Despite improved therapeutic concepts, the survival of patients with hepatocellular carcinoma (HCC) is limited. Liver transplantation (LT) is the best possible treatment for suitable patients. This therapy is of particular importance, because it not only removes the cancer but also cures the underlying structural liver disease. Due to the persistent lack of donor organs, however, the oncological prognosis after LT is of particular importance for fair organ allocation. Bonus points on the organ waiting list are rewarded for tumors within a certain tumor extent. In general, macrovascular invasion and extrahepatic tumor manifestation are considered to be contraindications for LT, as survival in these patients is very low. In recent years, however, microvascular invasion and poorly differentiated tumors have also turned out to be unfavorable. Most selection criteria for LT in HCC are still based on very simple imaging criteria like size and number without utilizing additional imaging characteristics inherent to the tumor nodule, which could be processed in a "virtual biopsy". Recently, diagnostic research has presented the clinical benefit of artificial intelligence (AI) in the use of deep-learning strategies for digital diagnosis of poorly differentiated or microvascular-infiltrated tumors. In addition, evaluation of TACE response is analyzed as a possibility to estimate LT survival. The aim of this review is to provide an overview of recent advances in HCC diagnosis and to classify the clinical relevance of these diagnostic and technical advances. Secondly, we discuss how these advances could affect the organ allocation process.

To assess the impact of the IDEAL (innovation, development, exploration, assessment and long-term) paradigm on the development of ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) in comparison to the evaluation of 2 other revolutionary innovations: laparoscopic cholecystectomy (LC) and robotic surgery. The assessment and development of disruptive procedures often follow a chaotic and unstructured approach. The IDEAL paradigm has offered a sequential 5-stage process to assess controversial surgical strategies like ALPPS, which was introduced in 2012 to expand liver surgery for primarily nonresectable disease. By October 2024, the international ALPPS registry collected 1349 cases from 146 centers in 46 countries. Early reports unveiled an alarming morbidity and perioperative mortality. Accumulating cases in the registry and a consensus conference enabled to reduce the initial 90-day mortality rates >15% to <5% in high-volume centers. Meta-analyses, long-term follow-up and a RCT were available through the growing data in the registry. In comparison, the development of LC was similarly marked by technical advances and a registry to highlight safety (especially bile duct injuries). A small multicenter RCT (and a larger one later) supported an unstoppable wave of rapid adoption by patients and surgeons. Robotic surgery is currently going through close scrutinization by many stakeholders in view of the massive promotion by the industry, but a compelling registry is still missing. ALPPS has now reached a high-level of evaluation with clear guidelines for use thanks to international collaborations and the IDEAL paradigm. This may serve as template for future evaluations of surgical innovations.

Background:Primarily unresectable liver tumors may be approached by the Associating Liver Partition and Portal vein Ligation for Staged Hepatectomy (ALPPS) procedure. Post-hepatectomy liver failure (PHLF) poses the most significant risk factor for poor outcomes. The AST-to-platelets ratio index (APRI)/albumin-to-bilirubin index (ALBI) score has been proposed as an easy and routinely available score to monitor liver function. Here, we explored the predictive capability of the APRI/ALBI score to determine PHLF and perioperative morbidity to help determine the optimal timing of the 2nd stage of ALPPS. Methods:Based on the international multicenter ALPPS registry, patients from 2012 to 2020 with an available APRI/ALBI score were included. Postoperative outcomes (clinically relevant PHLF B + C, 90-day mortality, and severe morbidity (≥ Clavien-Dindo 3b) after ALPPS stage II were assessed. The APRI/ALBI score was monitored perioperatively, and the predictive value was evaluated using logistic regression and receiver operating characteristics. Performance of APRI/ALBI score was compared to the ALPPS futility risk score in this cohort study. Results:Overall, 464 patients from 16 participating centers were included. Clinically relevant PHLF (B + C) was observed in 7.5% of patients, of which 63% ultimately died. After stage I, the APRI/ALBI score gradually recovered. The pre-stage II APRI/ALBI score significantly predicted clinically relevant PHLF [area under the curve (AUC) =0.78; P<0.001], 90-day mortality (AUC =0.67; P=0.002), and severe morbidity (AUC =0.65; P<0.001). Three clinically relevant APRI/ALBI score risk groups were defined: clinically relevant PHLF occurred in 3.1% in the low-, 8.7% in the intermediate-, and 28.0% in the high-risk groups. 90-day mortality was 6.8% in the low-, 15.9% in the intermediate-, and 19.4% in the high-risk groups. Integrated assessment of the established futility risk score in combination with the APRI/ALBI score documented further increased predictive potential for clinically relevant PHLF (AUC 0.81; P<0.001). Conclusions:The APRI/ALBI score allows for simple and dynamic liver function recovery monitoring after the first ALPPS stage. Inadequate recovery of the APRI/ALBI score until ALPPS stage II was associated with PHLF B + C, 90-day mortality, and severe morbidity. With the proposed risk model, optimized timing of the second stage of ALPPS may further increase the safety of this procedure.

