95%CI: 2-10%, Q = 7.3, p = 0.887) following PVE and 38% (95%CI: 18-63%, Q = 10.0, p = 0.019) following ALPPS. Though liver hypertrophy occurs following all three treatments in HCC patients, PVE balances effective hypertrophy with a short time frame and low major complication rate.

Laparoscopic portal branch ligation of the right caudate lobe concomitant with portal vein embolization for planned right hemihepatectomy in advanced hepatobiliary cancers.

BACKGROUND: The role of ligation of the portal venous branches to the caudate lobe (cPVL) as preparation for planned major hepatectomy is unclear. The aim of this study was to evaluate the efficacy of laparoscopic cPVL (Lap-cPVL) concomitant with transileocolic portal vein embolization of the right portal venous system (rTIPE), namely, Lap-cPVL/rTIPE, for planned right hemihepatectomy (rHx) in advanced hepatobiliary cancer patients. METHODS: Thirty-one patients who underwent rHx after rTIPE with/without Lap-cPVL between March 2013 and March 2020 were enrolled in this study. The Lap-cPVL was performed for the portal branches of the right caudate lobe. RESULTS: Eight of the 31 patients underwent Lap-cPVL/rTIPE. The degree of hypertrophy was significantly increased in Lap-cPVL/rTIPE (19.3%, range 6.5-25.6%) as compared to rTIPE (7.2%, range - 1.1 to 21.2%) (p=0.027). The functional kinetic growth rate was also significantly increased in Lap-cPVL/rTIPE (5.40%, range 2.17-5.97) than that in rTIPE (1.85%, range - 0.22 to 6.45%) (p=0.046). Postoperative liver failure ≧ grade B occurred in 21.7% of patients in rTIPE, while there was no postoperative liver failure ≧ grade B in Lap-cPVL/rTIPE. Mortality rates were zero after rHx in this study. CONCLUSIONS: Lap-cPVL/rTIPE is safe and provides an additional effect on liver hypertrophy in advanced hepatobiliary cancers.

In situ split plus portal vein ligation (ISLT) - a salvage procedure following inefficient portal vein embolization to gain adequate future liver remnant volume prior to extended liver resection.

BACKGROUND: Right extended liver resection is frequently required to achieve tumor-free margins. Portal venous embolization (PVE) of the prospective resected hepatic segments for conditioning segments II/III does not always induce adequate hypertrophy in segments II and III (future liver remnant volume (FLRV)) for extended right-resection. Here, we present the technique of in situ split dissection along segments II/III plus portal disruption to segments IV-VIII (ISLT) as a salvage procedure to overcome inadequate gain of FLRV after PVE. METHODS: In eight patients, FLRV was further pre-conditioned following failed PVE prior to hepatectomy (ISLT-group). We compared FLRV changes in the ISLT group with patients receiving extended right hepatectomy following sufficient PVE (PVEres-group). Survival of the ISLT-group was compared to PVEres patients and PVE patients with insufficient FLRV gain or tumor progress who did not receive further surgery (PVEnores-group). RESULTS: Patient characteristics and surgical outcome were comparable in both groups. The mean FLRV-to-body-weight ratio in the ISLT group was smaller than in the PVEres-group pre- and post-PVE. One intraoperative mortality due to a coronary infarction was observed for an ISLT patient. ISLT was successfully completed in the remaining seven ISLT patients. Liver function and 2-year survival of ~ 50% was comparable to patients with extended right hepatectomy after efficient PVE. Patients who received a PVE but who were not subsequently resected (PVEnores) demonstrated no survival beyond 4 months. CONCLUSION: Despite extended embolization of segments I and IV-VIII, ISLT should be considered if hypertrophy was not adequate. Liver function and overall survival after ISLT was comparable to patients with trisectionectomy after efficient PVE.

Reg3α and Reg3ß Expressions Followed by JAK2/STAT3 Activation Play a Pivotal Role in the Acceleration of Liver Hypertrophy in a Rat ALPPS Model.

