Enhancing future liver remnant hypertrophy: innovative preoperative strategies and emerging technologies

Introduction

For primary and secondary liver cancers, surgery offers the best chance for long-term survival (1,2). However, major hepatectomy is often limited by insufficient future liver remnant (FLR) size and functional reserve (3,4). Post-hepatectomy liver failure (PHLF) is still a leading cause of postoperative mortality (1,2,4-11), particularly in patients with cirrhosis, steatosis, or chemotherapy-induced injury (2,4,12,13).

The minimum FLR volume required to prevent PHLF depends on the condition of the remaining liver tissue (2,3). Patients with healthy livers typically require ≥20% FLR, while those with chemotherapy exposure or moderate steatosis need 30–40%, and cirrhotic patients require 40–50% (2). Accurate preoperative FLR assessment is thus essential for identifying high-risk patients and guiding hypertrophy interventions (5,14). Conventional evaluation uses computed tomography (CT) and magnetic resonance imaging (MRI) volumetry, normalized to body surface area or estimated total liver volume (14,15). However, volume alone inadequately reflects function, particularly when hepatic function varies regionally, spurring interest in integrated volumetric-functional assessments (6,7).

To mitigate PHLF risk and expand resectability, preoperative strategies have been developed to induce FLR hypertrophy (2,16,17). These techniques work by redirecting portal blood flow from diseased segments toward the FLR, thereby stimulating hepatocyte proliferation and enlarging functional capacity (1,2). This review examines established and emerging FLR augmentation strategies, their mechanisms, clinical effectiveness, risks, and future developments.

FLR volume enhancement methods

The biological basis of these approaches could date back to early 20th-century animal studies, which showed that partial occlusion of the portal vein triggers compensatory hypertrophy in the remaining hepatic segments (1). These seminal findings laid the groundwork for our understanding of liver regeneration and continue to guide contemporary preoperative strategies designed to enhance FLR volume by modulating portal venous hemodynamics.

Portal vein ligation (PVL)

PVL diverts portal flow to induce FLR hypertrophy through direct surgical ligation of branches supplying segments designated for resection, rather than percutaneous embolization (1,2,18-24). Historically, among the earliest liver regeneration methods (1), PVL serves as a first-stage procedure preceding definitive hepatectomy after adequate hypertrophy.

When comparing PVL and portal vein embolization (PVE), the available evidence regarding their relative efficacy in promoting hypertrophy remains conflicting. A retrospective study of patients with colorectal liver metastases (CRLMs) found comparable volumetric increases in segments 2–3, segment 4, and the caudate lobe following either intervention (25), supporting the notion that it is the diversion of portal flow itself—rather than the specific method employed—that serves as the primary driver of hypertrophy, which means PVE has largely replaced PVL because it is much more minimally invasive.

PVL shares similar indications with PVE but offers advantages when synchronous procedures (e.g., colorectal resection) permit same-stage ligation, obviating separate interventional radiology (25). Contraindications are also similar to PVE (severe hepatic dysfunction, coagulopathy, extensive FLR tumor). Complications include standard surgical risks (bleeding, infection, wound issues, laparotomy-related morbidity) plus portal manipulation sequelae (thrombosis, tumor progression) (2). Despite remaining valid for staged procedures, PVE has supplanted PVL as the preferred standalone approach due to reduced invasiveness and surgical morbidity.

PVE

Building upon the surgical concept of PVL, PVE was introduced in the mid-1980s and has since become the standard method for inducing FLR hypertrophy prior to major hepatic resection (1,2,16,17,26-31). The procedure involves percutaneous occlusion of portal venous branches supplying segments scheduled for resection (16,32), redirecting portal flow toward the FLR and triggering growth factor-mediated hepatocyte proliferation (1,33).

PVE could achieve a relative increase in FLR volume of 10–50%, depending on liver quality and embolization extent (2,16,25,26,34). Its efficacy is most often quantified by two key metrics—the degree of hypertrophy (DH) and the kinetic growth rate (KGR) (35-38). The procedure is generally undertaken 4–6 weeks before surgery to allow sufficient regenerative growth (2). Technical refinements include optimized access routes (transhepatic, transileocolic and transsplenic approaches) and embolic material selection (coils, particles, glue, vascular plugs) (16,32,34,39). Although various embolic agents are used—including PVA particles with coils and N-butyl cyanoacrylate (NBCA)—no single material has been definitively established as superior. Some studies suggest that NBCA-based embolization may induce faster or greater hypertrophy compared with particle-based techniques; however, results remain heterogeneous and operator-dependent. Combining central vascular plugs with NBCA enhances hypertrophy compared with glue alone (34), while transileocolic access provides a viable alternative when percutaneous routes are unfeasible (39).

The primary indication for PVE is major hepatectomy involving three or more segments, particularly when the projected FLR volume falls short of established safety thresholds—limits that vary depending on the presence of underlying parenchymal disease and prior exposure to hepatotoxic chemotherapy (2,5,16). Contraindications include severe portal hypertension, advanced cirrhosis with poor synthetic function, and diffuse bilobar metastases. Contraindications also include any general contraindication to major hepatectomy (16). Potential complications range from the relatively benign post-embolization syndrome to more serious adverse events such as hemorrhage and portal vein thrombosis within the FLR. Perhaps most concerning is the risk of tumor progression during the waiting period required for hypertrophy, a phenomenon thought to be driven by alterations in hepatic hemodynamics and local upregulation of growth factors (16,40). Concerns have been raised regarding potential tumor progression during the waiting interval after PVE, possibly related to growth factor upregulation and altered hepatic hemodynamics. While some retrospective studies suggest an increased risk of interval progression, others have not demonstrated a significant impact on long-term oncologic outcomes. Overall, available evidence remains heterogeneous and does not conclusively establish that PVE intrinsically accelerates tumor growth. Several factors have been identified as predictors of successful hypertrophic response, including the absence of porto-portal collateral vessels and higher baseline plasma protein concentrations (41). More recently, CT-based radiomics analysis has shown promise in identifying patients at risk for inadequate hypertrophy, which could guide the selection of alternative or supplementary interventions (42). Notwithstanding the development of newer techniques, PVE continues to serve as the benchmark approach for preoperative FLR augmentation (2,16). Reported rates of interval progression or failure to proceed to resection after PVE range from roughly 15–30% in published series. In some cohorts, up to one-quarter of patients develop new lesions during the waiting period, and a meaningful subset subsequently loses eligibility for curative surgery (43).

Transarterial chemoembolization combined with PVE (TACE + PVE)

TACE delivers chemotherapy via hepatic artery, followed by embolization to deprive tumors of nutrients (44). Combined TACE-PVE enables simultaneous tumor control and FLR hypertrophy in hepatocellular carcinoma (HCC) patients, mitigating tumor progression during the hypertrophy interval—a critical PVE limitation in aggressive malignancies (40).

The evidence base for combined TACE and PVE remains heterogeneous, consisting predominantly of retrospective series. Some reports suggest that the combination yields hypertrophy comparable to—or even exceeding—that achieved with PVE alone, while also providing enhanced local tumor control (45). In one comparative study of patients with marginal FLR volumes, percutaneous ablation liver partition with portal vein ligation (PALPP) produced greater FLR growth and higher rates of successful two-stage completion than TACE combined with PVE, although the latter strategy still enabled two-stage resection in 58.3% of cases (45). Despite these encouraging findings, procedural complexity, potential hepatic injury, and heterogeneity in patient selection limit firm conclusions. Prospective trials are needed to define its role more precisely.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)

ALPPS, described in 2012, is a two-stage procedure inducing rapid, substantial FLR hypertrophy through first-stage PVL combined with in-situ liver splitting (1,2,16,17,22,45-51). ALPPS is primarily indicated for patients with critically small FLR requiring rapid and substantial hypertrophy, particularly when the anticipated remnant volume is extremely low. Its indications are conceptually distinct from PVE, as ALPPS is typically selected as a primary strategy when accelerated regeneration is essential rather than as a salvage procedure after PVE failure (1).

ALPPS involves first-stage PVL combined with parenchymal splitting along the resection plane, preserving hepatic veins while fully isolating the FLR (2,16). This eliminates collateral pathways that attenuate hypertrophy after simple portal occlusion (16), achieving target FLR volume within 7–10 days versus 4–6 weeks for PVE (52,53). Rapid hypertrophy minimizes inter-stage interval and tumor progression risk (45), driven by portal flow diversion and splitting-induced inflammation that releases circulating growth factors (33,44,54).

