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For a highly selected group of patients with unresectable perihilar cholangiocarcinoma (pCCA), liver transplantation (LT) is a treatment option. The Dutch screening protocol comprises nonregional lymph node (LN) assessment by EUS, and whenever LN metastases are identified, further LT screening is precluded. The aim of this study is to investigate the yield of EUS in patients with pCCA who are potentially eligible for LT. In this retrospective, nationwide cohort study, all consecutive patients with suspected unresectable pCCA who underwent EUS in the screening protocol for LT were included from 2011 to 2021. During EUS, sampling of a "suspicious" nonregional LN was performed based on the endoscopist's discretion. The primary outcome was the added value of EUS, defined as the number of patients who were precluded from further screening because of malignant LNs. A total of 75 patients were included in whom 84 EUS procedures were performed, with EUS-guided tissue acquisition confirming malignancy in LNs in 3 of 75 (4%) patients. In the 43 who underwent surgical staging according to the protocol, nonregional LNs with malignancy were identified in 6 (14%) patients. Positive regional LNs were found in 7 patients in post-LT-resected specimens. Our current EUS screening for the detection of malignant LNs in patients with pCCA eligible for LT shows a limited but clinically important yield. EUS with systematic screening of all LN stations, both regional and nonregional, and the sampling of suspicious lymph nodes according to defined and set criteria could potentially increase this yield. [Display omitted] [ABSTRACT FROM AUTHOR]

Evaluation of morbidity and mortality after hepatic resection often lacks stratification by extent of resection or diagnosis. Although a liver resection for different indications may have technical similarities, postoperative outcomes differ. The aim of this systematic review and meta-analysis was to determine the risk of major complications and mortality after resection of intrahepatic cholangiocarcinoma. Meta-analysis was performed to assess postoperative mortality (in-hospital, 30-, and 90-day) and major complications (Clavien-Dindo grade ≥III). A total of 32 studies that reported on 19,503 patients were included. Pooled in-hospital, 30-day, and 90-day mortality were 5.9% (95% confidence interval 4.1–8.4); 4.6% (95% confidence interval 4.0–5.2); and 6.1% (95% confidence interval 5.0–7.3), respectively. Pooled proportion of major complications was 22.2% (95% confidence interval 17.7–27.5) for all resections. The pooled 90-day mortality was 3.1% (95% confidence interval 1.8–5.2) for a minor resection, 7.4% (95% confidence interval 5.9–9.3) for all major resections, and 11.4% (95% confidence interval 6.9–18.7) for extended resections (P =.001). Major complications were 38.8% (95% confidence interval 29.5–49) after a major hepatectomy compared to 11.3% (95% confidence interval 5.0–24.0) after a minor hepatectomy (P =.001). Asian studies had a pooled 90-day mortality of 4.4% (95% confidence interval 3.3–5.9) compared to 6.8% (95% confidence interval 5.6–8.2) for Western studies (P =.02). Cohorts with patients included before 2000 had a pooled 90-day mortality of 5.9% (95% confidence interval 4.8–7.3) compared to 6.8% (95% confidence interval 5.1–9.1) after 2000 (P =.44). When informing patients or comparing outcomes across hospitals, postoperative mortality rates after liver resection should be reported for 90-days with consideration of the diagnosis and the extent of liver resection. [ABSTRACT FROM AUTHOR]

