Robotic living donor hepatectomy is associated with superior outcomes for both the donor and the recipient compared to laparoscopic or open - A single center prospective registry study of 3,448 cases.

Minimally invasive donor hepatectomy is an emerging surgical technique in living donor liver transplantation (LDLT). We examined outcomes across open, laparoscopic, and robotic LDLT using a prospective registry. We analyzed 3,448 cases (1,724 donor-recipient pairs) from Jan 2011 to Mar 2023 (NCT06062706). Among donors, 724 (42%) were female. Adult-to-adult LDLT comprised 1,061 (62%) cases. 646 (37%) of the donors underwent open, 165 (10%) laparoscopic, and 913 (53%) robotic hepatectomies. PRIMARY OUTCOMES: donor overall morbidity was 4% (35/903) for robotic, 8% (13/165) laparoscopic, and 16% (106/646) open (p<0.001). Pediatric and adult recipient mortality was similar among the three donor hepatectomy approaches; robotic 1.5% and 7.0%, compared to 2.3% and 8.3% laparoscopic and 1.6% and 5.5% for open donor surgery, respectively (p=0.802, p=0.564). SECONDARY OUTCOMES: pediatric and adult recipient major morbidity after robotic hepatectomy was 15% and 23%, compared to 25% and 44% laparoscopic and 19% and 31% for open surgery, respectively (p=0.033, p<0.001). Graft and recipient 5-year survival was 90% and 93% for pediatric and 79% and 80% for adults, respectively. In conclusion, robotic LDLT was associated with superior outcomes when compared to the laparoscopic and open approaches. Both donors, and for the first time reported, recipients benefitted with lower morbidity rates in robotic surgery, emphasizing its potential in further advancing this field. IRB APPROVAL ID: RAC 2121012 CLINICALTRIALS.GOV: NCT06062706.

Higher Postoperative Mortality and Inferior Survival After Right-Sided Liver Resection for Perihilar Cholangiocarcinoma: Left-Sided Resection is Preferred When Possible.

BACKGROUND: A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA. METHODS: Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy-left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS). RESULTS: Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p < 0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p < 0.001). Median OS was 30 months (95% confidence interval [CI] 27-34) after left and 23 months (95% CI 20-25) after right liver resection (p < 0.001), and 33 months (95% CI 28-38), 27 months (95% CI 23-32), 25 months (95% CI 21-30), and 21 months (95% CI 18-24) after left, extended left, right, and extended right hepatectomy, respectively (p < 0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities. CONCLUSIONS: A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred.

Navigating the Labyrinth: Intensive Care Challenges for Patients with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) refers to the deterioration of liver function in individuals who already have chronic liver disease. In the setting of ACLF, liver damage leads to the failure of other organs and is associated with increased short-term mortality. Optimal medical management of patients with ACLF requires implementing complex treatment strategies, often in an intensive care unit (ICU). Failure of organs other than the liver distinguishes ACLF from other critical illnesses. Although there is growing evidence supporting the current approach to ACLF management, the mortality associated with this condition remains unacceptably high. In this review, we discuss considerations for ICU care of patients with ACLF and highlight areas for further research.

Predicting futility of upfront surgery in perihilar cholangiocarcinoma: Machine learning analytics model to optimize treatment allocation.

BACKGROUND: While resection remains the only curative option for perihilar cholangiocarcinoma, it is well known that such surgery is associated with a high risk of morbidity and mortality. Nevertheless, beyond facing life-threatening complications, patients may also develop early disease recurrence, defining a "futile" outcome in perihilar cholangiocarcinoma surgery. The aim of this study is to predict the high-risk category (futile group) where surgical benefits are reversed and alternative treatments may be considered. METHODS: The study cohort included prospectively maintained data from 27 Western tertiary referral centers: the population was divided into a development and a validation cohort. The Framingham Heart Study methodology was used to develop a preoperative scoring system predicting the "futile" outcome. RESULTS: A total of 2271 cases were analyzed: among them, 309 were classified within the "futile group" (13.6%). American Society of Anesthesiology (ASA) score ≥ 3 (OR 1.60; p = 0.005), bilirubin at diagnosis ≥50 mmol/L (OR 1.50; p = 0.025), Ca 19-9 ≥ 100 U/mL (OR 1.73; p = 0.013), preoperative cholangitis (OR 1.75; p = 0.002), portal vein involvement (OR 1.61; p = 0.020), tumor diameter ≥3 cm (OR 1.76; p < 0.001), and left-sided resection (OR 2.00; p < 0.001) were identified as independent predictors of futility. The point system developed, defined three (ie, low, intermediate, and high) risk classes, which showed good accuracy (AUC 0.755) when tested on the validation cohort. CONCLUSIONS: The possibility to accurately estimate, through a point system, the risk of severe postoperative morbidity and early recurrence, could be helpful in defining the best management strategy (surgery vs. nonsurgical treatments) according to preoperative features.