To explore the underlying mechanism of rapid liver hypertrophy by liver partition in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), liver partition at different sites was investigated. Increased inflammatory cytokines owing to the liver partition have been reportedly responsible. If this were true, rapid liver hypertrophy should be achieved regardless of where the liver was split. A male Sprague-Dawley rat model was created, in which a liver split was placed inside the portal vein ligated lobe (PiLL), in addition to the ALPPS and portal vein ligation (PVL) models. Liver regeneration rate, inflammatory cytokine levels, activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and expressions of regenerating islet-derived (Reg)3α and Reg3ß were investigated. The liver regeneration rate was significantly higher in the ALPPS group than in the PiLL group, whereas inflammatory cytokine levels were nearly equal. Additional volume increase in ALPPS group over PVL and PiLL groups was JAK2/STAT3-dependent. Reg3α and Reg3ß expressions were observed only in the ALPPS group. An increase in inflammatory cytokines was not enough to describe the mechanism of rapid liver hypertrophy in ALPPS. Expressions of Reg3α and Reg3ß could play an important role in conjunction with an activation of the JAK2/STAT3 pathway.

Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma.

PURPOSE: This study aimed at identifying prior therapy dosimetric parameters using 99mTc-labeled macro-aggregates of albumin (MAA) that are associated with contralateral hepatic hypertrophy occurring after unilobar radioembolization of hepatocellular carcinoma (HCC) performed with 90Y-loaded glass microspheres. METHODS: The dosimetry data of 73 HCC patients were collected prior to the treatment with 90Y-loaded microspheres for unilateral disease. The injected liver dose (ILD), the tumor dose (TD) and healthy injected liver dose (HILD) were calculated based on MAA quantification. Following treatment, the maximal hypertrophy (MHT) of an untreated lobe was calculated. RESULTS: Mean MHT was 35.4 ± 40.4%. When using continuous variables, the MHT was not correlated with any tested variable, i.e., injected activity, ILD, HILD or TD except with a percentage of future remnant liver (FRL) following the 90Y-microspheres injection  (r = -0.56). MHT ≥ 10% was significantly more frequent for patients with HILD ≥ 88 Gy, (52% of the cases), i.e., in 92.2% versus 65.7% for HILD < 88 Gy (p = 0.032). MHT ≥ 10% was also significantly more frequent for patients with a TD ≥ 205 Gy and a tumor volume (VT) ≥ 100 cm3 in patients with initial FRL < 50%. MHT ≥10% was seen in 83.9% for patients with either an HILD ≥ 88 Gy or a TD ≥ 205 Gy for tumors larger than 100cm3 (85% of the cases), versus only 54.5% (p = 0.0265) for patients with none of those parameters. MHT ≥10% was also associated with FRL and the Child-Pugh score. Using multivariate analysis, the Child-Pugh score (p < 0.0001), FRL (p = 0.0023) and HILD (p = 0.0029) were still significantly associated with MHT ≥10%. CONCLUSION: This study demonstrates for the first time that HILD is significantly associated with liver hypertrophy. There is also an impact of high tumor doses in large lesions in one subgroup of patients. Larger prospective studies evaluating the MAA dosimetric parameters have to be conducted to confirm these promising results.

Portal Vein Embolization: Correlation of Future Liver Remnant Hypertrophy to Type of Embolic Agent Used.

PURPOSE: The purpose of this study was to compare the effectiveness of portal vein embolization (PVE) with different embolic agents used at our centre. Specifically, the effectiveness of N-butyl cyanoacrylate (NBCA) glue is compared with that of polyvinyl alcohol (PVA) particles. METHODS: We performed a retrospective chart review of all patients (N = 77) who underwent PVE at our institution over a 5-year period. Pre- and postprocedural computed tomography or magnetic resonance imaging, when available, were used to measure the volume of total liver volume and future liver remnant (FLR). The absolute values obtained were used to calculate percentage of FLR. The growth in FLR was determined 4-6 weeks after PVE. Technical details of the procedure including the type and amount of embolic agent used were obtained from the chart reviews, electronic patient records, and radiology reports. Statistical analysis was performed using Kruskal-Wallis test, Wilcoxon rank sum test, and the Spearman correlation coefficient with post hoc analysis. Results are expressed as mean ± SD (P < .05 considered statistically significant). RESULTS: NBCA (n = 29) produced a mean change in FLR of 14.8% compared with 9.3% for PVA particles (n = 24; P = .007). Mean change in FLR was 10.1% in the group where a combination of NBCA and PVA particles was used (n = 24). The effect of glue volume and glue-to-lipiodol ratio on the outcome was not found to be statistically significant (P = .5 and .7, respectively). CONCLUSIONS: We conclude that NBCA glue is a better embolic agent than PVA particles in inducing liver hypertrophy.

Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment.

Activation of nuclear receptor CAR by an environmental pollutant perfluorooctanoic acid.