OBJECTIVE:To assess the impact of the IDEAL (innovation, development, exploration, assessment and long-term) paradigm on the development of ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) in comparison to the evaluation of 2 other revolutionary innovations: laparoscopic cholecystectomy (LC) and robotic surgery. BACKGROUND:The assessment and development of disruptive procedures often follow a chaotic and unstructured approach. The IDEAL paradigm has offered a sequential 5-stage process to assess controversial surgical strategies like ALPPS, which was introduced in 2012 to expand liver surgery for primarily nonresectable disease. RESULTS:By October 2024, the international ALPPS registry collected 1349 cases from 146 centers in 46 countries. Early reports unveiled an alarming morbidity and perioperative mortality. Accumulating cases in the registry and a consensus conference enabled to reduce the initial 90-day mortality rates >15% to <5% in high-volume centers. Meta-analyses, long-term follow-up and a RCT were available through the growing data in the registry. In comparison, the development of LC was similarly marked by technical advances and a registry to highlight safety (especially bile duct injuries). A small multicenter RCT (and a larger one later) supported an unstoppable wave of rapid adoption by patients and surgeons. Robotic surgery is currently going through close scrutinization by many stakeholders in view of the massive promotion by the industry, but a compelling registry is still missing. CONCLUSIONS:ALPPS has now reached a high-level of evaluation with clear guidelines for use thanks to international collaborations and the IDEAL paradigm. This may serve as template for future evaluations of surgical innovations.

In Germany, organ allocation is based on the MELD-system and lab-MELD is usually low in patients with hepatocellular carcinoma (HCC) in cirrhosis. Higher medical urgency can be achieved by standard exception for HCC (SE-HCC), if Milan criteria (MC) are met. Noteworthy, UNOS T2 reflects MC, but excludes singular lesions < 2 cm. Thus, SE-HCC is awarded to patients with one lesion between 2 and 5 cm or 2 to 3 lesions between 1 and 3 cm. These criteria are static and do not reflect biological properties of HCC.We present a retrospective cohort of 111 patients, who underwent liver transplantation at UKSH, Campus Kiel between 2007 and 2017. No difference was found in overall survival for patient cohorts using Milan, UCSF, up-to-seven, and French-AFP criteria. However, there was a significantly reduced survival, if microvascular invasion was detected in the explanted organ and in patients with HCC-recurrence. The exclusive use of static selection criteria including MC appear to limit the access to liver transplantation.

Abstract Background Perioperative morbidity and mortality remain a point of concern for the Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS) procedure. Post-hepatectomy liver failure (PHLF) after the second step poses the most significant risk factor for futile outcome. Recovery of liver function after the first step of ALPPS is critically important to allow for sufficient liver function after this surgery. The APRI+ALBI score has been proposed as an easily assessable score to monitor liver function and its dynamic recovery. Aims We explored if the APRI+ALBI score was able to assess liver function recovery after the first step of ALPPS and allow for optimal timing of the 2nd step. Methods Based on the ALPPS registry, patients from 2012 to 2020 with available APRI+ALBI score were included. Postoperative outcomes (PHLF A – C, PHLF B + C, 90-day mortality and severe morbidity) were defined as per standard definitions. The APRI/ALBI score was monitored perioperatively. Results Overall, 464 patients from 16 international participating centers in the ALPPS registry were included. Clinically relevant PHLF (B + C) was observed in 7.5 % and of these 63 % of patients ultimately died due to liver failure. The APRI+ALBI score immediately increased after each surgical intervention and continuously decrease thereafter. Failure of the APRI+ALBI score to decrease until the 2nd step of ALPPS predicted PHLF B+C (p = 0.001; AUC 0.78). Particularly patients with high APRI+ALBI scores and short interstage intervals were at risk to develop PHLF B+C. Conclusion The APRI+ALBI score objectifies liver function recovery after the 1st step of ALPPS and failure to sufficiently decreased is associated with a higher risk for PHLF B+C. This might allow for optimized planning of the 2nd step of ALPPS to allow for sufficient liver function recovery to minimize the risk for PHLF B+C and associated futile outcome.