Portal and Hepatic Venous Territorial Mapping in Healthy Human Livers: Virtual Three-Dimensional Computed Tomography Size-Shape-Topography Study.

OBJECTIVES: This study aimed to assess portal and hepatic venous volumes as related to the planning of complex liver resections and segmental liver transplant. MATERIALS AND METHODS: We analyzed 3-dimensional computed tomography of portal and hepatic vein territorial maps of 140 potential living related liver donors. Portal and hepatic vein maps were simulated both separately and in overlap (cross-mapping) to calculate inflow and outflow volumes. RESULTS: In total liver volume, the right hemiliver was always dominant (mean 64.7 ± 4.8%) and the right medial sector (mean 36.4 ± 6.8%) and segment 8 (mean 19.1 ± 4.3%) accounted for the largest volumes, whereas the left medial sector(mean 13.5 ± 3.1%) and segment 4A (mean 5.8 ± 1.8%) accounted for the smallest volumes (with exclusion of caudate lobe). The right hepatic vein was dominant for both right hemiliver and right lateral sector and had the largest drainage volume in total liver volume (mean 40.0 ± 11.2%). The left hepatic vein was dominant for both left hemiliver and left lateral sector but had the smallest drainage volume fortotal liver volume (mean 21.3 ± 5.0%). The middle hepatic vein drained 50.2 ± 12.5% of the right medial sector and 75.8 ± 15.4% of the left medial sector. In 67 cases, an accessory vein (inferior hepatic vein) drained 16.5 ± 13.2% ofthe right hemiliver, 31.4 ± 25.1% ofthe right lateral sector, 26.6 ± 23.2% of segment 7, and 37.4 ± 31.3% of segment 6. CONCLUSIONS: The portal and hepatic vein territorial anatomy was characterized by extensive individual variability. An extremely smallremnant volume (<25% of total liver volume) precluded a minority of virtual extended left and a majority of extended right hepatectomies. Left trisectionectomy was associated with risky drainage from the middle hepatic vein, extensive segment 6 remnant congestion volume in 8% of cases, and right lateral sector-favorable inferior hepatic vein large drainage pattern in 13% of livers.

Sex Disparities in Outcomes Following Major Liver Surgery: New Powers of Estrogen?

AIM: To explore potential sex differences in outcomes and regenerative parameters post major hepatectomies. BACKGROUND: Although controversial, sex differences in liver regeneration have been reported for animals. Whether sex disparity exists in human liver regeneration is unknown. METHODS: Data from consecutive hepatectomy patients (55 females, 67 males) and from the international ALPPS (Associating-Liver-Partition-and-Portal-vein-ligation-for-Staged-hepatectomy, a two stage hepatectomy) registry (449 females, 729 males) were analyzed. Endpoints were severe morbidity (≥3b Clavien-Dindo grades), Model for End-stage Liver Disease (MELD) scores, and ALPPS interstage intervals. For validation and mechanistic insight, female-male ALPSS mouse models were established. t , χ 2 , or Mann-Whitney tests were used for comparisons. Univariate/multivariate analyses were performed with sensitivity inclusion. RESULTS: Following major hepatectomy (Hx), males had more severe complications ( P =0.03) and higher liver dysfunction (MELD) P =0.0001) than females. Multivariate analysis established male sex as a predictor of complications after ALPPS stage 1 (odds ratio=1.78; 95% confidence interval: 1.126-2.89; P =0.01), and of enhanced liver dysfunction after stage 2 (odds ratio=1.93; 95% confidence interval: 1.01-3.69; P =0.045). Female patients displayed shorter interstage intervals (<2 weeks, 64% females versus 56% males, P =0.01), however, not in postmenopausal subgroups. In mice, females regenerated faster than males after ALPPS stage 1, an effect that was lost upon estrogen antagonism. CONCLUSIONS: Poorer outcomes after major surgery in males and shorter ALPPS interstage intervals in females not necessarily suggest a superior regenerative capacity of female liver. The loss of interstage advantages in postmenopausal women and the mouse experiments point to estrogen as the driver behind these sex disparities. Estrogen's benefits call for an assessment in postmenopausal women, and perhaps men, undergoing major liver surgery.