ALPPS carries elevated morbidity (≈30–40%) and mortality (approximately 4–5% in contemporary series) compared with standard two-stage surgery, although outcomes have improved with refined patient selection and increasing institutional experience (1,2,55). Complications include splitting-related trauma and rapid sequential major operations, including bile leaks, infection, ascites, and hepatic failure. Consequently, ALPPS is reserved for minimal FLR unresponsive to alternatives or cases requiring rapid hypertrophy (e.g., extensive colorectal metastases) (2,45). Modified techniques—including PALPP (ablation-assisted partition) and laparoscopic approaches—reduce morbidity while preserving rapid hypertrophy (45,55). PALPP substitutes microwave/radiofrequency ablation for surgical splitting, demonstrating accelerated FLR growth and potentially fewer complications than classical ALPPS when compared to TACE + PVE (45,55). Hypertrophic response in ALPPS is strongly influenced by the initial FLR volume, with smaller remnants typically demonstrating greater relative hypertrophy, although this does not always translate into proportional functional gain (56). ALPPS is feasible in patients with fibrosis or early cirrhosis, but the timing of the second stage may need adjustment compared to those with healthy livers (57). Importantly, available data in CRLM suggest that ALPPS does not intrinsically accelerate tumor progression compared with conventional staged approaches (58).

Liver venous deprivation (LVD)

LVD induces hypertrophy through simultaneous portal inflow deprivation and hepatic venous outflow obstruction, creating intensified regenerative signaling and redistribution of intrahepatic hemodynamics (17,35,37,38,44,53,59-64). This dual vascular modulation is thought to amplify shear stress and cytokine-mediated regenerative pathways compared with portal occlusion alone. Clinically, LVD has demonstrated greater and faster volumetric hypertrophy than PVE in several retrospective series, although long-term functional superiority remains under investigation (35,59,60).

Studies comparing LVD (also known as DVE or RASPE) to PVE alone have shown encouraging results. One retrospective study showed RASPE achieved greater volume increase (61.18% vs. 28.98%, P<0.0001) and enabled more extensive resections with reduced PHLF (65). A meta-analysis of eight studies reported enhanced FLR hypertrophy with DVE (66% vs. 27%, P=0.01), fewer surgical dropouts, and lower PHLF and mortality, though higher-quality evidence is needed (35). The DRAGON collaborative found PVE/HVE increased hypertrophy (59% vs. 48%, P=0.02) and resectability (90% vs. 68%, P=0.007) compared to PVE alone (36). A propensity score-matched study in patients with extensive CRLMs and high risk of poor regeneration showed better outcomes with LVD than with PVE. LVD resulted in greater FLR hypertrophy (16% vs. 11%, P=0.02) and a higher KGR (3.9% vs. 2.4% per week, P=0.006), allowing for safer extended liver resections (38). In Klatskin tumor patients, LVD achieved a higher median FLR ratio (58% vs. 37%, P=0.02) and 1.6-fold volume gain versus PVE, confirming safety and efficacy in high-risk populations (66).

Conversely, Khayat et al. found no hypertrophy difference between LVD and PVE at 39 days in non-cirrhotic colorectal metastases patients (63), suggesting LVD advantages may be context-dependent. LVD demonstrates high technical success with low complication rates, though bleeding and hematoma remain major risks (64,67). Hepatic vein embolization can be performed via a transjugular or transfemoral route. The transfemoral approach may be preferred in some cases due to shorter procedure time and easier catheter access (67,68).

LVD benefits patients requiring major hepatectomy with insufficient FLR, particularly for colorectal metastases or perihilar cholangiocarcinoma, and also serves as a salvage procedure after inadequate PVE response (53,69). Designed to accelerate hypertrophy beyond PVE while maintaining lower morbidity than ALPPS, LVD achieved median kinetic growth of 3.4%/week with 74% resection completion, 6.5% complications, and 3% PHLF rates in the EuroLVD registry (216 patients, 8 centers) (67). Oncological outcomes for colorectal metastases appear comparable to PVE (37,62). Functional assessment now complements volumetry: hepatobiliary scintigraphy (HBS) shows FLR-F gain >150% reliably predicts PHLF avoidance (negative predictive value 1.00), potentially refining surgical timing beyond volume thresholds alone (70). TACE-LVD combinations for HCC show early promise in simultaneously promoting hypertrophy and controlling tumor progression (71).

Innovative preoperative strategies and emerging technologies

Beyond portal vein occlusion and liver partitioning, emerging strategies aim to accelerate FLR hypertrophy and enhance functional recovery. It is important to note that, in contrast to established clinical techniques such as PVE, LVD, and ALPPS, many pharmacologic, growth factor–based, and cell-based approaches remain in early-phase clinical investigation or preclinical development. Therefore, their current role should be considered exploratory rather than standard of care.

Drug formulations

Pharmacological approaches are emerging as valuable additions to mechanical strategies like PVE, LVD, or ALPPS. The aim is twofold: to enhance regeneration in FLRs weakened by steatosis or fibrosis, and to boost the cytokine and growth factor response triggered by these procedures. Foundational studies have outlined key regenerative pathways—such as interleukin 6 (IL-6)/JAK-STAT, hepatocyte growth factor (HGF)/c-MET, bile acid-farnesoid X receptor (FXR), FGF19/FGFR4, and thyroid hormone–TR-β—and shown how chronic inflammation, lipotoxicity, and fibrosis can impair their activity (33). Below, the most clinically advanced drug classes are summarized.

Bile-acid-FXR agonists

FXR activation promotes hepatocyte proliferation, cholangiocyte protection and metabolic re-programming toward β-oxidation. Second-generation non-steroidal FXR agonists (e.g., cilofexor) and the steroidal agent obeticholic acid have shown significant histological improvement in MASH and fibrosis, positioning the FXR axis as a credible target to boost FLR quality before major hepatectomy (72). A contemporary critical review highlights pre-clinical data in partial-hepatectomy models in which FXR agonism shortened the priming phase and accelerated DNA synthesis (72).

FGF19 analogues

Aldafermin (NGM282) is an engineered FGF19 that signals through FGFR4/β-Klotho to drive cell-cycle entry while avoiding native oncogenic motifs. In a 160-patient phase-2b trial, aldafermin reduced fibrosis biomarkers and ballooning and was generally well tolerated (73). Although not yet tested specifically in the pre-operative setting, rapid reductions in liver fat and inflammatory activity suggest a window for use before or during portal-flow-based hypertrophy induction.

Thyroid hormone receptor-β (THR-β) agonists

Resmetirom selectively targets hepatic THR-β to enhance mitochondrial oxidation and lipid clearance. The 2024 MAESTRO-NASH phase-3 trial demonstrated both NASH resolution and ≥1-stage fibrosis improvement versus placebo without excess serious adverse events (74). Improved mitochondrial function and reduced oxidative stress may translate into faster, more energy-efficient FLR hypertrophy, warranting formal peri-operative studies.

GLP-1 receptor agonists (GLP-1RA)

Beyond weight loss, long-acting GLP-1RA such as semaglutide reduces steatosis, ballooning and portal pressure. A 2025 NEJM phase-3 study in 800 MASH patients reported 62.9% histological improvement and 33% fibrosis regression with weekly semaglutide 2.4 mg (75). Because steatotic FLR is an independent PHLF risk factor, GLP-1RA could be deployed during the 4–6-week waiting period after PVE to enhance both liver health and systemic metabolic status.

Cytokine-modulating strategies

IL-6 is a classic priming cytokine, but its cis- vs. trans-signalling balance determines trophic versus fibrogenic outcomes. A 2024 mechanistic review shows this duality and summarises therapeutic approaches that tilt the axis toward regeneration (76). Proof-of-concept studies in animal models show that blocking IL-6 trans-signalling with the soluble decoy sgp130 can attenuate steatosis-related regeneration deficits while preserving canonical IL-6 priming (77). Though this approach remains experimental, we can still believe that such selective modulation might synergize with portal diversion strategies by enhancing the early inflammatory burst without causing fibrosis.