Background and Aims: Alterations in liver histology influence the liver’s capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate. Methods: This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis. Results: In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =−0.1 and r =−0.08, respectively), and future liver remnant ( r =−0.15 and r =−0.06, respectively). Conclusions: ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage.

Objective: The aim of this study was to assess the impact of postoperative hypophosphatemia on liver regeneration after major liver surgery in the scenario of Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) and living liver donation (LLD).Background: Hypophosphatemia has been described to reflect the metabolic demands of regenerating hepatocytes. Both ALPPS and LLD are characterized by an exceptionally strong liver regeneration and may be of particular interest in the context of posthepatectomy hypophosphatemia.Methods: Serum phosphate changes within the first 7 postoperative days after ALPPS (n=61) and LLD (n=54) were prospectively assessed and correlated with standardized volumetry after 1 week. In a translational approach, postoperative phosphate changes were investigated in mice and in vitro.Results: After ALPPS stage 1 and LLD, serum phosphate levels significantly dropped from a preoperative median of 1.08 mmol/L [interquartile range (IQR) 0.92-1.23] and 1.07 mmol/L (IQR 0.91-1.21) to a postoperative median nadir of 0.68 and 0.52 mmol/L, respectively. A pronounced phosphate drop correlated well with increased liver hypertrophy (P<0.001). Patients with a low drop of phosphate showed a higher incidence of posthepatectomy liver failure after ALPPS (7% vs 31%, P=0.041). Like in humans, phosphate drop correlated significantly with degree of hypertrophy in murine ALPPS and hepatectomy models (P<0.001). Blocking phosphate transporter (Slc20a1) inhibited cellular phosphate uptake and hepatocyte proliferation in vitro.Conclusion: Phosphate drop after hepatectomy is a direct surrogate marker for liver hypertrophy. Perioperative implementation of serum phosphate analysis has the potential to detect patients with insufficient regenerative capacity at an early stage.

Supplementary Figure 1. ITPP increases O2 dissociation from hemoglobin. Supplementary Figure 2. Impact of ITPP on tumor burden, hypoxia and survival in the CT- 26/BALB model. Supplementary Figure 3. Impact of ITPP on metabolic and immune parameters in the CT- 26/BALB model at day 17. Supplementary Figure 4. Impact of ITPP on malignant tumor phenotype in the CT-26/BALB model at day 17. Supplementary Figure 5. Impact of oxygen levels and ITPP on cancer cells in vitro. One day after seeding MC-38 and CT-26 cells at hypoxia, cells were exposed or not to normoxia (A-C), or exposed to ITPP or saline (D-F) for 24h. Supplementary Figure 6. Impact of ITPP on tumor vasculature in the MC-38/B6 model at day 17. Supplementary Figure 7. Impact of ITPP on tumor vasculature in the CT-26/BALB model at day 17. Supplementary Figure 8. Long-term impact of ITPP on hypoxic response and tumor vasculature in the CT-26/BALB model.

Surgical liver failure (SLF) develops when a marginal amount of hepatic mass is left after surgery, such as following excessive resection. SLF is the commonest cause of death due to liver surgery; however, its etiology remains obscure. Using mouse models of standard hepatectomy (sHx) (68%, resulting in full regeneration) or extended hepatectomy (eHx) (86%/91%, causing SLF), we explored the causes of early SLF related to portal hyperafflux. Assessing the levels of HIF2A with or without oxygenating agent inositol trispyrophosphate (ITPP) indicated hypoxia early after eHx. Subsequently, lipid oxidation (PPARA/PGC1α) was downregulated and associated with persisting steatosis. Mild oxidation with low-dose ITPP reduced the levels of HIF2A, restored downstream PPARA/PGC1α expression along with lipid oxidation activities (LOAs), and normalized steatosis and other metabolic or regenerative SLF deficiencies. Promotion of LOA with L-carnitine likewise normalized the SLF phenotype, and both ITPP and L-carnitine markedly raised survival in lethal SLF. In patients who underwent hepatectomy, pronounced increases in serum carnitine levels (reflecting LOA) were associated with better recovery. Lipid oxidation thus provides a link between the hyperafflux of O2-poor portal blood, the metabolic/regenerative deficits, and the increased mortality typifying SLF. Stimulation of lipid oxidation-the prime regenerative energy source-particularly through L-carnitine may offer a safe and feasible way to reduce SLF risks in the clinic.