Liver growth prediction in ALPPS - A multicenter analysis from the international ALPPS registry.

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.

Consensus care recommendations for alfapump® in cirrhotic patients with refractory or recurrent ascites.

BACKGROUND: The alfapump® is an implantable class III medical device that pumps ascitic fluid from the peritoneal space to the urinary bladder from where it is excreted. The pump reduces or abrogates the need for repeated paracentesis in patients with recurrent or refractory ascites. AIMS: To improve outcomes for alfapump® implantation and pre- and post-implant patient management in both clinical trial and real-world settings by development of consensus recommendations. METHODS: The alfapump® working group consisting of hepatologists and surgeons with extensive experience in implantation of the alfapump® and patient management met on two occasions: (1) to determine the key areas where recommendations should be made; and (2) to discuss the experiences of the working group within those areas and formulate draft statements. Developed statements were submitted to the group and consensus sought on relevance and wording through a collaborative iterative approach in order to consolidate the recommendations into consensus statements. Only recommendations agreed upon unanimously were included. RESULTS: Twenty-three consensus recommendations were developed in the areas of pre-implantation procedure, (three statements), surgical implant procedure (11 statements), immediate post-implant care (three statements) and long-term management (six statements). CONCLUSIONS: The consensus statements are a valuable reference resource for physicians managing patients with the alfapump® and for those considering management strategies for patients with refractory ascites.

Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development.

BACKGROUND: Toll-like receptors (TLRs) are key players in innate immunity and modulation of TLR signaling has been demonstrated to profoundly affect proliferation and growth in different types of cancer. However, the role of TLRs in human intrahepatic cholangiocarcinoma (ICC) pathogenesis remains largely unexplored. AIMS: We set out to determine if TLRs play any role in ICCs which could potentially make them useful treatment targets. METHODS: Tissue microarrays containing samples from 9 human ICCs and normal livers were examined immunohistochemically for TLR4, TLR7, and TLR9 expression. Proliferation of human ICC cell line HuCCT1 was measured by MTS assay following treatment with CpG-ODN (TLR9 agonist), imiquimod (TLR7 agonist), chloroquine (TLR7 and TLR9 inhibitor) and IRS-954 (TLR7 and TLR9 antagonist). The in vivo effects of CQ and IRS-954 on tumor development were also examined in a NOD-SCID mouse xenograft model of human ICC. RESULTS: TLR4 was expressed in all normal human bile duct epithelium but absent in the majority (60%) of ICCs. TLR7 and TLR9 were expressed in 80% of human ICCs. However, TLR7 was absent in all cases of normal human bile duct epithelium and only one was TLR9 positive. HuCCT1 cell proliferation in vitro significantly increased following IMQ or CpG-ODN treatment (P < 0.03 and P < 0.002, respectively) but decreased with CQ (P < 0.02). In the mouse xenograft model there was significant reduction in size of tumors from CQ and IRS-954 treated mice compared to untreated controls. CONCLUSION: TLR7 and TLR9 should be further explored for their potential as actionable targets in the treatment of ICC.

Repeated hepatectomy after ALPPS for recurrence of colorectal liver metastasis: the edge of limits?

BACKGROUND: Repeated liver resections for the recurrence of colorectal liver metastasis (CRLM) are described as safe and have similar oncological outcomes compared to first hepatectomy. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is performed in patients with conventionally non-resectable CRLM. Repeated resections after ALPPS has not yet been described. METHODS: Patients that underwent repeated liver resection in recurrence of CRLM after ALPPS were included in this study. The primary endpoint was morbidity and secondary endpoints were mortality, resection margin and survival. RESULTS: Thirty patients were included in this study. During ALPPS, most of the patients had classical split (60%, n = 18) and clearance of the FLR (77%, n = 23). Hepatic recurrence was treated with non-anatomical resection (57%, n = 17), resection combined with local ablation (13%, n = 4), open ablation (13%, n = 4), segmentectomy (10%, n = 3) or subtotal segmentectomy (7%, n = 2). Six patients (20%) developed complications (10% minor complications). No post-hepatectomy liver failure or perioperative mortality was observed. One-year patient survival was 87%. Five patients received a third hepatectomy. CONCLUSION: Repeated resections after ALPPS for CRLM in selected patients are safe and feasible with low morbidity and no mortality. Survival seems to be comparable with repeated resections after conventional hepatectomy.

