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Background: Preoperative patient selection in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is not always reliable with currently available scores, particularly in patients with primary liver tumor. This study aims to (I) to determine whether comorbidities and patients characteristics are a risk factor in ALPPS and (II) to create a score predicting 90-day mortality preoperatively. Methods: Thirteen high-volume centers participated in this retrospective multicentric study. A risk analysis based on patient characteristics, underlying disease and procedure type was performed to identify risk factors and model the CAPRA score. A nonparametric receiver operating characteristic analysis was performed to estimate the predictive ability of our score against the Charlson Comorbidity Index (CCI), the age-adjusted CCI (aCCI), the ALPPS risk score before Stage 1 (ALPPS-RS I) and Stage 2 (ALPPS-RS2). The model was internally validated applying bootstrapping. Results: A total of 451 patients were included. Mortality was 14.4%. The CAPRA score is calculated based on the following formula: (0.1*age) - (2*BSA) +1 (in the presence of primary liver tumor) +1 (in the presence of severe cardiovascular disease) +2 (in the presence of moderate or severe diabetes) +2 (in the presence of renal disease) +2 (if classic ALPPS is planned). The predictive ability was 0.837 for the CAPRA score, 0.443 for CCI, 0.519 for aCCI, 0.693 for ALPPS-RS I and 0.807 for ALPPS-RS2. After 1,000 cycles of bootstrapping the C statistic was 0.793. The accuracy plot revealed a cut-off for optimal prediction of postoperative mortality of 4.70. Conclusions: Comorbidities play an important role in ALPPS and should be carefully considered when planning the procedure. By assessing the patients preoperative condition in relation to ALPPS, the CAPRA score has a very good ability to predict postoperative mortality.

Background While ALPPS triggers a fast liver hypertrophy, it is still unclear which factors matter most to achieve accelerated hypertrophy within a short period of time. The aim of the study was to identify patient-intrinsic factors related to the growth of the future liver remnant (FLR). Methods This cohort study is composed of data derived from the International ALPPS Registry from November 2011 and October 2018. We analyse the influence of demographic, tumour type and perioperative data on the growth of the FLR. The volume of the FLR was calculated in millilitre and percentage using computed-tomography (CT) scans before and after stage 1, both according to Vauthey formula. Results A total of 734 patients were included from 99 centres. The median sFLR at stage 1 and stage 2 was 0.23 (IQR, 0.18–0.28) and 0.39 (IQR: 0.31–0.46), respectively. The variables associated with a lower increase from sFLR1 to sFLR2 were age˃68 years (p = .02), height ˃1.76 m (p ˂ .01), weight ˃83 kg (p ˂ .01), BMI˃28 (p ˂ .01), male gender (p ˂ .01), antihypertensive therapy (p ˂ .01), operation time ˃370 minutes (p ˂ .01) and hospital stay˃14 days (p ˂ .01). The time required to reach sufficient volume for stage 2, male gender accounts 40.3% in group ˂7 days, compared with 50% of female, and female present 15.3% in group ˃14 days compared with 20.6% of male. Conclusions Height, weight, FLR size and gender could be the variables that most constantly influence both daily growths, the interstage increase and the standardized FLR before the second stage.

Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.

Background Liver surgery and transplantation currently represent the only curative treatment options for primary and secondary hepatic malignancies. Despite the ability of the liver to regenerate after tissue loss, 25–30% future liver remnant is considered the minimum requirement to prevent serious risk for post-hepatectomy liver failure. Purpose The aim of this review is to depict the various interventions for liver parenchyma augmentation–assisting surgery enabling extended liver resections. The article summarizes one- and two-stage procedures with a focus on hypertrophy- and corresponding resection rates. Conclusions To induce liver parenchymal augmentation prior to hepatectomy, most techniques rely on portal vein occlusion, but more recently inclusion of parenchymal splitting, hepatic vein occlusion, and partial liver transplantation has extended the technical armamentarium. Safely accomplishing major and ultimately total hepatectomy by these techniques requires integration into a meaningful oncological concept. The advent of highly effective chemotherapeutic regimen in the neo-adjuvant, interstage, and adjuvant setting has underlined an aggressive surgical approach in the given setting to convert formerly “palliative” disease into a curative and sometimes in a “chronic” disease.