Supplementary Methods and Figure Legends

Patients who have undergone a transplantation have a significantly increased risk of developing a malignancy compared to the normal population. The risk of tumour development depends mainly on the type of the transplanted organ, the dose and duration of immunosuppression, as well as the patient's medical history, and may require individualised pre-transplant and post-transplant care. Standard immunosuppression is usually based on a combination of tacrolimus with mycophenolic acid/enteric-coated mycophenolic acid or, more rarely, a mTor inhibitor. Induction therapy may allow baseline immunosuppression to be delayed and/or started at a reduced dose. The most frequent long-term complications after liver transplantation include calcineurin inhibitor-associated nephrotoxicity; in addition, transplanted patients have an increased cardiovascular (kidney transplantation), infection and tumour risk (liver, kidney transplantation), depending on the time course after transplantation and the type of immunosuppression. To minimise long-term complications, individualised immunosuppression is recommended, taking comorbidities into account.

Background: Associating liver partition and portal vein ligation (ALPPS) has evolved as a treatment strategy for patients with liver tumors who are not amenable for upfront hepatectomy because of an insufficient future liver remnant (FLR). Aim of this study was to test the applicability of ultrasound guided parenchyma sparing surgery to ALPPS concept, by non-anatomically shifting the plane of transection in favor of FLR, resulting in a new technical variant of ALPPS, entitled parenchyma sparing ALPPS (psALPPS). Materials and Methods: Patients who could not safely undergo right trisectionectomy ALPPS because of insufficient FLR were considered eligible for psALPPS, consisting in liver partition through segment 4 using ultrasound guidance. Results: Between April 2017 and April 2021, five patients with median age of 68 years (range: 66-78), four male and one female, underwent psALPPS for colorectal liver metastases (N=2), intrahepatic cholangiocarcinoma (N=2), and hepatocellular carcinoma (N=1). Standardized FLR (sFLR) for segments 2-3 before stage 1 surgery would have been a median of 11.6%. PsALPPS could double the sFLR at stage 1 resulting in an increase of ps-sFLR from a median of 22.7% (at stage 1) to 34.0% (at stage 2) after a median interstage interval of 15 days. All patients tolerated surgery well and no major complications were recorded. Conclusions: Applying the principles of parenchyma sparing surgery to ALPPS offers the advantage to maximize FLR and simultaneously reduce ischemic injury of segment 4 compared to conventional ALPPS. In this way, psALPPS may markedly increase resectability while reducing morbidity.

BACKGROUNDThe surgical management of bile duct injuries (BDIs) after laparoscopic cholecystectomy (LC) is challenging and the optimal timing of surgery remains unclear. The primary aim of this study was to systematically evaluate the evidence behind the timing of BDI repair after LC in the literature.AIMTo assess timing of surgical repair of BDI and postoperative complications.METHODSThe MEDLINE, EMBASE, and The Cochrane Library databases were systematically screened up to August 2021. Risk of bias was assessed via the Newcastle Ottawa scale. The primary outcomes of this review included the timing of BDI repair and postoperative complications.RESULTSA total of 439 abstracts were screened, and 24 studies were included with 15609 patients included in this review. Of the 5229 BDIs reported, 4934 (94%) were classified as major injury. Timing of bile duct repair was immediate (14%, n = 705), early (28%, n = 1367), delayed (28%, n = 1367), or late (26%, n = 1286). Standardization of definition for timing of repair was remarkably poor among studies. Definitions for immediate repair ranged from < 24 h to 6 wk after LC while early repair ranged from < 24 h to 12 wk. Likewise, delayed (> 24 h to > 12 wk after LC) and late repair (> 6 wk after LC) showed a broad overlap.CONCLUSIONThe lack of standardization among studies precludes any conclusive recommendation on optimal timing of BDI repair after LC. This finding indicates an urgent need for a standardized reporting system of BDI repair.

Introduction: Robotic-assisted liver surgery (RALS) with its known limitations is gaining more importance. The fluorescent dye, indocyanine green (ICG), is a way to overcome some of these limitations. It accumulates in or around hepatic masses. The integrated near-infrared cameras help to visualize this accumulation. We aimed to compare the influence of ICG staining on the surgical and oncological outcomes in patients undergoing RALS. Material and Methods: Patients who underwent RALS between 2014 and 2021 at the Department of General Surgery at the University Hospital Schleswig-Holstein, Campus Kiel, were included. In 2019, ICG-supported RALS was introduced. Results: Fifty-four patients were included, with twenty-eight patients (50.9%) receiving preoperative ICG. Hepatocellular carcinoma (32.1%) was the main entity resected, followed by the metastasis of colorectal cancers (17%) and focal nodular hyperplasia (15.1%). ICG staining worked for different tumor entities, but diffuse staining was noted in patients with liver cirrhosis. However, ICG-supported RALS lasted shorter (142.7 ± 61.8 min vs. 246.4 ± 98.6 min, p < 0.001), tumors resected in the ICG cohort were significantly smaller (27.1 ± 25.0 mm vs. 47.6 ± 35.2 mm, p = 0.021) and more R0 resections were achieved by ICG-supported RALS (96.3% vs. 80.8%, p = 0.075). Conclusions: ICG-supported RALS achieve surgically and oncologically safe results, while overcoming the limitations of RALS.