Perfluorocarboxylic acids (PFCAs) including perfluorooctanoic acid (PFOA) are environmental pollutants showing high accumulation, thermochemical stability and hepatocarcinogenicity. Peroxisome proliferator-activated receptor α is suggested to mediate their toxicities, but the precise mechanism remains unclear. Previous reports also imply a possible role of constitutive androstane receptor (CAR), a key transcription factor for the xenobiotic-induced expression of various genes involved in drug metabolism and disposition as well as hepatocarcinogenesis. Therefore, we have investigated whether PFCAs activate CAR. In wild-type but not Car-null mice, mRNA levels of Cyp2b10, a CAR target gene, were increased by PFOA treatment. PFCA treatment induced the nuclear translocation of CAR in mouse livers. Since CAR activators are divided into two types, ligand-type activators and phenobarbital-like indirect activators, we investigated whether PFCAs are CAR ligands or not using the cell-based reporter gene assay that can detect CAR ligands but not indirect activators. As results, neither PFCAs nor phenobarbital increased reporter activities. Interestingly, in mouse hepatocytes, pretreatment with the protein phosphatase inhibitor okadaic acid prevented an increase in Cyp2b10 mRNA levels induced by phenobarbital as reported, but not that by PFOA. Finally, in human hepatocyte-like HepaRG cells, PFOA treatment increased mRNA levels of CYP2B6, a CAR target gene, as did phenobarbital. Taken together, our present results suggest that PFCAs including PFOA are indirect activators of mouse and human CAR and that the mechanism might be different from that for phenobarbital. The results imply a role of CAR in the hepatotoxicity of PFCAs.

Radioembolization of hepatocellular carcinoma activates liver regeneration, induces inflammation and endothelial stress and activates coagulation.

BACKGROUND & AIMS: Radioembolization may rarely induce liver disease resulting in a syndrome that is similar to veno-occlusive disease complicating bone marrow transplantation where inflammation, endothelial cell activation and thrombosis are likely involved. We hypothesized that similar mechanisms could be implicated in radioembolization-induced liver disease (REILD). Moreover, lobar radioembolization may induce hypertrophy of the non-treated hemiliver most probably by inducing liver regeneration. METHODS: In patients with hepatocellular carcinoma, we prospectively studied serum levels of markers of liver regeneration, oxidative stress, pro-inflammatory pathways, endothelial activation and coagulation parameters over 2 months after radioembolization. RESULTS: Although REILD did not occur among 14 treated patients, a decrease in effective liver blood flow was observed. Radioembolization was followed by a persistent increase in pro-inflammatory (interleukin 6 and 8) and oxidative stress (malondyaldehide) markers, an induction of endothelial injury markers (vW factor and PAI-1) and an activation of the coagulation cascade (factor VIII, PAI-1, D-Dimer) as well as a significant increase in factors related to liver regeneration (FGF-19 and HGF). CONCLUSION: Radioembolization activates liver regeneration, produces oxidative stress, activates inflammatory cytokines and induces endothelial injury with partial activation of the coagulation cascade. These findings may have implications in the pathogenesis, prevention and therapy of REILD and in the development of new therapies to enhance hypertrophy with a surgical perspective.

Present status and future perspectives of ALPPS (associating liver partition and portal vein ligation for staged hepatectomy).

First International Consensus Meeting, Hamburg, Germany, 27-28 February 2015 More than 160 participants took part in the conference for 2 days. A total of 58 world renown experts on ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) were invited from all over the world. The faculty was divided into many different subgroups that were in contact during the 2-3 months before the conference analyzing all the most important aspects of this technique and summarizing it in a common structured work to be presented during the congress, giving final recommendations in the form of bulleted point statements. The aim was to gain a solid basis of preliminary agreement on many controversial aspects of ALPPS. A poster area was also organized with 35 posters reporting mostly mono-institutional experiences on single aspects of the technique from all five continents.

Small animal magnetic resonance imaging: an efficient tool to assess liver volume and intrahepatic vascular anatomy.