Objective: This study investigates whether liver grafts donated after circulatory death (DCD) that are declined by the entire Eurotransplant region can be salvaged with abdominal normothermic regional perfusion (aNRP). Background: aNRP is increasingly used for DCD liver grafts because it prevents typical complications. However, it is unclear whether aNRP is capable to rescue pretransplant declined liver grafts by providing the opportunity to test function during donation. Methods: Donor livers from DCD donors, declined by all centers in the Eurotransplant region, were included for this study. The comparator cohort included standard DCD livers and livers donated after brain death, transplanted in the same time period. Results: After the withdrawal of life-sustaining treatment, 28 from the 43 donors had a circulatory death within 2 hours, in which case aNRP was initiated. Of these 28 cases, in 3 cases perfusion problems occurred, 5 grafts were declined based on liver assessment, and 20 liver grafts were transplanted. The main differences during aNRP between the transplanted grafts and the assessed nontransplanted grafts were alanine transaminase levels of 53 U/L (34–68 U/L) versus 367 U/L (318–488 U/L) (P =0.001) and bile production in 100% versus 50% of the grafts (P =0.024). The 12-month graft and patient survival were both 95%, similar to the comparator cohort. The incidence of ischemic cholangiopathy was 11%, which was lower than in the standard DCD cohort (18%). Conclusion: aNRP can safely select and thus is able to rescue DCD liver grafts that were deemed unsuitable for transplantation, while preventing primary nonfunction and minimizing ischemic cholangiopathy. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the incidence and risk factors of primary and secondary liver failure after major liver resection for perihilar cholangiocarcinoma. All patients who underwent a major liver resection for presumed perihilar cholangiocarcinoma between 2000 and 2020 at 2 tertiary-referral hospitals were included. Liver failure was defined according to the International Study Group for Liver Surgery criteria, and only grade B/C was considered clinically relevant. Primary liver failure was defined as failure without any underlying postoperative cause, and secondary liver failure was defined as liver failure with an onset after an underlying postoperative complication as a cause. The incidence of liver failure and 90-day mortality were 20.9% and 17.0% in the 253 included patients, respectively. The incidences of primary liver failure was 9.1% and secondary liver failure was 11.9%. Abdominal sepsis, portal vein thrombosis, and arterial thrombosis were the most frequent causes. The absence of preoperative remnant liver assessment and blood loss were independent risk factors for primary liver failure. Independent risk factors for secondary liver failure were Eastern Cooperative Oncology group performance status, percutaneous biliary drainage, and preoperative cholangitis. Liver failure after major liver resection for perihilar cholangiocarcinoma occurred in 1 of every 5 patients. The proposed subdivision into primary and secondary liver failure could help to understand differences in outcomes between centers and help to reduce liver failure. [ABSTRACT FROM AUTHOR]

Objective: To test the total burden of complications in the early postoperative period after liver transplantation (LT) between donation after circulatory death (DCD) and donation after brain death (DBD) grafts with the novel Comprehensive Complication Index (CCI). Background: LTis complex surgery and the increasing use of high-risk grafts is pressuring current postoperative outcomes. DCD grafts in particular are associated with ischemic-type biliary lesions (ITBL) with subsequent impaired graft survival rates. Methods: Retrospective single-center study of all LT since the start of DCD program (2001-2015). CCI (at hospital discharge and after 6 months) was the result of all complications weighted by their Clavien-Dindo grade. A multiple logistic regression model was used to identify factors associated with a complex postoperative course (CCI at 6 months >60). Results: In total, 441 cases were included: 115 DCD and 326 DBD grafts. Median in-hospital CCI was comparable for both groups (DCD 38.2; DBD 36.7; P = 0.429). Six-month postoperative median CCI was significantly higher for DCD grafts (53.4 vs 47.2; P = 0.041). Moreover, more DCD recipients underwent retransplantation for ITBL in this period (4% vs 1%; P= 0.031). Logistic regression identified recipient BMI (P = 0.046), recipient warm ischemia time (odds ratio, OR, 1.032; 95% CI, 1.008-1.056; P = 0.008), and DCD graft (OR 3.913; 95% CI 1.200-12.767; P = 0.024) as risk factors for a CCI >60. Conclusions: This analysis shows a comparable complication rate during the index hospital stay for DCD and DBD LT, but the CCI increases significantly for DCD recipients in 6 months after transplantation. Reduction of biliary complications, especially ITBL, is needed to improve the outcomes for DCD grafts. [ABSTRACT FROM AUTHOR]

Background: This study analyzes the outcome of esophageal resection in patients 70 or more years of age, compared with patients aged less than 70 years and identifies risk factors for worse outcome in the elderly. Methods: Comorbidity, postoperative morbidity, in-hospital mortality and survival rates were compared between 811 patients aged less than 70 years and 250 patients aged 70 years or more who underwent esophagectomy for esophageal cancer in a single high-volume center from 1985 to 2005. Results: Groups were similar regarding surgical approach, resectability, and tumor stage. More patients aged 70 years or more had cardiovascular and respiratory concomitant disease. Among patients aged 70 years or more, the prevalence of adenocarcinoma and Barrett''s transformation was higher (67% versus 53% for patients aged less than 70 years, and 22% versus 15%, respectively). There were no differences in surgical complications (20% versus 17%). Nonsurgical complications occurred more in patients aged 70 years or more (35% versus 27%) and operative mortality was higher among elderly patients (8.4 versus 3.8%), as was in-hospital mortality (11.6% versus 5.4%). The disease-specific 5-year survival was lower for patients aged 70 years or more (27% versus 34%). The 1-year survival, reflecting the impact of operative morbidity and mortality, was 58% for patients aged 70 years or more and 68% for the patients aged less than 70 years (p = 0.002). Among patients aged 70 years or more, respiratory comorbidity and thoracoabdominal resection were risk factors for the occurrence of nonsurgical complications and respiratory comorbidity for in-hospital mortality. Conclusions: Older patients have increased operative and in-hospital mortality and decreased 5-year survival after esophageal resection for cancer. Our results indicate that especially thoracoabdominal resection for esophageal carcinoma should be carefully considered for patients older than 70 years who suffer from respiratory disease. [Copyright &y& Elsevier]