IntroductionObesity is frequently associated with its hepatic manifestation, the nonalcoholic fatty liver disease (NAFLD). The most effective treatment for morbid obesity is bariatric surgery (BS) also improving NAFLD and liver function. In patients where NAFLD has already progressed to liver cirrhosis, BS can be considered a high-risk procedure. Hence, consideration of the procedure and the most appropriate timing is crucial.Material and MethodsObese patients suffering from NAFLD who underwent BS from two German University Medical Centers were retrospectively analyzed.ResultsTwenty-seven patients underwent BS. Most common procedures were laparoscopic Roux-en-Y-gastric (RYGB) and laparoscopic sleeve gastrectomy (SG). All patients suffered from liver cirrhosis Child A. A preoperative transjugular portosystemic shunt (TIPS) was established in three patients and failed in another patient. Postoperative complications consisted of wound healing disorders (n = 2), anastomotic bleeding (n = 1), and leak from the staple line (n = 1). This patient suffered from intraoperatively detected macroscopic liver cirrhosis. Excess weight loss was 73% and 85% after 1 and 2 years, respectively. Two patients suffered from postoperative aggravation of their liver function, resulting in a higher Child–Pugh score, while three could be removed from the waiting list for a liver transplantation.ConclusionBS leads to weight loss, both after SG and RYGB, and potential improvement of liver function in liver cirrhosis. These patients need to be considered with care when evaluated for BS. Preoperative TIPS implantation may reduce the perioperative risk in selected patients.

The therapeutic spectrum of hepatocellular carcinoma (HCC) in cirrhosis has expanded over the last decade and consists of surgical, interventional and systemic approaches. The tumor stage and liver function are important for the therapeutic strategy. Curation can be achieved by liver resection or transplantation. Access to transplantation is limited by organ shortage and waiting time. Locoregional therapies can be used as a bridge to transplant or for down-sizing in a neoadjuvant setting as well as palliative therapy. Advanced stages might benefit from systemic or immunotherapy. Modern multimodal therapy planning, timing and reevaluation are part of the tasks of tumor boards specialised in the liver, including the option of liver transplantation. Therapies can be used alone or in combination and according to the experience of the center. A curative strategy should always be pursued at initial presentation.

Liver transplantation (LT) is the only definitive treatment to cure hepatocellular carcinoma (HCC) in cirrhosis. Waiting-list candidates are selected by the model for end-stage liver disease (MELD). However, many indications are not sufficiently represented by labMELD. For HCC, patients are selected by Milan-criteria: Milan-in qualifies for standard exception (SE) and better organ access on the waiting list; while Milan-out patients are restricted to labMELD and might benefit from extended criteria donor (ECD)-grafts. We analyzed a cohort of 102 patients (2011–2020). Patients with labMELD (no SE, Milan-out, n = 56) and matchMELD (SE-HCC, Milan-in, n = 46) were compared. The median overall survival was not significantly different (p = 0.759). No difference was found in time on the waiting list (p = 0.881), donor risk index (p = 0.697) or median costs (p = 0.204, EUR 43,500 (EUR 17,800–185,000) for labMELD and EUR 30,300 (EUR 17,200–395,900) for matchMELD). Costs were triggered by a cut-off labMELD of 12 points. Overall, the deficit increased by EUR 580 per labMELD point. Cost drivers were re-operation (p < 0.001), infection with multiresistant germs (p = 0.020), dialysis (p = 0.017), operation time (p = 0.012) and transfusions (p < 0.001). In conclusion, this study demonstrates that LT for HCC is successful and cost-effective in low labMELD patients independent of Milan-criteria. Therefore, ECD-grafts are favorized in Milan-out HCC patients with low labMELD.

Dieser Artikel soll einen Überblick über den Einsatz und mögliche Probleme der immunsuppressiven Therapie nach solider Organtransplantation (SOT) geben. Für einige Immunsuppressiva sind andere Empfehlungen bezüglich der angestrebten Talblutspiegel angegeben, als dies in der Fachinformation empfohlen ist. Wir möchten ausdrücklich darauf hinweisen, dass es sich hierbei um die persönliche Meinung der Autor*innen handelt.