Background: ALPPS is found to increase the resectability of primary and secondary liver malignancy at the advanced stage. The aim of the study was to verify the surgical and oncological outcome of ALPPS for intrahepatic cholangiocarcinoma (ICC). Methods: The study cohort was based on the ALPPS registry with patients from 31 international centers between August 2009 and January 2018. Propensity score matched patients receiving chemotherapy only were selected from the SEER database as controls for the survival analysis. Results: One hundred and two patients undergoing ALPPS were recruited, 99 completed the second stage with median inter-stage duration of 11 days. The median kinetic growth rate was 23 ml/day. R0 resection was achieved in 87 (85%). Initially high rates of morbidity and mortality decreased steadily to a 29% severe complication rate and 7% 90-day morbidity in the last 2 years. Post-hepatectomy liver failure remained the main cause of 90-day mortality. Multivariate analysis revealed insufficient future liver remnant at the stage-2 operation (FLR2) to be the only risk factor for severe complications (OR 2.91, p = 0.02). The propensity score matching analysis showed a superior overall survival in the ALPPS group compared to palliative chemotherapy (median overall survival: 26.4 months vs 14 months; 1-, 2-, and 3-year survival rates: 82.4%, 70.5% and 39.6% vs 51.2%, 21.4% and 11.3%, respectively, p < 0.01). The survival benefit, however, was not confirmed in the subgroup analysis for patients with insufficient FLR2 or multifocal ICC. Conclusion: ALPPS showed high efficacy in achieving R0 resections in locally advanced ICC. To get the most oncological benefit from this aggressive surgery, ALPPS would be restricted to patients with single lesions and sufficient FLR2.

Background: Successful use of ablation for small hepatocellular carcinomas (HCC) has led to interest in the role of ablation for colorectal liver metastases (CRLM). However, there remains a lack of clarity about the use of ablation for colorectal liver metastases (CRLM), specifically its efficacy compared with hepatic resection. Methods: A systematic review of the literature on ablation or resection of colorectal liver metastases was performed using MEDLINE, Cochrane Library, and Embase until December 2018. The aim of this study was to summarize the evidence for ablation vs. resection in the treatment of CRLM. Results: This review identified 1,773 studies of which 18 were eligible for inclusion. In the majority of the studies, overall survival (OS) and disease-free survival (DFS) were significantly higher and local recurrence (LR) rates were significantly lower in the resection groups. On subgroup analysis of solitary CRLM, resection was associated with improved OS, DFS, and reduced LR. Three series assessed the outcome of resection vs. ablation for technically resectable CRLM, and showed improved outcome in the resection group. In fact, there were no studies showing a survival advantage of ablation compared to resection in the treatment of CRLM. Conclusions: Resection remains the "gold standard" in the treatment of CRLM and should not be replaced by ablation at present. This review supports the use of ablation only as an adjunct to resection and as a single treatment option when resection is not safely possible.

OBJECTIVE: Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has been tested in various indications and clinical scenarios, leading to steady improvements in safety. This report presents the current status of ALPPS. SUMMARY BACKGROUND DATA: ALPPS offers improved resectability, but drawbacks are regularly pointed out regarding safety and oncologic benefits. METHODS: During the 12th biennial congress of the European African-Hepato-Pancreato-Biliary Association (Mainz, Germany, May 23-26, 2017) an expert meeting "10th anniversary of ALPP" was held to discuss indications, management, mechanisms of regeneration, as well as pitfalls of this novel technique. The aim of the meeting was to make an inventory of what has been achieved and what remains unclear in ALPPS. RESULTS: Precise knowledge of liver anatomy and its variations is paramount for success in ALPPS. Technical modifications, mainly less invasive approaches like partial, mini- or laparoscopic ALPPS, mostly aiming at minimizing the extensiveness of the first-stage procedure, are associated with improved safety. In fibrotic/cirrhotic livers the degree of future liver remnant hypertrophy after ALPPS appears some less than that in noncirrhotic. Recent data from the only prospective randomized controlled trial confirmed significant higher resection rates in ALPPS with similar peri-operative morbidity and mortality rates compared with conventional 2-stage hepatectomy including portal vein embolization. ALPPS is effective reliably even after failure of portal vein embolization. CONCLUSIONS: Although ALPPS is now an established 2-stage hepatectomy additional data are warranted to further refine indication and technical aspects. Long-term oncological outcome results are needed to establish the place of ALPPS in patients with initially nonresectable liver tumors.

The ability of the liver to restore its original volume following tissue loss has been associated with the Hippo-YAP1 pathway, a key controller of organ size. Yes-associated protein 1 (YAP1)-a growth effector usually restrained by Hippo signaling-is believed to be of particular importance; however, its role in liver regeneration remains ill-defined. To explore its function, we knocked down YAP1 prior to standard 70%-hepatectomy (sHx) using a hepatocyte-specific nanoformulation. Knockdown was effective during the major parenchymal growth phase (S-phase/M-phase peaks at 32 hours/48 hours post-sHx). Liver weight gain was completely suppressed by the knockdown at 32 hours, but was reaccelerated toward 48 hours. Likewise, proliferative markers, Ccna2/b2 and YAP1 target gene expression were downregulated at 32 hours, but re-elevated at 48 hours post-sHx. Nonetheless, knockdown slightly compromised survival after sHx. When assessing a model of resection-induced liver failure (extended 86%-hepatectomy, eHx) featuring deficient S- and M-phase progression, YAP1 was not induced at 32 hours, but upregulated at 48 hours post-eHx, confirming its dissociation from M-phase regulation. Therefore, YAP1 is vital to push hepatocytes into cycle and through the S-phase, but is not required for further cell cycle progression during liver regeneration. The examination of YAP1 in human livers suggested its function is conserved in the regenerating mammalian liver.