How to Handle Arterial Conduits in Liver Transplantation? Evidence From the First Multicenter Risk Analysis.

OBJECTIVE: The aims of the present study were to identify independent risk factors for conduit occlusion, compare outcomes of different AC placement sites, and investigate whether postoperative platelet antiaggregation is protective. BACKGROUND: Arterial conduits (AC) in liver transplantation (LT) offer an effective rescue option when regular arterial graft revascularization is not feasible. However, the role of the conduit placement site and postoperative antiaggregation is insufficiently answered in the literature. STUDY DESIGN: This is an international, multicenter cohort study of adult deceased donor LT requiring AC. The study included 14 LT centers and covered the period from January 2007 to December 2016. Primary endpoint was arterial occlusion/patency. Secondary endpoints included intra- and perioperative outcomes and graft and patient survival. RESULTS: The cohort was composed of 565 LT. Infrarenal aortic placement was performed in 77% of ACs whereas supraceliac placement in 20%. Early occlusion (≤30 days) occurred in 8% of cases. Primary patency was equivalent for supraceliac, infrarenal, and iliac conduits. Multivariate analysis identified donor age >40 years, coronary artery bypass, and no aspirin after LT as independent risk factors for early occlusion. Postoperative antiaggregation regimen differed among centers and was given in 49% of cases. Graft survival was significantly superior for patients receiving aggregation inhibitors after LT. CONCLUSION: When AC is required for rescue graft revascularization, the conduit placement site seems to be negligible and should follow the surgeon's preference. In this high-risk group, the study supports the concept of postoperative antiaggregation in LT requiring AC.

First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases.

OBJECTIVES: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS. BACKGROUND: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking. METHODS: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis. RESULTS: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001). CONCLUSIONS: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

ALPPS for Locally Advanced Intrahepatic Cholangiocarcinoma: Did Aggressive Surgery Lead to the Oncological Benefit? An International Multi-center Study.

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.

ALPPS in neuroendocrine liver metastases not amenable for conventional resection - lessons learned from an interim analysis of the International ALPPS Registry.

BACKGROUND: Surgery is the most effective treatment option for neuroendocrine liver metastases (NELM). This study investigated the role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a novel strategy in treatment of NELM. METHODS: The International ALPPS Registry was reviewed to study patients who underwent ALPPS for NELM. RESULTS: From 2010 to 2017, 954 ALPPS procedures from 135 international centers were recorded in the International ALPPS Registry. Of them, 24 (2.5%) were performed for NELM. Twenty-one patients entered the final analysis. Overall grade ≥3b morbidity was 9% after stage 1 and 27% after stage 2. Ninety-day mortality was 5%. R0 resection was achieved in 19 cases (90%) at stage 2. Median follow-up was 28 (19-48) months. Median disease free survival (DFS) was 17.3 (95% CI: 7.1-27.4) months, 1-year and 2-year DFS was 73.2% and 41.8%, respectively. Median overall survival (OS) was not reached. One-year and 2-year OS was 95.2% and 95.2%, respectively. CONCLUSIONS: ALPPS appears to be a suitable strategy for inclusion in the multimodal armamentarium of well-selected patients with neuroendocrine liver metastases. In light of the morbidity in this initial series and a high rate of disease-recurrence, the procedure should be taken with caution.

Renal Impairment Is Associated with Reduced Outcome After Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy.

BACKGROUND: Impaired postoperative renal function is associated with increased morbidity and mortality after liver resection. The role of impaired renal function in the two-stage hepatectomy setting of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is unknown. METHODS: An international multicenter cohort of ALPPS patients captured in the ALPPS Registry was analyzed. Particular attention was drawn to the renal function in the interstage interval to determine outcome after stage 2 surgery. Interstage renal impairment (RI) was defined as an increase of serum creatinine of ≥ 0.3 mg/dl referring to a preoperative value or an increase of serum creatinine of ≥ 1.5× of the preoperative value on the fifth postoperative day after stage 1. RESULTS: A total of 705 patients were identified of which 7.5% had an interstage RI. Patients developing an interstage RI were significantly older. During stage 1, a longer operation time, higher rate of intraoperative transfusions, and additional procedures were observed in patients that developed interstage RI. After stage 1, interstage RI patients had more major complications and higher interstage mortality (1% vs. 8%, p < 0.001). Furthermore, these patients developed more and severe complications after completion of stage 2. Mortality of patients with interstage RI was 38% vs. 8% without interstage RI. In 41% of patients with interstage RI, the renal function recovered before stage 2; however, the mortality after stage 2 remained 28% in those patients. Risk factors for the development of an interstage RI were age over 67 years, prolonged operative time, and additional procedure during stage 1. CONCLUSION: This study shows that interstage RI is a predictor for interstage and post-stage 2 morbidity and perioperative mortality. The causality of impaired renal function on outcome, however, remains unknown. Interstage RI may directly cause adverse outcome but may also be a surrogate marker for major complications.