BACKGROUND: To develop a noninvasive technique to assess liver volumetry and intrahepatic portal vein anatomy in a mouse model of liver regeneration. MATERIALS AND METHODS: Fifty-two C57BL/6 male mice underwent magnetic resonance imaging (MRI) of the liver using a 4.7 T small animal MRI system after no treatment, 70% partial hepatectomy (PH), or selective portal vein embolization. The protocol consisted of the following sequences: three-dimensional-encoded spoiled gradient-echo sequence (repetition time per echo time 15 per 2.7 ms, flip angle 20°) for volumetry, and two-dimensional-encoded time-of-flight angiography sequence (repetition time per echo time 18 per 6.4 ms, flip angle 80°) for vessel visualization. Liver volume and portal vein segmentation was performed using a dedicated postprocessing software. In animals with portal vein embolization, portography served as reference standard. True liver volume was measured after sacrificing the animals. Measurements were carried out by two independent observers with subsequent analysis by the Cohen κ-test for interobserver agreement. RESULTS: MRI liver volumetry highly correlated with the true liver volume measurement using a conventional method in both the untreated liver and the liver remnant after 70% PH with a high interobserver correlation coefficient of 0.94 (95% confidence interval, 0.80-0.98 for untreated liver [P < 0.001] and 0.90-0.97 after 70% PH [P < 0.001]). The diagnostic accuracy of magnetic resonance angiography for the occlusion of one branch of the portal vein was 0.95 (95% confidence interval, 0.84-1). The level of agreement between the two observers for the description of intrahepatic vascular anatomy was excellent (Cohen κ value = 0.925). CONCLUSIONS: This protocol may be used for noninvasive liver volumetry and visualization of portal vein anatomy in mice. It will serve the dynamic study of new strategies to enhance liver regeneration in vivo.

Anatomical Quantitative Volumetric Evaluation of Liver Segments in Hepatocellular Carcinoma Patients Treated with Selective Internal Radiation Therapy: Key Parameters Influencing Untreated Liver Hypertrophy.

Background: Factors affecting morphological changes in the liver following selective internal radiation therapy (SIRT) are unclear, and the available literature focuses on non-anatomical volumetric assessment techniques in a lobar treatment setting. This study aimed to investigate quantitative changes in the liver post-SIRT using an anatomical volumetric approach in hepatocellular carcinoma (HCC) patients with different levels of treatment selectivity and evaluate the parameters affecting those changes. This retrospective, single-institution, IRB-approved study included 88 HCC patients. Whole liver, liver segments, tumor burden, and spleen volumes were quantified on MRI at baseline and 3/6/12 months post-SIRT using a segmentation-based 3D software relying on liver vascular anatomy. Treatment characteristics, longitudinal clinical/laboratory, and imaging data were analyzed. The Student's t-test and Wilcoxon test evaluated volumetric parameters evolution. Spearman correlation was used to assess the association between variables. Uni/multivariate analyses investigated factors influencing untreated liver volume (uLV) increase. Results: Most patients were cirrhotic (92%) men (86%) with Child-Pugh A (84%). Absolute and relative uLV kept increasing at 3/6/12 months post-SIRT vs. baseline (all, p ≤ 0.005) and was maximal during the first 6 months. Absolute uLV increase was greater in Child-Pugh A5/A6 vs. ≥B7 at 3 months (A5, p = 0.004; A6, p = 0.007) and 6 months (A5, p = 0.072; A6, p = 0.031) vs. baseline. When the Child-Pugh class worsened at 3 or 6 months post-SIRT, uLV did not change significantly, whereas it increased at 3/6/12 months vs. baseline (all p ≤ 0.015) when liver function remained stable. The Child-Pugh score was inversely correlated with absolute and relative uLV increase at 3 months (rho = -0.21, p = 0.047; rho = -0.229, p = 0.048). In multivariate analysis, uLV increase was influenced at 3 months by younger age (p = 0.013), administered 90Y activity (p = 0.003), and baseline spleen volume (p = 0.023). At 6 months, uLV increase was impacted by younger age (p = 0.006), whereas treatment with glass microspheres (vs. resin) demonstrated a clear trend towards better hypertrophy (f = 3.833, p = 0.058). The amount (percentage) of treated liver strongly impacted the relative uLV increase at 3/6/12 months (all f ≥ 8.407, p ≤ 0.01). Conclusion: Liver function (preserved baseline and stable post-SIRT) favored uLV hypertrophy. Younger patients, smaller baseline spleen volume, higher administered 90Y activity, and a larger amount of treated liver were associated with a higher degree of untreated liver hypertrophy. These factors should be considered in surgical candidates undergoing neoadjuvant SIRT.

Current Perspectives and Progress in Preoperative Portal Vein Embolization with Stem Cell Augmentation (PVESA).