The perioperative feasibility of these agents remains uncertain. Most pharmacologic interventions require several weeks to achieve meaningful histologic or metabolic improvement, which may not align with oncologic timelines in patients awaiting resection. In addition, although current human trials have not demonstrated clear tumor-promoting effects, long-term oncologic neutrality in the peri-hepatectomy setting remains insufficiently studied. Importantly, robust data demonstrating improved surgical or survival outcomes in humans are currently lacking. Therefore, these strategies should be considered investigational and complementary rather than substitutes for established hypertrophy-inducing techniques. These pharmacologic strategies intersect mechanistically with growth factor and cell-based approaches, but remain largely investigational (33,78).

Another key focus is enhancing the health and regenerative ability of liver tissue, especially in patients with steatosis or fibrosis. Conditions like metabolic dysfunction-associated steatotic liver disease (MASLD) can impair regeneration and are linked to a higher risk of PHLF (78). Medications that reduce steatosis, inflammation, or fibrosis may help improve the liver’s capacity to grow in response to hypertrophy-inducing procedures. Targeting metabolic or fibrotic pathways could enhance both the quality and volume of the FLR. However, more research and clinical trials are needed to turn these findings into practical preoperative strategies. This area also overlaps with growth factor and cell-based therapies, which aim to deliver bioactive molecules or cells that support regeneration. Figure 1 shows the pharmacological agents and their molecular targets involved in promoting liver regeneration.

Figure 1 Mechanistic overview of strategies to enhance FLR hypertrophy. Arrows indicate regenerative effects. Purple: pharmacological agents improving metabolic and inflammatory status; green: growth factors and delivery systems stimulating hepatocyte proliferation; blue: cell-based therapies promoting regeneration via paracrine signaling or cellular replacement. FLR, future liver remnant; FXR, farnesoid X receptor; GLP-1RA, GLP-1 receptor agonists; HGF, hepatocyte growth factor; IL-6, interleukin 6; MSC, mesenchymal stem cell; TCA, taurocholic acid; THR-β, thyroid hormone receptor-β; TNF-α, tumor necrosis factor alpha.

Growth factors

HGF is a key stimulator of hepatocyte proliferation in liver regeneration (33,78-86). Other growth factors [epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), and insulin-like growth factor (IGF)] also play important roles (33,87).

Translation to clinical practice faces challenges, including dosage optimization, delivery methods, and concerns about tumor stimulation. Current research is exploring innovative delivery strategies aimed at improving both the safety profile and therapeutic efficacy of growth factor therapy. These strategies encompass gene therapy approaches designed to induce local growth factor production within the FLR itself, as well as nanoparticle- or hydrogel-based systems engineered for sustained, site-specific release directly to hepatic tissue (87). Notably, hydrogel-encapsulated mesenchymal stem cell (MSC)-conditioned medium—which contains a rich milieu of paracrine factors, including multiple growth factors—has demonstrated encouraging results in promoting functional liver regeneration within steatotic liver models (87). While the clinical application of exogenous growth factors to enhance FLR hypertrophy remains investigational, advances in understanding liver regeneration pathways and refinements in targeted delivery systems may well pave the way for future therapeutic integration. The growth factors and delivery modalities designed to enhance FLR regeneration are illustrated in Figure 1.

Cell-based therapies (stem cell therapy)

Cell-based therapies aim to enhance FLR regeneration primarily through paracrine signaling and, potentially, cellular replacement (33,87-89). Preclinical investigations have explored various stem cell populations, including MSCs, unrestricted somatic stem cells, and small hepatic progenitor cells, whereas clinical trials have primarily focused on CD133⁺ bone marrow-derived MSCs and hematopoietic stem cells (87,90). Accumulating evidence indicates that combining stem cell administration with PVE [portal vein embolization with stem cell administration (PVESA)] not only appears safe but also enhances hypertrophic outcomes beyond those achieved with PVE alone (88). This approach may prove especially beneficial for patients with diminished hepatic reserve or comorbidities that blunt the typical hypertrophic response to PVE. From a mechanistic standpoint, MSCs secrete paracrine mediators such as HGF that promote hepatocyte proliferation, with preliminary clinical evidence demonstrating improvements in both FLR volume and functional capacity following stem cell therapy (89,91).

A number of technical and biological questions, however, remain to be addressed. These include determining optimal stem cell selection criteria, procurement strategies, and delivery protocols. Current research efforts are focused on potential refinements—stem cell preconditioning, genetic modification to enhance regenerative potency, and the application of cell-free derivatives such as extracellular vesicles (78,92). Although early results show promise, PVESA will require rigorous validation in preclinical models that faithfully recapitulate tumor-bearing, injured livers, alongside adequately powered clinical trials, before it can be considered for routine implementation (88). Perhaps the most compelling rationale for stem cell-based approaches lies in their dual capacity to augment both volumetric and functional regeneration of the FLR. This becomes particularly relevant in patients with compromised parenchyma, where conventional methods such as PVE or ALPPS may yield suboptimal hypertrophy or carry prohibitive risk. In the setting of cirrhotic or chemotherapy-injured livers—where hepatocyte proliferative capacity is fundamentally impaired—stem cells may help restore a more permissive regenerative microenvironment (57,87,93). Moreover, by amplifying the hypertrophic response, these therapies could shorten the interval to resection, thereby reducing the window during which tumor progression might occur (33,89,90,92). Importantly, integrating stem cell therapy with vascular manipulation techniques such as PVE or LVD may yield synergistic benefits, combining hemodynamic redirection with cellular augmentation to optimize FLR outcomes (88,91). Figure 1 shows cell-based therapies and the main cell types that contribute to FLR hypertrophy. Despite promising early data, the absence of large-scale randomized trials, unresolved questions regarding oncologic safety, and logistical challenges related to cell preparation and delivery currently limit routine clinical application.

Advanced imaging and monitoring technologies

Precise assessment and longitudinal monitoring of FLR hypertrophy are critical to surgical planning and risk stratification for PHLF. Computed tomography (CT) and magnetic resonance imaging (MRI) remain the mainstays of volumetric assessment (14,15). However, these conventional modalities provide primarily anatomical information and may inadequately capture functional reserve, particularly in patients with underlying parenchymal disease, where volume and function can be discordant (6,7). Newer imaging techniques are addressing these limitations by enabling integrated assessment of both morphology and function, as well as characterization of hemodynamic changes induced by preoperative interventions.

One important advancement is the use of ^99mTc-mebrofenin HBS, which evaluates liver function by assessing how hepatocytes absorb and clear a radiotracer (15,17). This method has proven useful in predicting how well the liver will functionally grow after PVE and in identifying patients who may be at risk for poor hypertrophy or PHLF (88). By defining a functional liver reserve threshold, HBS can identify patients unlikely to respond adequately to PVE alone and who may benefit more from alternative approaches such as ALPPS or LVD (88). However, its use may be limited in some settings due to restricted availability and higher cost.

In addition, indocyanine green (ICG) clearance testing remains a widely used global functional assessment tool and provides complementary information to regional imaging-based functional evaluation.

Four-dimensional (4D) flow MRI provides time-resolved, three-dimensional assessment of portal venous hemodynamics with superior accuracy compared to Doppler ultrasound. This technique quantifies portal blood flow, velocity, wall shear stress (WSS), and energy loss, with portal velocity to the FLR showing strong correlation with hypertrophic response. Through its ability to detect hemodynamic alterations in the early post-PVE period, 4D flow MRI holds promise for earlier prediction of hypertrophy and more expeditious surgical timing once adequate regeneration appears likely, thereby potentially reducing the risk of interval tumor progression (40). Clinical validation and widespread adoption have thus far been constrained by the need for specialized infrastructure and technical expertise.

Preoperative CT-based radiomics represents an emerging investigational tool that leverages quantitative imaging features to identify patterns potentially predictive of suboptimal hypertrophy—information often beyond the reach of traditional clinical parameters. Notably, one externally validated clinical-radiomic model demonstrated possible value in anticipating inadequate response to PVE, although statistical significance was not achieved (42). Looking ahead, radiomics holds promise for enabling more individualized surgical planning, particularly when combined with functional imaging modalities such as HBS or 4D-flow MRI. The integration of these complementary techniques could markedly enhance predictive precision.

In current practice, serial CT or MRI examinations are typically employed to calculate the KGR and DH, metrics that guide decisions regarding optimal surgical timing (35,37,94). These considerations are especially critical for accelerated strategies such as ALPPS or LVD, where hypertrophy kinetics differ substantially (59,94). The integration of volumetric, functional, and hemodynamic data serves to refine risk stratification and ultimately reduce the incidence of PHLF.

