Michael Linecker

Challenges to Liver Transplantation and Strategies to Improve Outcomes

Liver transplantation (LT) is a highly successful treatment for many patients with nonmalignant and malignant liver diseases. However, there is a worldwide shortage of available organs; many patients deteriorate or die while on waiting lists. We review the important clinical challenges to LT and the best use of the scarce organs. We focus on changes in indications for LT and discuss scoring systems to best match donors with recipients and optimize outcomes, particularly for the sickest patients. We also cover controversial guidelines for the use of LT in patients with hepatocellular carcinoma and cholangiocarcinoma. Strategies to increase the number of functional donor organs involve techniques to perfuse the organs before implantation. Partial LT (living donor and split liver transplantation) techniques might help to overcome organ shortages, and we discuss small-for-size syndrome. Many new developments could increase the success of this procedure, which is already one of the major achievements in medicine during the second part of the 20th century.

Meta‐analysis of associating liver partition with portal vein ligation and portal vein occlusion for two‐stage hepatectomy

Discussion is ongoing regarding whether associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) or portal vein occlusion is better in staged hepatectomy. The aim of this study was to compare available strategies using a two‐stage approach in extended hepatectomy.

ALPPS--Where Do We Stand, Where Do We Go?: Eight Recommendations From the First International Expert Meeting.

A ssociated Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) has been associated with many controversial issues since its introduction by Dr Hans Schlitt from Regensburg and the first multicenter series published by Schnitzbauer et al in this journal in 2012. The inaugural report and editorial elicited a tremendous interest from the surgical community followed by a series of letters to the editors highlighting a high rate of complications and mortality in this first series; few at the same time realized the high potential of this new approach. The method rapidly spread beyond Germany, and groups from many countries began reporting their experiences mostly in terms of small case series. Concomitantly, various analyses were performed using the growing international registry (available at: www.alpps.net). Opinions ranged from basically no indication to ALPPS to one of the most striking surgical innovations in liver surgery. In view of accumulating personal experience by many groups and vivid debates at almost each liver meeting, but in the absence of definitive data, it was felt that an expert meeting on ALPPS would be worthwhile as a first step to pave the way for a consensus. After discussing this with colleagues, who have been working on the forefront of ALPPS and after receiving many positive feedbacks from the HPB community, the first expert meeting on ALPPS was held in Hamburg, Germany, in February 2015. An international faculty of 55 members, all with experiences in the ALPPS procedure, together with another 81 registered participants from all continents (many of them also with

Risk Assessment in High- and Low-MELD Liver Transplantation.

Allocation of liver grafts triggers emotional debates, as those patients, not receiving an organ, are prone to death. We analyzed a high–Model of End‐stage Liver Disease (MELD) cohort (laboratory MELD score ≥30, n = 100, median laboratory MELD score of 35; interquartile range 31–37) of liver transplant recipients at our center during the past 10 years and compared results with a low‐MELD group, matched by propensity scoring for donor age, recipient age, and cold ischemia time. End points of our study were cumulative posttransplantation morbidity, cost, and survival. Six different prediction models, including donor age x recipient MELD (D‐MELD), Difference between listing MELD and MELD at transplant (Delta MELD), donor‐risk index (DRI), Survival Outcomes Following Liver Transplant (SOFT), balance‐of‐risk (BAR), and University of California Los Angeles–Futility Risk Score (UCLA‐FRS), were applied in both cohorts to identify risk for poor outcome and high cost. All score models were compared with a clinical‐oriented decision, based on the combination of hemofiltration plus ventilation. Median intensive care unit and hospital stays were 8 and 26 days, respectively, after liver transplantation of high‐MELD patients, with a significantly increased morbidity compared with low‐MELD patients (median comprehensive complication index 56 vs. 36 points [maximum points 100] and double cost [median US

The ALPPS Risk Score: Avoiding Futile Use of ALPPS.

179 631 vs. US

Survival after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for advanced colorectal liver metastases: A case-matched comparison with palliative systemic therapy

80 229]). Five‐year survival, however, was only 8% less than that of low‐MELD patients (70% vs. 78%). Most prediction scores showed disappointing low positive predictive values for posttransplantation mortality, such as mortality above thresholds, despite good specificity. The clinical observation of hemofiltration plus ventilation in high‐MELD patients was even superior in this respect compared with D‐MELD, DRI, Delta MELD, and UCLA‐FRS but inferior to SOFT and BAR models. Of all models tested, only the BAR score was linearly associated with complications. In conclusion, the BAR score was most useful for risk classification in liver transplantation, based on expected posttransplantation mortality and morbidity. Difficult decisions to accept liver grafts in high‐risk recipients may thus be guided by additional BAR score calculation, to increase the safe use of scarce organs.