Portal vein embolization with stem cell augmentation (PVESA) is an emerging approach for enhancing the growth of the liver segment that will remain after surgery (i.e., future liver remnant, FLR) in patients with liver cancer. Conventional portal vein embolization (PVE) aims to induce preoperative FLR growth, but it has a risk of failure in patients with underlying liver dysfunction and comorbid illnesses. PVESA combines PVE with stem cell therapy to potentially improve FLR size and function more effectively and efficiently. Various types of stem cells can help improve liver growth by secreting paracrine signals for hepatocyte growth or by transforming into hepatocytes. Mesenchymal stem cells (MSCs), unrestricted somatic stem cells, and small hepatocyte-like progenitor cells have been used to augment liver growth in preclinical animal models, while clinical studies have demonstrated the benefit of CD133 + bone marrow-derived MSCs and hematopoietic stem cells. These investigations have shown that PVESA is generally safe and enhances liver growth after PVE. However, optimizing the selection, collection, and application of stem cells remains crucial to maximize benefits and minimize risks. Additionally, advanced stem cell technologies, such as priming, genetic modification, and extracellular vesicle-based therapy, that could further enhance efficacy outcomes should be evaluated. Despite its potential, PVESA requires more investigations, particularly mechanistic studies that involve orthotopic animal models of liver cancer with concomitant liver injury as well as larger human trials.

Different pathways of constitutive androstane receptor-mediated liver hypertrophy and hepatocarcinogenesis in mice treated with piperonyl butoxide or decabromodiphenyl ether.

The constitutive androstane receptor (CAR) is essential for Cyp2b induction, liver hypertrophy, and hepatocarcinogenesis in response to phenobarbital (PB). Liver hypertrophy with Cyp2b induction is a major mode of action of hepatocarcinogenesis in rodents. However, it remains unclear whether CAR is involved in the response to many other nongenotoxic hepatocarcinogens besides PB. In this study, we investigated CAR involvement in liver hypertrophy and hepatocarcinogenesis of Cyp2b-inducing nongenotoxic hepatocarcinogens, piperonyl butoxide (PBO), and decabromodiphenyl ether (DBDE), using wild-type and CAR knockout (CARKO) male mice. PB was used as the positive control. In the wild-type mice, 4-week treatment with PBO, DBDE, or PB induced hepatocellular hypertrophy with increased Cyp2b10 messenger RNA and Cyp2b protein expression. In CARKO mice, only PBO showed liver hypertrophy with Cyp2b10 and Cyp3a11 induction. After 27-week treatment following diethylnitrosamine initiation, PBO and PB generated many eosinophilic altered foci/adenomas in wild-type mice; however, the lesions were far less frequent in CARKO mice. DBDE increased the multiplicity of basophilic altered foci/adenomas in wild-type and CARKO mice. Our findings indicate that murine CAR plays major roles in hepatocarcinogenesis but not in liver hypertrophy of PBO. DBDE may act via CAR-independent pathways during hepatocarcinogenesis.

Significance of Skeletal Muscle Loss in Liver Hypertrophy in Patients Undergoing Portal Vein Embolization Before Major Hepatectomy: Assessment With Body Composition and Nutritional Indicators.

BACKGROUND/AIM: The relationship between body composition including skeletal muscle and liver hypertrophy initiated by portal vein embolization (PVE) for major hepatectomy has not been clarified. This study aimed to investigate the effects of skeletal muscle, body adipose, and nutritional indicators on liver hypertrophy. PATIENTS AND METHODS: Fifty-nine patients who underwent PVE scheduled for major right-sided hepatectomy were included. The skeletal muscle area of L3 as skeletal muscle index was calculated. The relationship between skeletal muscle loss and clinical variables was assessed. We also evaluated the relationship between >30% liver growth or >12% liver growth/week after PVE. RESULTS: Skeletal muscle loss was observed in 39 patients (66.1%) and associated with zinc deficiency, visceral adipose index, liver growth rate, and liver growth rate/week. Multivariate analysis indicated that future liver volume and skeletal muscle index were associated with >30% liver growth, and functional future liver volume and skeletal muscle index were associated with >12% liver growth/week. CONCLUSION: Loss of skeletal muscle, and a small future remnant liver volume, attenuates liver hypertrophy initiated by PVE. Strength building and nutritional supplementation may have positive effects on liver hypertrophy after PVE.

Portal Vein Embolization: Rationale, Techniques, and Outcomes to Maximize Remnant Liver Hypertrophy with a Focus on Contemporary Strategies.