Background: Esophagectomy with gastric tube reconstruction is the surgical treatment for cancer of the esophagus. Perfusion of the anastomotic site of the tube depends exclusively on microcirculation, making it susceptible to hypoperfusion. It is unknown whether vasodilatation is superior to increased perfusion pressure to improve gastric tissue perfusion of the anastomosis. Methods: We performed a gastric tube reconstruction in 12 pigs, mean body weight 32 ± 2 kg. Besides systemic hemodynamic parameters, gastric microvascular blood flow (MBF) was assessed with laser Doppler flowmetry and gastric microvascular HbO2 saturation (μHbSO2) and Hb concentration (μHbcon) with spectrophotometry. Animals were randomized over 2 groups: with and without intravenous nitroglycerin (NTG). In both groups, mean arterial pressure (MAP) was increased from 50 to 110 mmHg with infusion of norepinephrine; in the NTG group, central venous pressure was maintained below 10 mmHg throughout the experiment with NTG. Results: Except for central venous and pulmonary capillary wedge pressures, all hemodynamic parameters were similar in both groups. Especially in corpus and fundus, MBF decreased following surgery. However, overall MBF was significantly higher in the NTG group. Increasing MAP had no effect on fundus MBF. Gastric μHbSO2 and μHbcon were not different between groups and did not change at higher MAP levels. Conclusion: In our experimental model of gastric tube reconstruction, tissue perfusion is severely compromised; this effect is aggravated by systemic hypotension independent from cardiac output. Impaired venous outflow might contribute to this effect and can be counteracted with infusion of nitroglycerine. [Copyright &y& Elsevier]

Since the introduction of the Model for End-stage Liver disease criteria in 2002, more combined liver kidney transplants are performed. Until 2017, no standard allocation policy for combined liver kidney transplant (CLKT) was available and each transplant center decided eligibility for CLKT or liver transplant alone (LTA) on a case-by-case basis. The aim of this systematic review was to compare the clinical outcomes of CLKT compared to LTA in patients with renal dysfunction. Databases were systematically searched for studies published between January 2010 and March 2021. Outcomes were expressed as risk ratios and pooled with a random-effects model. The primary outcome was patient survival. Four studies were included. No differences were observed for mortality risk at 1 year (risk ratio (RR) 1.03 [confidence interval (CI) 0.97–1.09], 3 years (RR 1.06 [CI 0.99–1.13]) and 5 years (RR 1.08 [CI 0.98–1.19]). The risk of graft loss was similar in the first year (RR 1.10 [CI 0.93–1.30], while 3-year risk of graft loss was significantly lower in CLKT patients (RR 1.15 [CI 1.08–1.24]). CLKT has similar short-term graft and patient survival as LTA in patients with renal dysfunction. More data is needed to decide from which KDIGO stage patients benefit the most from CLKT. • This is the first systematic review to compare combined liver-kidney transplants (CLKT) to liver transplant alone (LTA). • Until 2017 no allocation policy existed to determine who was eligible for CLKT or LTA. • CLKT has similar short-term graft and patient survival as LTA in patients with renal dysfunction. • Risk of graft loss was significantly higher at 3 years for LTA compared to CLKT with renal dysfunction. • CLKT seems to be an appropriate therapeutic option for patients with both end stage liver and renal dysfunction. [ABSTRACT FROM AUTHOR]

Background & Aims Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell–mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non–small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 + and CD8 + T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. Methods We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 + and CD4 + T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Results Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 + and CD4 + T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 + TIL, compared with other CD8 + TIL. Compared with TIL that did not express these inhibitory receptors, CD8 + and CD4 + TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 + and CD4 + TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. Conclusions The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. [ABSTRACT FROM AUTHOR]