Comparative analysis of different methods

Preoperative strategies designed to enhance FLR hypertrophy differ markedly in their underlying mechanisms, efficacy, timing, associated risks, and influence on surgical outcomes. A comprehensive comparative understanding of these approaches is therefore essential to support sound clinical decision-making and to ensure that treatment strategies are optimally tailored to each patient’s specific circumstances. While volumetric hypertrophy remains the most frequently reported endpoint, contemporary evidence increasingly supports prioritizing functional gain over absolute volume increase, particularly in steatotic, chemotherapy-injured, or cirrhotic livers where volume-function mismatch is common.

FLR hypertrophy rates

The hypertrophic efficacy of these techniques varies substantially across modalities. PVE generally yields a 27–54% increase in FLR volume within 4–6 weeks, corresponding to kinetic growth rates of approximately 2–3% per week (16,35,64). PVL achieves similar results, with reported hypertrophy rates of 43.1% compared with 53.4% for PVE—a difference that was not statistically significant (25). In contrast, ALPPS induces considerably faster regeneration, producing 60–80% volumetric gain within only 7–14 days through the combined effects of portal ligation and parenchymal splitting (1,94). Notably, LVD appears to elicit an even stronger hypertrophic response than PVE, with several studies documenting FLR increases of 59–66% and kinetic growth rates ranging from 3.2 to 3.9% per week (38,59). TACE + PVE approximates or slightly exceeds PVE, though PALPP outperforms TACE + PVE (58.5 vs. 7.7 mL/week) (45). Radioembolization yields slower hypertrophy (35.4%) with concurrent tumor control (95,96). PVESA shows promise in early studies, enhancing PVE-induced hypertrophy, though human quantitative data remain limited (88). Table 1 summarizes hypertrophy rates, kinetic growth rates, and time-to-adequacy for each modality.

Indications and contraindications

Indications center on major hepatectomy with insufficient FLR (<20% healthy liver, 30–40% chemotherapy-exposed/steatotic, 40–50% cirrhotic) (2). PVE, most widely used, suits most insufficient FLR cases except severe hepatic dysfunction, uncontrolled coagulopathy, or extensive FLR tumor (16). PVL is often reserved for scenarios where surgical access is already planned, such as synchronous colorectal resection (25). ALPPS is typically indicated for patients with very small FLRs or those who have failed PVE, but its higher morbidity limits its use to carefully selected cases, particularly for CRLMs (1,94). LVD addresses similar indications as PVE when accelerated hypertrophy is needed or post-PVE salvage (38,61). TACE + PVE prioritizes HCC with concurrent tumor control (45). RFA-based approaches like PALPP are suitable for patients requiring rapid hypertrophy with a minimally invasive first stage, particularly for HCC or colorectal metastases (55). Radioembolization combines hypertrophy with tumor control in HCC or oligometastatic disease (95,96). PVESA is still experimental but it shows promise for patients with compromised livers where standard techniques may be insufficient (88). Universal contraindications include severe hepatic dysfunction, extensive FLR tumor burden, uncontrolled coagulopathy, and significant comorbidities. Table 2 comparatively summarizes indications, contraindications, advantages, and limitations.

Complications

Complication profiles reflect procedural invasiveness. PVE demonstrates favorable safety with post-embolization syndrome (pain, fever, transient dysfunction), bleeding, portal thrombosis, and tumor progression during hypertrophy (16,40). PVL adds surgical risks (bleeding, infection, wound complications) to portal-related sequelae (25). ALPPS exhibits the highest morbidity (44%) and mortality (11%), including bile leaks, infection, ascites, and hepatic failure from splitting trauma and dual-stage operations (97,98). LVD shows 7% complication rate (hemorrhage, hematoma) with low PHLF incidence (37,67). TACE + PVE risks dual vascular insult but maintains comparable rates to PVE (45). PALPP demonstrates reduced morbidity versus ALPPS (mild ascites, fever), though larger validation is needed (45,94). Radioembolization carries radiation hepatotoxicity risk with minimal major complications and PHLF (96,99). PVESA appears safe initially, but stem cell-related risks (immune reactions, tumor promotion) require further investigation (88).

Surgical resection rates and outcomes

The success of FLR augmentation strategies is gauged by progression to curative hepatectomy. PVE achieves resection rates of 68–85%, with failures mainly from insufficient hypertrophy or tumor progression (28,29). PVL has comparable resection rates, with Capussotti et al. reporting successful resection in the majority of cases (25). A ALPPS achieves up to 95% resection but with higher morbidity and mortality (1,94,100). Retrospective studies demonstrate LVD superiority over PVE in colorectal metastases: enhanced hypertrophy (49% vs. 27%, P=0.01), kinetic growth rate (3.9% vs. 2.4%/week, P=0.006), and extended resection rates (93% vs. 55%, P=0.008) without increased PHLF or mortality (37,38). TACE+PVE achieves 58–76% resection rates, though PALPP surpasses this via accelerated hypertrophy (45). Radioembolization yields variable resection rates due to slower hypertrophy but provides concurrent tumor control (95,96). PVESA shows promise, though limited clinical data preclude definitive assessment (88). Long-term oncologic outcomes [overall survival (OS) and disease-free survival (DFS)] for colorectal metastases remain comparable between PVE and LVD at 1- and 3-year follow-up (37). ALPPS outcomes are similar but tempered by higher complication rates (57). TACE + PVE and radioembolization may improve DFS by controlling tumor growth, but data are limited (44,71).

Clinical decision-making considerations

Contemporary clinical practice increasingly favors a function-first paradigm, in which functional assessment (e.g., HBS, gadoxetate-enhanced MRI, ICG clearance) guides surgical timing and strategy selection rather than volumetry alone. Integrating functional and volumetric assessment is recommended, especially when liver quality is questionable (6,101-103).

Selecting the appropriate FLR augmentation technique requires addressing three questions: (I) what functional reserve ensures safe resection? (II) How rapidly must the FLR grow to maintain resectability? (III) What oncologic risk does surgical delay pose? PVE remains first-line given its safety and availability. However, when oncologic timelines are compressed or FLR volume is marginal, PVE/HVE or LVD achieves faster hypertrophy. The prospective multicenter DRAGON1 trial demonstrated that LVD achieves high resection completion rates without increasing embolization-related mortality (37,60,101,104). Because each FLR augmentation technique exhibits distinct growth kinetics, early milestone reassessment becomes essential—typically at 1–3 weeks following PVE/HVE and 3–6 weeks after PVE. When hypertrophy plateaus or disease progression threatens resectability, prompt adjustment of strategy is warranted (37,60,104). The comparative timelines from procedure to surgical eligibility across different FLR augmentation methods are illustrated in Figure 2.

Figure 2 Future liver remnant augmentation strategies: timeline comparison. ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; LVD, liver venous deprivation; PALPP, percutaneous ablation liver partition with portal vein ligation; PVE, portal vein embolization; PVL, portal vein ligation; TACE, transarterial chemoembolization.

When comparing LVD and ALPPS, the distinction largely centers on growth kinetics, procedural invasiveness, and patient risk profile. ALPPS induces the fastest and most pronounced volumetric hypertrophy, making it suitable for patients with critically small FLR requiring urgent resection. However, this benefit comes at the cost of higher surgical morbidity and the need for two closely staged major operations. In contrast, LVD achieves accelerated hypertrophy compared to PVE while maintaining a minimally invasive, single-session interventional approach. It may therefore be preferred in patients with marginal FLR who require faster regeneration than PVE can provide, but in whom the surgical risk of ALPPS is considered excessive. From an oncologic perspective, LVD allows continuation of systemic therapy during the hypertrophy interval in selected cases, whereas ALPPS minimizes inter-stage time but commits the patient to a surgical pathway early. Functional outcomes should also be considered, as rapid volumetric gain in ALPPS may not always equate to proportional functional recovery.

FLR augmentation strategies must be tailored to the disease context. In CRLM with chemotherapy-induced injury and aggressive biology, PVE/HVE shortens the high-risk waiting interval while preserving surgical intent. Bridging systemic therapy requires careful calibration to avoid impairing hepatic regeneration. For HCC with macrovascular invasion or high progression risk, combined hypertrophy and tumor control approaches are advantageous. Radiation lobectomy using Y-90 provides sustained contralateral hypertrophy with tumor suppression and may be combined with PVE in selected cases. Gadoxetate-enhanced MRI enables parallel monitoring of treatment response and remnant function, optimizing surgical timing (6,96,105-110). In perihilar cholangiocarcinoma, combining biliary drainage with PVE/HVE accelerates surgical readiness and reduces PHLF risk versus PVE alone (66).