Objective: To evaluate the regional distribution of ventilation in horses during spontaneous breathing and controlled mechanical ventilation (CMV) using electrical impedance tomography (EIT). Study design: Prospective, experimental case series. Animals: Four anaesthetized experimental horses. Methods: Horses were anaesthetized with isoflurane in an oxygen-air mixture and medetomidine continuous rate infusion, placed in dorsal recumbency with an EIT belt around the thorax, and allowed to breathe spontaneously until PaCO2 reached 13.3 kPa (100 mmHg), when volume CMV was started. For each horse, the EIT signal was recorded for at least 2 minutes immediately before (T1), and at 30 (n = 3) or 60 (n = 1) minutes after the start of CMV (T2). The centre of ventilation (CoV), dependent silent spaces (DSS) (likely to represent atelectatic lung areas), non-dependent silent spaces (NSS) (likely to represent lung areas with low ventilation) and total ventilated area (TVA) were evaluated. Cardiac output (CO) was measured and venous admixture and oxygen delivery (DO2) were calculated at T1 and T2. Data are presented as median and range. Results: After the initiation of CMV, the CoV moved ventrally towards the non-dependent lung by 10% [from 57.4% (49.6–60.2%) to 48.3% (41.9–54.4%)]. DSS increased [from 4.1% (0.2–13.9%) to 18.7% (7.5–27.5%)], while NSS [21.7% (9.4–29.2%) to 9.9% (1.0–20.7%)] and TVA [920 (699–1051) to 837 (662–961) pixels] decreased. CO, venous admixture and DO2 also decreased. Conclusions and clinical relevance: In spontaneously breathing anaesthetized horses in dorsal recumbency, ventilation was essentially centred within the dependent dorsal lung regions and moved towards non-dependent ventral regions as soon as CMV was started. This shows a major lack of ventilation in the dependent lung, which may be indicative of atelectasis.

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.

BACKGROUND Solid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome. The novel antihypoxic molecule myo-inositoltrispyrophosphate (ITPP, OXY111A) acts as an allosteric effector of hemoglobin and promotes normoxia in hypoxic tumors. In preclinical studies, tumor growth was reduced and survival prolonged. Additionally, a beneficial side effect profile was observed. METHODS In this first Ib/IIa clinical trial we will assess safety and tolerability of OXY111A as well as a proof of concept regarding efficacy in patients with non-resectable primary and secondary tumors of the liver, pancreas, and biliary tract. The study design is exploratory, prospective, open-labelled and mono-centric. The study is divided in a dose escalation part with a maximum of 48 subjects and an extension part, in which 21 subjects will be included. DISCUSSION The novel antihypoxic compound OXY111A has been tested in several cancer animal models showing beneficial effects for both survival and low side effect profiles. This first in patient application of OXY111A will reveal potential beneficial outcomes if anti-hypoxic therapy is added to standard cytotoxic treatment in patients with primary and secondary hepatopancreatobiliary tumors. TRIAL REGISTRATION Institution Ethical Board Approval ID: KEK-ZH-Nr. 2014-0374; Swiss regulatory authority Swissmedic (2015DR1009); ClinicalTrials.gov Identifier: NCT02528526 , prospectively registered on November 11(th), 2014.

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.

BACKGROUND The body is dependent on the exogenous supply of omega-3 polyunsaturated fatty acids (n3-PUFA). These essential fatty acids are key players in regulating metabolic signaling but also exert anti-inflammatory and anti-carcinogenic properties. The liver is a major metabolic organ involved in fatty acid metabolism. Under experimental conditions, n3-PUFA exert beneficial effect on hepatic steatosis, regeneration and inflammatory insults such as ischemic injury after surgery. Some of these effects have also been observed in human subjects. However, it is unclear whether perioperative administration of n3-PUFA is sufficient to protect the liver from ischemic injury. Therefore, we designed a randomized controlled trial (RCT) assessing n3-PUFA (pre-) conditioning strategies in patients scheduled for liver surgery. METHODS/DESIGN The Omegaven trial is a multi-centric, double-blind, randomized, placebo- controlled trial applying two single doses of Omegaven or placebo on 258 patients undergoing major liver resection. Primary endpoints are morbidity and mortality one month after hospital discharge, defined by the Clavien- Dindo classification of surgical complications (Ann Surg 240(2):205-13, 2004) as well as the Comprehensive Complication Index (CCI) (Ann Surg 258(1):1-7, 2013). Secondary outcome variables include length of Intensive Care Unit (ICU) and hospital stay, postoperative liver function tests, fatty acid and eicosanoid concentration, inflammatory markers in serum and in liver tissue. An interim analysis is scheduled after the first 30 patients per randomization group. DISCUSSION Long-term administration of n3-PUFA have a beneficial effect on metabolism and hepatic injury. Patients often require surgery without much delay, thus long-term n3-PUFA uptake is not possible. Also, lack of compliance may lead to incomplete n3-PUFA substitution. Hence, perioperative Omegaven™ may provide an easy and controllable way to ensure hepaative application of tic protection