Hepatectomy remains the gold standard for curative therapy for patients with limited primary or metastatic hepatic tumors as it offers the best survival rates. In recent years, the indication for partial hepatectomy has evolved away from what will be removed from the patient to the volume and function of the future liver remnant (FLR), i.e., what will remain. With this regard, liver regeneration strategies have become paramount in transforming patients who previously had poor prognoses into ones who, after major hepatic resection with negative margins, have had their risk of post-hepatectomy liver failure minimized. Preoperative portal vein embolization (PVE) via the purposeful occlusion of select portal vein branches to promote contralateral hepatic lobar hypertrophy has become the accepted standard for liver regeneration. Advances in embolic materials, selection of treatment approaches, and PVE with hepatic venous deprivation or concurrent transcatheter arterial embolization/radioembolization are all active areas of research. To date, the optimal combination of embolic material to maximize FLR growth is not yet known. Knowledge of hepatic segmentation and portal venous anatomy is essential before performing PVE. In addition, the indications for PVE, the methods for assessing hepatic lobar hypertrophy, and the possible complications of PVE need to be fully understood before undertaking the procedure. The goal of this article is to discuss the rationale, indications, techniques, and outcomes of PVE before major hepatectomy.

Partial liver irradiation in rats induces the hypertrophy of nonirradiated liver lobes through hepatocyte proliferation†.

Irradiation of the liver induces a regenerative response in the nonirradiated part of the liver. It is unclear whether this leads to actual liver enlargement. The aim of this study was to evaluate the weight of compensatory hypertrophy that occurs in nonirradiated livers and to clarify the mechanism of hypertrophy from the viewpoint of hepatocyte proliferation. The anterior liver lobes (anterior lobes) were irradiated with 60 Gy of X-rays (X60 Gy) under opening laparotomy. Body weights and liver lobe weights were measured before and at 1, 4, 8 and 12 weeks after irradiation, and serum and liver tissue samples were analyzed at each time point. The anterior lobes atrophied progressively, whereas the posterior liver lobes (posterior lobes) hypertrophied in the X-ray irradiated (X-irradiated) group. Although temporary liver damage was observed after irradiation, liver function did not decrease at any time point. Hepatocyte degeneration and loss were observed in the anterior lobes of the X-irradiated group, and significant fibrosis developed 8 weeks postirradiation. Following irradiation, the proportion of Ki-67-positive cells in the anterior lobes decreased markedly in the early postirradiation period, whereas the proportion of positive cells in the posterior lobes increased, peaking at 4 weeks postirradiation (P < 0.05). Increased tumor necrosis factor-α expression was observed only in the anterior liver lobes of the X-irradiated group at 1 and 4 weeks postirradiation. Partial liver irradiation with X60 Gy induced compensatory hypertrophy of nonirradiated liver lobes. This study suggests that liver hypertrophy after partial liver irradiation is caused by increased hepatocyte mitosis.

Safety and Efficacy of Liver Venous Deprivation Following Transarterial Chemoembolization Before Major Hepatectomy for Hepatocellular Carcinoma.

Objective: This study aimed to evaluate the safety and efficacy of liver venous deprivation (LVD) following transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Methods: Between January 2021 and December 2022, HCC patients indicated for hepatectomy with initial insufficient future liver remnant (FLR) underwent LVD after TACE to induce preoperative liver hypertrophy. Results: Twenty-seven HCC patients with a median age of 55 years underwent LVD. No TACE or LVD procedure-associated complications occurred, except for 1 case presenting with grade A liver failure after LVD (then recovered after 7 days). The FLR volume was 29.3% (interquartile range [IQR] = 7.5) and 48.9% (IQR = 8.6) of the total liver volume before and after LVD, respectively (p < 0.001). The degree of hypertrophy and FLR hypertrophy rate were 14.8% (IQR = 8.4) and 55.2% (IQR = 36.7), respectively. All 27 patients demonstrated sufficient FLR after LVD (24 patients at three weeks post-LVD, one at six weeks, and two at ten weeks), but only 21 patients accepted surgery. Postoperative histopathology showed 16 patients with cirrhosis and five with mild fibrosis (F1, F2). One patient presented with severe intraoperative bleeding due to damage of left hepatic vein and developed grade C liver failure, then died on day 32 postoperation. Conclusion: LVD following TACE seems to be a safe, effective, and feasible method of inducing significant FLR regeneration in HCC, even in well-selected cirrhotic livers. Comparative studies with a large patient population and multicenter data are needed for further evaluation.