Surgical timing should rely on functional and volumetric parameters rather than fixed intervals. FLR function assessed by HBS or gadoxetate-enhanced MRI independently predicts PHLF risk and confirms true functional hypertrophy, addressing volume-function mismatch (6,101-103,111). When integrated with serial volumetry and kinetic growth tracking, function-based thresholds permit earlier surgical clearance in responders and timely escalation—such as PVE to PVE/HVE conversion—in patients with inadequate hypertrophy, reducing dropout risk.

A simplified decision-oriented framework may help clarify the selection between LVD and ALPPS: (I) extremely small FLR (<15–20%) with urgent need for resection → ALPPS may be preferred due to its rapid and pronounced hypertrophy. (II) Marginal FLR (20–30%) requiring accelerated growth but with high surgical risk → LVD may be favored, given its minimally invasive nature and lower morbidity. (III) Patients with significant comorbidities or limited tolerance for staged major surgery → LVD may provide a safer alternative. (IV) Situations requiring maximal and fastest volumetric expansion regardless of invasiveness → ALPPS remains the most potent strategy. Final strategy selection should integrate functional assessment, oncologic urgency, and institutional expertise.

Optimal outcomes require a coordinated institutional workflow. Centers should establish standardized algorithms defining preferred pathways: PVE as baseline, PVE/HVE when oncologic windows narrow or baseline FLR is marginal, and Y-90 strategies when tumor control predominates. Protocols must incorporate functional assessment (HBS or gadoxetate-enhanced MRI with defined thresholds) and reassessment schedules matched to each technique’s hypertrophic kinetics (37,60,104). This framework reduces variability, accelerates resection in responders, and establishes clear transition criteria for non-responders. Figure 3 presents an algorithm that integrates FLR volumetry, functional evaluation, and patient-specific factors to guide individualized strategy selection.

Figure 3 Decision tree for FLR enhancement technique selection. ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; CT, computed tomography; DH, degree of hypertrophy; FLR, future liver remnant; HBS, hepatobiliary scintigraphy; HCC, hepatocellular carcinoma; KGR, kinetic growth rate; LVD, liver venous deprivation; MRI, magnetic resonance imaging; PVE, portal vein embolization; PVESA, portal vein embolization with stem cell administration; TACE, transarterial chemoembolization.

Conclusions

FLR augmentation has expanded surgical eligibility and reduced PHLF. Established approaches—PVE, PVL, and ALPPS—form the current backbone of practice, while newer techniques such as LVD, combination strategies (TACE + PVE, PALPP), radioembolization, PVESA, and advanced imaging modalities are continually being refined. Choosing the most appropriate method for a given patient requires careful appraisal of hypertrophy kinetics, procedural risks, and oncologic outcomes within the framework of close multidisciplinary collaboration.

Despite significant progress, several challenges persist. Most comparative studies remain retrospective or confined to small cohorts, limiting the strength of current evidence (36,59,88). Well-designed prospective randomized controlled trials—such as those comparing LVD with PVE, ALPPS with LVD, and TACE + PVE with PALPP in hepatocellular carcinoma—are urgently needed to establish robust, evidence-based guidelines. Although the DRAGON 1 trial has assessed the safety and feasibility of PVE/HVE, larger multicenter efforts like DRAGON 2 will be essential for harmonizing protocols and defining best practice standards (45,60).

Our mechanistic understanding of liver regeneration, while steadily improving, is still incomplete. Even with the identification of pivotal mediators such as IL-6, tumor necrosis factor (TNF)-alpha, and HGF (33,78,112-118), many aspects remain to be clarified. Future translational investigations that integrate genomic, proteomic, and metabolomic data—ideally supported by refined animal models (52)—could uncover novel therapeutic targets for pharmacologic or cell-based strategies capable of enhancing regeneration without inadvertently promoting tumor growth. Emerging modalities will require thorough clinical validation. Stem-cell therapies, growth-factor delivery systems (including nanoparticle-encapsulated HGF and hydrogels), and radioembolization all warrant large-scale trials to define their safety profiles, optimal dosing regimens, administration methods, and effects on both volumetric and functional regeneration (88,96,99). Likewise, pharmacologic interventions must be evaluated not only for efficacy but also for any potential tumor-stimulating effects, particularly when combined with vascular manipulation techniques (87,96). For cell-based therapies, consistent standardization of cell sources, dosages, and delivery routes remains crucial, alongside exploration of adjunct strategies such as genetic modification and extracellular-vesicle-based delivery (88). Long-term follow-up will be indispensable for assessing the durability, functional benefit, and oncologic safety of these interventions.

Tumor progression during the hypertrophy interval remains a persistent and clinically important limitation, as it may render some patients ineligible for definitive surgery (41). Consequently, integrated approaches that pair hypertrophy induction with tumor-directed treatments—such as TACE, radioembolization, neoadjuvant chemotherapy, or targeted agents—merit further study to achieve an optimal balance between regeneration and oncologic control (45,95). In parallel, the incorporation of advanced imaging technologies (e.g., 4D-flow MRI and HBS) and predictive analytic tools (such as radiomics) is enabling increasingly precise, function-based assessment and more individualized surgical timing, particularly for accelerated strategies (35,37,94). In parallel, artificial intelligence (AI)-based predictive models are increasingly being explored to estimate FLR hypertrophy and functional recovery. Machine learning algorithms integrating clinical, radiomic, and laboratory parameters have shown potential in predicting insufficient hypertrophy and PHLF. Although most current studies remain retrospective and require external validation, AI-assisted decision support may further refine individualized timing and strategy selection in the future. Through sustained commitment to rigorous clinical research, deeper mechanistic insight, and effective multidisciplinary collaboration, coupled with thoughtful validation of emerging technologies, the field is well-positioned to broaden surgical eligibility and further improve outcomes for patients with liver malignancies worldwide.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-151/prf