Continuous low flow ascites drainage through the urinary bladder via the Alfapump system in palliative patients with malignant ascites.

BACKGROUND: Malignant Ascites (MA) is a therapeutic dilemma significantly impairing patients' quality of life (QoL). The Sequana Medical alfapump System (AP), a subcutaneous, externally rechargeable, implantable device, continually draining ascites via the urinary bladder, has been well established in liver cirrhosis, but not yet in MA. The AP-system was evaluated in cancer patients in reducing the need for large volume paracentesis (LVP). METHODS: A retrospective multicentre evaluation of all eligible patients who received an AP for MA-palliation was performed. AP was evaluated for its ability to reduce LVP and cross-correlated with adverse events (AE), survival and retrospective physician-reported QoL. RESULTS: Seventeen patients with median age of 63 years (range: 18-81), 70.6% female, across 7 primary tumour types were analysed. Median duration of AP-implantation was 60 min (range: 30-270) and median post-implantation hospital stay: 4 days (range: 2-24). Twelve protocol-defined AE occurred in 5 patients (29.4%): 4 kidney failures, 4 pump/catheter-related blockages, 3 infections/peritonitis and 1 wound dehiscence. Median ascitic volume (AV) pumped daily was 303.6 ml/day (range:5.6-989.3) and median total AV drained was 28 L (range: 1-638.6). Median patient post-AP-survival was 111 days (range:10-715) and median pump survival was 89 days (range: 0-715). Median number of paracenteses was 4 (range: 1-15) per patient pre-implant versus 1 (range: 0-1) post-implant (p = 0.005). 71% of patients were reported to have an improvement of at least one physician reported QoL-parameters. CONCLUSIONS: AP appears to be effective in palliating patients with MA by an acceptable morbidity profile. Its broader implementation in oncology services should be further explored. TRIAL REGISTRATION: NCT03200106; June 27, 2017.

Defining Benchmark Outcomes for ALPPS.

OBJECTIVE: The aim of this study was to use the concept of benchmarking to establish robust and standardized outcome references after the procedure ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy). BACKGROUND AND AIMS: The recently developed ALPPS procedure, aiming at removing primarily unresectable liver tumors, has been criticized for safety issues with high variations in the reported morbidity/mortality rates depending on patient, disease, technical characteristics, and center experience. No reference values for relevant outcome parameters are available. METHODS: Among 1036 patients registered in the international ALPPS registry, 120 (12%) were benchmark cases fulfilling 4 criteria: patients ≤67 years of age, with colorectal metastases, without simultaneous abdominal procedures, and centers having performed ≥30 cases. Benchmark values, defined as the 75th percentile of the median outcome parameters of the centers, were established for 10 clinically relevant domains. RESULTS: The benchmark values were completion of stage 2: ≥96%, postoperative liver failure (ISGLS-criteria) after stage 2: ≤5%, ICU stay after ALPPS stages 1 and 2: ≤1 and ≤2 days, respectively, interstage interval: ≤16 days, hospital stay after ALPPS stage 2: ≤10 days, rates of overall morbidity in combining both stage 1 and 2: ≤65% and for major complications (grade ≥3a): ≤38%, 90-day comprehensive complication index was ≤22, the 30-, 90-day, and 6-month mortality was ≤4%, ≤5%, and 6%, respectively, the overall 1-year, recurrence-free, liver-tumor-free, and extrahepatic disease-free survival was ≥86%, ≥50%, ≥57%, and ≥65%, respectively. CONCLUSIONS: This benchmark analysis sets key reference values for ALPPS, indicating similar outcome as other types of major hepatectomies. Benchmark cutoffs offer valid tools not only for comparisons with other procedures, but also to assess higher risk groups of patients or different indications than colorectal metastases.

Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer.

Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.