Ablation Strategies for Locally Advanced Pancreatic Cancer

Objectives: To create a prediction model identifying futile outcome in ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) before stage 1 and stage 2 surgery. Background: ALPPS is a 2-stage hepatectomy, which incorporates parenchymal transection at stage 1 enabling resection of extensive liver tumors. One of the major criticisms of ALPPS is the associated high mortality rate up to 20%. Methods: Using the International ALPPS Registry, a risk analysis for futile outcome (defined as 90-day or in-hospital mortality) was performed. Futility was modeled using multivariate regression analysis and a futility risk score formula was computed on the basis of the relative size of logistic model regression coefficients. Results: Among 528 ALPPS patients from 38 centers, a futile outcome was observed in 47 patients (9%). The pre-stage 1 model included age 67 years or older [odds ratio (OR) = 5.7], and tumor entity (OR = 3.8 for biliary tumors) as independent predictors of futility from multivariate analysis. For the pre-stage 1 model scores of 0, 1, 2, 3, 4 and 5 were associated with futile risk of 2.7%, 4.9%, 8.6%, 15%, 24%, and 37%. The pre-stage 2 model included major complications (grade ≥ 3b) after stage 1 (OR = 3.4), serum bilirubin (OR = 4.4), serum creatinine (OR = 5.4), and cumulative pre-stage 1 risk score (OR = 1.9). The model predicted futility risk of 5%, 10%, 20%, and 50% for patients with scores of 3.9, 4.7, 5.5, and 6.9, respectively. Conclusions: Both models have an excellent prediction to assess the individual risk of futile outcome after ALPPS surgery and can be used to avoid futile use of ALPPS.

Lymph node dissection in resectable perihilar cholangiocarcinoma: a systematic review

Background. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows the resection of colorectal liver metastases with curative intent which would otherwise be unresectable and only eligible for palliative systemic therapy. This study aimed to compare outcomes of ALPPS in patients with otherwise unresectable colorectal liver metastases with matched historic controls treated with palliative systemic treatment. Methods. All patients with colorectal liver metastases from the international ALPPS registry were identified and analyzed. Survival data were compared according to the extent of disease. Otherwise unresectable ALPPS patients were defined by at least 2 of the following criteria: ≥6 metastasis, ≥2 future remnant liver metastasis, ≥6 involved segments excluding segment 1. These patients were matched with patients included in 2, phase 3, metastatic, colorectal cancer trials (CAIRO and CAIRO2) using propensity scoring in order to compare survival. Results. Of 295 patients with colorectal liver metastases in the ALPPS registry, 70 patients had otherwise unresectable disease defined by the proposed criteria. Two‐year overall survival was 49% and 72% for patients with ≥2 and <2 criteria, respectively (P = .002). Median disease‐free survival was 6 months compared to 12 months (P < .001) in the ≥2 and <2 criteria groups, respectively. Median overall survival was comparable between ALPPS patients with ≥2 criteria and case‐matched patients who received palliative treatment (24.0 vs 17.6 months, P = .088). Conclusion. Early oncologic outcomes of patients with advanced liver metastases undergoing ALPPS were not superior to results of matched patients receiving systemic treatment with palliative intent. Careful patient selection is essential in order to improve outcomes.

How much liver needs to be transected in ALPPS? A translational study investigating the concept of less invasiveness.

With the advent of novel and somewhat effective chemotherapy against pancreas cancer, several groups developed a new interest on locally advanced pancreatic cancer (LAPC). Unresectable tumors constitute up to 80% of pancreatic cancer (PC) at the time of diagnosis and are associated with a 5-year overall survival of less than 5%. To control those tumors locally, with perhaps improved patients survival, significant advances were made over the last 2 decades in the development of ablation methods including cryoablation, radiofrequency ablation, microwave ablation, high intensity focused ultrasound and irreversible electroporation (IRE). Many suggested a call for caution for possible severe or lethal complications in using such techniques on the pancreas. Most fears were on the heating or freezing of the pancreas, while non-thermal ablation (IRE) could offer safer approaches. The multimodal therapies along with high-resolution imaging guidance have created some enthusiasm toward ablation for LAPC. The impact of ablation techniques on primarily non-resectable PC remains, however, unclear.

Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss

BACKGROUND Perihilar cholangiocarcinoma is usually unresectable at the time of diagnosis. Only few patients are candidates for a potential curative treatment. For those patients, prognosis is strongly related to negative resection margin and lymph node status. Thus, a certain benchmark of lymph node count is necessary to secure relevant lymph node recovery and to avoid understaging. However, the required minimum number of retrieved lymph nodes remains unclear for perihilar cholangiocarcinoma. The 7th American Joint Committee on Cancer tumor, nodes, metastases edition increased the requirement for the histologic examination of lymph nodes in perihilar cholangiocarcinoma patients from 3 to 15. The applicability of such recommendation appears difficult and questionable. Therefore, the purpose of this systematic review is to evaluate the number of retrieved lymph nodes for staging of patients undergoing surgery for perihilar cholangiocarcinoma. METHODS The MEDLINE, EMBASE, and The Cochrane Library databases were systematically screened up to December 2014. All studies reporting the number of lymph node count in perihilar cholangiocarcinoma were included and assessed for eligibility. RESULTS A total of 725 abstracts were screened and 20 studies were included for analysis, comprising almost 4,000 patients. The cumulative median lymph node count was 7 (2 to 24). A median lymph node count greater than or equal to 15 was reported in 9% of perihilar cholangiocarcinoma patients and could only be achieved in extended lymphadenectomy. Subgroup analysis revealed a median lymph node count of 7 (range 7 to 9), which was associated with the detection of most lymph node positive patients and showed the lowest risk for understaging patients. Lymph node count greater than or equal to 15 did not increase detection rate of lymph node positive patients. CONCLUSIONS This systematic analysis suggests that lymph node count greater than or equal to 7 is adequate for prognostic staging, while lymph node count greater than or equal to 15 does not improve detection of patients with positive lymph nodes.