Funding: This study was supported by the Gansu Provincial Youth Science and Technology Fund (No. 24JRRA1086).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-151/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Del Basso C, Gaillard M, Lainas P, et al. Current strategies to induce liver remnant hypertrophy before major liver resection. World J Hepatol 2021;13:1629-41. [Crossref] [PubMed]
2. Entezari P, Toskich BB, Kim E, et al. Promoting Surgical Resection through Future Liver Remnant Hypertrophy. Radiographics 2022;42:2166-83. [Crossref] [PubMed]
3. Dixon M, Cruz J, Sarwani N, et al. The Future Liver Remnant : Definition, Evaluation, and Management. Am Surg 2021;87:276-86. [Crossref] [PubMed]
4. Kishi Y, Vauthey JN. Issues to be considered to address the future liver remnant prior to major hepatectomy. Surg Today 2021;51:472-84. [Crossref] [PubMed]
5. Boubaddi M, Marichez A, Adam JP, et al. Comprehensive Review of Future Liver Remnant (FLR) Assessment and Hypertrophy Techniques Before Major Hepatectomy: How to Assess and Manage the FLR. Ann Surg Oncol 2024;31:9205-20. [Crossref] [PubMed]
6. Sofue K, Shimada R, Ueshima E, et al. Evaluation and Prediction of Post-Hepatectomy Liver Failure Using Imaging Techniques: Value of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging. Korean J Radiol 2024;25:24-32. [Crossref] [PubMed]
7. Yu QJ, Luo YC, Zuo ZW, et al. Utility of gadoxetate disodium-enhanced magnetic resonance imaging in evaluating liver failure risk after major hepatic resection. Quant Imaging Med Surg 2024;14:3731-43. [Crossref] [PubMed]
8. Vassanasiri W, Rungsakulkij N, Suragul W, et al. Early postoperative serum aspartate aminotransferase for prediction of post-hepatectomy liver failure. Perioper Med (Lond) 2022;11:51. [Crossref] [PubMed]
9. Tsujita Y, Sofue K, Komatsu S, et al. Prediction of post-hepatectomy liver failure using gadoxetic acid-enhanced magnetic resonance imaging for hepatocellular carcinoma with portal vein invasion. Eur J Radiol 2020;130:109189. [Crossref] [PubMed]
10. Chen X, Kuang M, Hu ZH, et al. Prediction of post-hepatectomy liver failure and long-term prognosis after curative resection of hepatocellular carcinoma using liver stiffness measurement. Arab J Gastroenterol 2022;23:82-8. [Crossref] [PubMed]
11. Tashiro H, Onoe T, Tanimine N, et al. Utility of Machine Learning in the Prediction of Post-Hepatectomy Liver Failure in Liver Cancer. J Hepatocell Carcinoma 2024;11:1323-30. [Crossref] [PubMed]
12. Kong FH, Miao XY, Zou H, et al. End-stage liver disease score and future liver remnant volume predict post-hepatectomy liver failure in hepatocellular carcinoma. World J Clin Cases 2019;7:3734-41. [Crossref] [PubMed]
13. Zou H, Tao Y, Wang ZM. Integration of Child-Pugh score with future liver remnant yields improved prediction of liver dysfunction risk for HBV-related hepatocellular carcinoma following hepatic resection. Oncol Lett 2017;13:3631-7. [Crossref] [PubMed]
14. Reese T, Gilg S, Erdmann J, et al. Future liver remnant volumetry: an E-AHPBA international survey of current practice among liver surgeons. HPB (Oxford) 2025;27:861-8. [Crossref] [PubMed]
15. Martel G, Cieslak KP, Huang R, et al. Comparison of techniques for volumetric analysis of the future liver remnant: implications for major hepatic resections. HPB (Oxford) 2015;17:1051-7. [Crossref] [PubMed]
16. Li D, Madoff DC. Portal vein embolization for induction of selective hepatic hypertrophy prior to major hepatectomy: rationale, techniques, outcomes and future directions. Cancer Biol Med 2016;13:426-42. [Crossref] [PubMed]
17. Memeo R, Conticchio M, Deshayes E, et al. Optimization of the future remnant liver: review of the current strategies in Europe. Hepatobiliary Surg Nutr 2021;10:350-63. [Crossref] [PubMed]
18. Tochii K, Iwata H, Sugimoto T, et al. Two-Stage Portal Vein Ligation Facilitates Liver Regeneration Safely in Rats with Liver Cirrhosis. J Invest Surg 2022;35:549-59. [Crossref] [PubMed]
19. Heil J, Schadde E. Simultaneous portal and hepatic vein embolization before major liver resection. Langenbecks Arch Surg 2021;406:1295-305. [Crossref] [PubMed]
20. Coco D, Leanza S. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in colorectal liver metastases: review of the literature. Clin Exp Hepatol 2021;7:125-33. [Crossref] [PubMed]
21. Qin Y, Li C, Ge X, et al. MMP2/9 downregulation is responsible for hepatic function recovery in cirrhotic rats following associating liver partition and portal vein ligation for staged hepatectomy. Ann Transl Med 2022;10:468. [Crossref] [PubMed]
22. Zhang Y, He X, Ma P, et al. Establishment of a Rat Model of Liver Venous Deprivation: Simultaneous Portal and Hepatic Vein Ligation. J Clin Transl Hepatol 2023;11:393-404. [Crossref] [PubMed]
23. Baili E, Tsilimigras DI, Moris D, et al. Technical modifications and outcomes after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) for primary liver malignancies: A systematic review. Surg Oncol 2020;33:70-80. [Crossref] [PubMed]
24. Zhang W, Zhu X, Tang Y, et al. Kupffer cells depletion alters cytokine expression and delays liver regeneration after Radio-frequency-assisted Liver Partition with Portal Vein Ligation. Mol Immunol 2022;144:71-7. [Crossref] [PubMed]
25. Capussotti L, Muratore A, Baracchi F, et al. Portal vein ligation as an efficient method of increasing the future liver remnant volume in the surgical treatment of colorectal metastases. Arch Surg 2008;143:978-82; discussion 982. [Crossref] [PubMed]
26. Kohno S, Isoda H, Ono A, et al. Portal Vein Embolization: Radiological Findings Predicting Future Liver Remnant Hypertrophy. AJR Am J Roentgenol 2020;214:687-93. [Crossref] [PubMed]
27. Charles J, Nezami N, Loya M, et al. Portal Vein Embolization: Rationale, Techniques, and Outcomes to Maximize Remnant Liver Hypertrophy with a Focus on Contemporary Strategies. Life (Basel) 2023;13:279. [Crossref] [PubMed]
28. Cassese G, Han HS, Lee B, et al. Portal vein embolization failure: Current strategies and future perspectives to improve liver hypertrophy before major oncological liver resection. World J Gastrointest Oncol 2022;14:2088-96. [Crossref] [PubMed]
29. Gavriilidis P, Marangoni G, Ahmad J, et al. Simultaneous portal and hepatic vein embolization is better than portal embolization or ALPPS for hypertrophy of future liver remnant before major hepatectomy: A systematic review and network meta-analysis. Hepatobiliary Pancreat Dis Int 2023;22:221-7. [Crossref] [PubMed]
30. Soykan EA, Aarts BM, Lopez-Yurda M, et al. Predictive Factors for Hypertrophy of the Future Liver Remnant After Portal Vein Embolization: A Systematic Review. Cardiovasc Intervent Radiol 2021;44:1355-66. [Crossref] [PubMed]
31. Santhakumar C, Ormiston W, McCall JL, et al. Portal vein embolization with absolute ethanol to induce hypertrophy of the future liver remnant. CVIR Endovasc 2022;5:36. [Crossref] [PubMed]
32. Hashimoto M, Ouchi Y, Yata S, et al. The Guidelines for Percutaneous Transhepatic Portal Vein Embolization: English Version. Interv Radiol (Higashimatsuyama) 2024;9:41-8. [Crossref] [PubMed]
33. Ma X, Huang T, Chen X, et al. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025;10:63. [Crossref] [PubMed]
34. Carling U, Røsok B, Berger S, et al. Portal Vein Embolization Using N-Butyl Cyanoacrylate-Glue: What Impact Does a Central Vascular Plug Have? Cardiovasc Intervent Radiol 2022;45:450-8. [Crossref] [PubMed]
35. Bell RJ, Hakeem AR, Pandanaboyana S, et al. Portal vein embolization versus dual vein embolization for management of the future liver remnant in patients undergoing major hepatectomy: meta-analysis. BJS Open 2022;6:zrac131. [Crossref] [PubMed]
36. Heil J, Korenblik R, Heid F, et al. Preoperative portal vein or portal and hepatic vein embolization: DRAGON collaborative group analysis. Br J Surg 2021;108:834-42. [Crossref] [PubMed]
37. Cassese G, Troisi RI, Khayat S, et al. Liver Venous Deprivation Versus Portal Vein Embolization Before Major Hepatectomy for Colorectal Liver Metastases: A Retrospective Comparison of Short- and Medium-Term Outcomes. J Gastrointest Surg 2023;27:296-305. [Crossref] [PubMed]
38. Haddad A, Khavandi MM, Lendoire M, et al. Propensity Score-Matched Analysis of Liver Venous Deprivation and Portal Vein Embolization Before Planned Hepatectomy in Patients with Extensive Colorectal Liver Metastases and High-Risk Factors for Inadequate Regeneration. Ann Surg Oncol 2025;32:1752-61. [Crossref] [PubMed]
39. Kimura K, Minagawa R, Yamaoka T, et al. Transileocolic Portal Vein Embolization Increases Remnant Liver Volume After Major Hepatectomy. In Vivo 2024;38:2761-6. [Crossref] [PubMed]
40. Al-Sharif E, Simoneau E, Hassanain M. Portal vein embolization effect on colorectal cancer liver metastasis progression: Lessons learned. World J Clin Oncol 2015;6:142-6. [Crossref] [PubMed]
41. Zeile M, Bakal A, Volkmer JE, et al. Identification of cofactors influencing hypertrophy of the future liver remnant after portal vein embolization—the effect of collaterals on embolized liver volume. Br J Radiol 2016;89:20160306. [Crossref] [PubMed]
42. Stavrou G, Donati M, Ringe K, Peitgen H, Oldhafer K. Liver remnant hypertrophy induction – How often do we really use it in the time of computer assisted surgery? Adv Med Sci 2012;57:251-8. [Crossref] [PubMed]
43. Hoekstra LT, van Lienden KP, Doets A, et al. Tumor progression after preoperative portal vein embolization. Ann Surg 2012;256:812-7; discussion 817-8. [Crossref] [PubMed]
44. Wang Q, Brismar TB, Björk D, et al. Development and External Validation of a Combined Clinical-Radiomic Model for Predicting Insufficient Hypertrophy of the Future Liver Remnant following Portal Vein Embolization. Ann Surg Oncol 2025;32:1795-807. [Crossref] [PubMed]
45. Ye TW, Fu TW, Du CF, et al. Comparison of percutaneous microwave/radiofrequency ablation liver partition and portal vein embolization versus transarterial chemoembolization and portal vein embolization for planned hepatectomy with insufficient future liver remnant. BMC Cancer 2024;24:985. [Crossref] [PubMed]
46. Balci D, Sakamoto Y, Li J, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure for cholangiocarcinoma. Int J Surg 2020;82S:97-102. [Crossref] [PubMed]
47. Lang H, Baumgart J, Mittler J. Associated Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) Registry: What Have We Learned? Gut Liver 2020;14:699-706. [Crossref] [PubMed]
48. Wen XD, Xiao L. Associating liver partition and portal vein ligation for staged hepatectomy in the treatment of colorectal cancer liver metastases. World J Gastrointest Surg 2021;13:814-21. [Crossref] [PubMed]
49. Zhang J, Yang X, Fang J, et al. Evolution of associating liver partition and portal vein ligation for staged hepatectomy from 2012 to 2021: A bibliometric analysis. Int J Surg 2022;103:106648. Review. [Crossref] [PubMed]
50. Lai Q, Mennini G, Larghi Laureiro Z, et al. Uncommon indications for associating liver partition and portal vein ligation for staged hepatectomy: a systematic review. Hepatobiliary Surg Nutr 2021;10:210-25. [Crossref] [PubMed]
51. Hernandez-Alejandro R, Ruffolo LI, Alikhanov R, et al. Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure for colorectal liver metastasis. Int J Surg 2020;82S:103-8. [Crossref] [PubMed]
52. Hu C, Xu Z, Du Y. A Mouse Model of the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Procedure Aided by Microscopy. J Vis Exp 2024;
53. Jiao LR, Fajardo Puerta AB, Gall TMH, et al. Rapid Induction of Liver Regeneration for Major Hepatectomy (REBIRTH): A Randomized Controlled Trial of Portal Vein Embolisation versus ALPPS Assisted with Radiofrequency. Cancers (Basel) 2019;11:302. [Crossref] [PubMed]
54. Chebaro A, Buc E, Durin T, et al. Liver Venous Deprivation or Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy?: A Retrospective Multicentric Study. Ann Surg 2021;274:874-80. [Crossref] [PubMed]
55. Liu J, Zhang C, Hong D, et al. Percutaneous microwave ablation liver partition and portal vein embolization for planned hepatectomy due to large gastrointestinal stromal tumor metastases: A case report. Medicine (Baltimore) 2017;96:e8271. [Crossref] [PubMed]
56. Romic I, Augustin G, Pavlek G, et al. Correlation between the liver transection line localization and future liver remnant hypertrophy in associating liver partition and portal vein ligation for staged hepatectomy. Front Surg 2024;11:1369962. [Crossref] [PubMed]
57. Romic I, Augustin G, Pavlek G, et al. Correlation between the liver transection line localization and future liver remnant hypertrophy in associating liver partition and portal vein ligation for staged hepatectomy. Front Surg 2024;11:1369962. [Crossref] [PubMed]
58. Kambakamba P, Linecker M, Schneider M, et al. Impact of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) on growth of colorectal liver metastases. Surgery 2018;163:311-7. [Crossref] [PubMed]
59. Hung KC, Wang HP, Li WF, et al. Single center experience with ALPPS and timing with stage 2 in patients with fibrotic/cirrhotic liver. Updates Surg 2024;76:1213-21. [Crossref] [PubMed]
60. Korenblik R, James S, Smits J, et al. Safety and efficacy of combined portal and hepatic vein embolisation in patients with colorectal liver metastases (DRAGON1): a multicentre, single-arm clinical trial. Lancet Reg Health Eur 2025;53:101284. [Crossref] [PubMed]
61. Cassese G, Han HS, Al Farai A, et al. Future remnant liver optimization: preoperative assessment, volume augmentation procedures and management of PVE failure. Minerva Surg 2022;77:368-79. [Crossref] [PubMed]
62. Guiu B, Herrero A, Panaro F. Liver venous deprivation: a bright future for liver metastases—but what about hepatocellular carcinoma? Hepatobiliary Surg Nutr 2021;10:270-2. [Crossref] [PubMed]
63. Khayat S, Cassese G, Quenet F, et al. Oncological Outcomes after Liver Venous Deprivation for Colorectal Liver Metastases: A Single Center Experience. Cancers (Basel) 2021;13:200. [Crossref] [PubMed]
64. Böning G, Fehrenbach U, Auer TA, et al. Liver Venous Deprivation (LVD) Versus Portal Vein Embolization (PVE) Alone Prior to Extended Hepatectomy: A Matched Pair Analysis. Cardiovasc Intervent Radiol 2022;45:950-7. [Crossref] [PubMed]
65. Laurent C, Fernandez B, Marichez A, et al. Radiological Simultaneous Portohepatic Vein Embolization (RASPE) Before Major Hepatectomy: A Better Way to Optimize Liver Hypertrophy Compared to Portal Vein Embolization. Ann Surg 2020;272:199-205. [Crossref] [PubMed]
66. Hocquelet A, Sotiriadis C, Duran R, et al. Preoperative Portal Vein Embolization Alone with Biliary Drainage Compared to a Combination of Simultaneous Portal Vein, Right Hepatic Vein Embolization and Biliary Drainage in Klatskin Tumor. Cardiovasc Intervent Radiol 2018;41:1885-91. [Crossref] [PubMed]
67. Joliat GR, Chevallier P, Wigmore S, et al. First results from the international registry on liver venous deprivation (EuroLVD). HPB (Oxford) 2025;27:1020-7. [Crossref] [PubMed]
68. Steffen DA, Najafi A, Binkert CA. Transfemoral hepatic vein catheterization reduces procedure time in double vein embolization. CVIR Endovasc 2024;7:49. [Crossref] [PubMed]
69. Korenblik R, Olij B, Aldrighetti LA, et al. Dragon 1 Protocol Manuscript: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy. Cardiovasc Intervent Radiol 2022;45:1391-8. [Crossref] [PubMed]
70. Smet H, Martin D, Uldry E, et al. Tc‐99m mebrofenin hepatobiliary scintigraphy to assess future liver remnant function before major liver surgery. J Surg Oncol 2023;128:1312-9. [Crossref] [PubMed]
71. Zhang S, Song R, Hou C, et al. Simultaneous Liver Venous Deprivation Following Hepatic Arterial Chemoembolization Before Major Hepatectomy for Hepatocellular Carcinoma: A New Methods to Achieve Hypertrophy Liver Remnant. J Hepatocell Carcinoma 2025;12:219-29. [Crossref] [PubMed]
72. Ding C, Wang Z, Dou X, et al. Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis. Aging Dis 2024;15:1508-36. [Crossref] [PubMed]
73. Rinella ME, Lieu HD, Kowdley KV, et al. A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis. Hepatology 2024;79:674-89. [Crossref] [PubMed]
74. Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med 2024;390:497-509. [Crossref] [PubMed]
75. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med 2025;392:2089-99. [Crossref] [PubMed]
76. Wang MJ, Zhang HL, Chen F, et al. The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases. Exp Hematol Oncol 2024;13:62. [Crossref] [PubMed]
77. Gunes A, Schmitt C, Bilodeau L, et al. IL-6 TransSignaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease. Diabetes 2023;72:1820-34. [Crossref] [PubMed]
78. Liu Q, Wang S, Fu J, et al. Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations. Clin Transl Med 2024;14:e1812. [Crossref] [PubMed]
79. Kimura M, Moteki H, Ogihara M. Role of Hepatocyte Growth Regulators in Liver Regeneration. Cells 2023;12:208. [Crossref] [PubMed]
80. Huang M, Jiao J, Cai H, et al. C-C motif chemokine ligand 5 confines liver regeneration by down-regulating reparative macrophage-derived hepatocyte growth factor in a forkhead box O 3a-dependent manner. Hepatology 2022;76:1706-22. [Crossref] [PubMed]
81. Zhao Q, Wu J, Feng M, et al. CXCL13 suppresses liver regeneration through the negative regulation of HGF signaling. Cell Death Dis 2025;16:361. [Crossref] [PubMed]
82. Rizvi F, Everton E, Smith AR, et al. Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA. Nat Commun 2021;12:613. [Crossref] [PubMed]
83. Jindal A, Jagdish RK, Kumar A. Hepatic Regeneration in Cirrhosis. J Clin Exp Hepatol 2022;12:603-16. [Crossref] [PubMed]
84. Abu Rmilah AA, Zhou W, Nyberg SL. Hormonal Contribution to Liver Regeneration. Mayo Clin Proc Innov Qual Outcomes 2020;4:315-38. [Crossref] [PubMed]
85. Dehlke K, Krause L, Tyufekchieva S, et al. Predicting liver regeneration following major resection. Sci Rep 2022;12:13396. [Crossref] [PubMed]
86. Dong X, Lu S, Tian Y, et al. Bavachinin protects the liver in NAFLD by promoting regeneration via targeting PCNA. J Adv Res 2024;55:131-44. [Crossref] [PubMed]
87. Kasahara N, Teratani T, Doi J, et al. Controlled release of hydrogel-encapsulated mesenchymal stem cells-conditioned medium promotes functional liver regeneration after hepatectomy in metabolic dysfunction-associated steatotic liver disease. Stem Cell Res Ther 2024;15:395. [Crossref] [PubMed]
88. Barcena AJR, Owens TC, Melancon S, et al. Current Perspectives and Progress in Preoperative Portal Vein Embolization with Stem Cell Augmentation (PVESA). Stem Cell Rev Rep 2024;20:1236-51. [Crossref] [PubMed]
89. Xie Y, Zhang Z, Pan Y, et al. Stem cells therapies for liver diseases: for current practice and future goals. Hepatol Int 2025;19:1051-76. [Crossref] [PubMed]
90. Zhang X, Li S, Hao L, et al. Influencing factors and mechanism of hepatocyte regeneration. J Transl Med 2025;23:493. [Crossref] [PubMed]
91. Huang WC, Li YC, Chen PX, et al. Mesenchymal stem cell therapy as a game-changer in liver diseases: review of current clinical trials. Stem Cell Res Ther 2025;16:3. [Crossref] [PubMed]
92. Niu H, Wang YN, Ding Y, et al. Stem cell-based therapeutic strategies for liver aging. Liver Res 2025;9:118-31. [Crossref] [PubMed]
93. Zhang L, Deng Y, Bai X, et al. Cell therapy for end-stage liver disease: Current state and clinical challenge. Chin Med J (Engl) 2024;137:2808-20. [Crossref] [PubMed]
94. Hong de F. Percutaneous Microwave Ablation Liver Partition and Portal Vein Embolization for Rapid Liver Regeneration: A Minimally Invasive First Step of ALPPS for Hepatocellular Carcinoma. Ann Surg 2016;264:e1-2. [Crossref] [PubMed]
95. Teo JY, Goh BK. Contra-lateral liver lobe hypertrophy after unilobar Y90 radioembolization: an alternative to portal vein embolization? World J Gastroenterol 2015;21:3170-3. [Crossref] [PubMed]
96. Ahmed A, Stauffer JA, LeGout JD, et al. The use of neoadjuvant lobar radioembolization prior to major hepatic resection for malignancy results in a low rate of post hepatectomy liver failure. J Gastrointest Oncol 2021;12:751-61. [Crossref] [PubMed]
97. Chan KS, Low JK, Shelat VG. Associated liver partition and portal vein ligation for staged hepatectomy: a review. Transl Gastroenterol Hepatol 2020;5:37. [Crossref] [PubMed]
98. Khajeh E, Ramouz A, Dooghaie Moghadam A, et al. Efficacy of Technical Modifications to the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) Procedure: A Systematic Review and Meta-Analysis. Ann Surg Open 2022;3:e221. [Crossref] [PubMed]
99. Gulec SA, Pennington K, Hall M, et al. Preoperative Y-90 microsphere selective internal radiation treatment for tumor downsizing and future liver remnant recruitment: a novel approach to improving the safety of major hepatic resections. World J Surg Oncol 2009;7:6. [Crossref] [PubMed]
100. Wong P, Vien P, Kessler J, et al. Augmenting the Future Liver Remnant Prior to Major Hepatectomy: A Review of Options on the Menu. Ann Surg Oncol 2025;32:5694-709. [Crossref] [PubMed]
101. Primavesi F, Maglione M, Cipriani F, et al. E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy. Br J Surg 2023;110:1331-47. [Crossref] [PubMed]
102. Arntz PJW, Deroose CM, Marcus C, et al. Joint EANM/SNMMI/IHPBA procedure guideline for [99mTc]Tc-mebrofenin hepatobiliary scintigraphy SPECT/CT in the quantitative assessment of the future liver remnant function. HPB 2023;25:1131-44.
103. Lauscher JC, Dixon MEB, Jada G, et al. Prediction of post-hepatectomy liver failure by preoperative gadoxetate disodium-enhanced magnetic resonance imaging. HPB (Oxford) 2024;26:782-8. [Crossref] [PubMed]
104. Yang L, Yang M, Wang T, et al. Comparison of liver venous deprivation with portal vein embolization alone in patients undergoing major liver resection: a systematic review and meta-analysis. HPB (Oxford) 2024;26:1329-38. [Crossref] [PubMed]
105. Bekki Y, Mahamid A, Lewis S, et al. Radiological and pathological assessment with EOB-MRI after Y90 radiation lobectomy prior to liver resection for hepatocellular carcinoma. HPB (Oxford) 2022;24:2185-92. [Crossref] [PubMed]
106. Addeo P, de Mathelin P, De Marini P, et al. Sequential Y(90) liver radioembolization and portal vein embolization: an additional strategy to downstage liver tumors and to enhance liver hypertrophy before major hepatectomies. Langenbecks Arch Surg 2023;408:339. [Crossref] [PubMed]
107. Arar A, Heglin A, Veluri S, et al. Radioembolization of HCC and secondary hepatic tumors: a comprehensive review. Q J Nucl Med Mol Imaging 2024;68:270-87. [Crossref] [PubMed]
108. Badar W, Yu Q, Patel M, et al. Transarterial Radioembolization for Management of Hepatocellular Carcinoma. Oncologist 2024;29:117-22. [Crossref] [PubMed]
109. Entezari P, Gabr A, Kennedy K, et al. Radiation Lobectomy: An Overview of Concept and Applications, Technical Considerations, Outcomes. Semin Intervent Radiol 2021;38:419-24. [Crossref] [PubMed]
110. Yu Q, Wang Y, Ungchusri E, et al. Modified Radiation Lobectomy Strategy of Radioembolization for Right-Sided Unresectable Primary Liver Tumors. J Vasc Interv Radiol 2024;35:989-997.e2. [Crossref] [PubMed]
111. Bartholomä WC, Gilg S, Lundberg P, et al. Magnetic resonance-derived hepatic uptake index improves the identification of patients at risk of severe post-hepatectomy liver failure. Br J Surg 2025;112:znaf103. [Crossref] [PubMed]
112. Huang R, Zhang X, Gracia-Sancho J, et al. Liver regeneration: Cellular origin and molecular mechanisms. Liver Int 2022;42:1486-95. [Crossref] [PubMed]
113. Sergeeva O, Sviridov E, Zatsepin T. Noncoding RNA in Liver Regeneration—From Molecular Mechanisms to Clinical Implications. Semin Liver Dis 2020;40:70-83. [Crossref] [PubMed]
114. Li W, Li L, Hui L. Cell Plasticity in Liver Regeneration. Trends Cell Biol 2020;30:329-38. [Crossref] [PubMed]
115. Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2020;100:62-73. [Crossref] [PubMed]
116. Pretzsch E, Nieß H, Khaled NB, et al. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022;23:12942. [Crossref] [PubMed]
117. Yin Y, Sichler A, Ecker J, et al. Gut microbiota promote liver regeneration through hepatic membrane phospholipid biosynthesis. J Hepatol 2023;78:820-35. [Crossref] [PubMed]
118. Campana L, Esser H, Huch M, et al. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat Rev Mol Cell Biol 2021;22:608-24. [Crossref] [PubMed]