Procalcitonin in early allograft dysfunction after orthotopic liver transplantation: a retrospective single centre study.

BACKGROUND: Ischemia-reperfusion injury (IRI) is the pathophysiological hallmark of hepatic dysfunction after orthotopic liver transplantation (OLT). Related to IRI, early allograft dysfunction (EAD) after OLT affects short- and long-term outcome. During inflammatory states, the liver seems to be the main source of procalcitonin (PCT), which has been shown to increase independently of bacterial infection. This study investigates the association of PCT, IRI and EAD as well as the predictive value of PCT during the first postoperative week in terms of short- and long-term outcome after OLT. METHODS: Patients ≥ 18 years undergoing OLT between January 2016 and April 2020 at the University Hospital of Zurich were eligible for this retrospective study. Patients with incomplete PCT data on postoperative days (POD) 1 + 2 or combined liver-kidney transplantation were excluded. The PCT course during the first postoperative week, its association with EAD, defined by the criteria of Olthoff, and IRI, defined as aminotransferase level > 2000 IU/L within 2 PODs, were analysed. Finally, 90-day as well as 12-month graft and patient survival were assessed. RESULTS: Of 234 patients undergoing OLT, 110 patients were included. Overall, EAD and IRI patients had significantly higher median PCT values on POD 2 [31.3 (9.7-53.8) mcg/l vs. 11.1 (5.3-25.0) mcg/l; p < 0.001 and 27.7 (9.7-51.9) mcg/l vs. 11.5 (5.5-25.2) mcg/l; p < 0.001] and impaired 90-day graft survival (79.2% vs. 95.2%; p = 0.01 and 80.4% vs. 93.8%; p = 0.033). IRI patients with PCT < 15 mcg/l on POD 2 had reduced 90-day graft and patient survival (57.9% vs. 93.8%; p = 0.001 and 68.4% vs. 93.8%; p = 0.008) as well as impaired 12-month graft and patient survival (57.9% vs. 96.3%; p = 0.001 and 68.4% vs. 96.3%; p = 0.008), while the outcome of IRI patients with PCT > 15 mcg/l on POD 2 was comparable to that of patients without IRI/EAD. CONCLUSION: Generally, PCT is increased in the early postoperative phase after OLT. Patients with EAD and IRI have a significantly increased PCT maximum on POD 2, and impaired 90-day graft survival. PCT measurement may have potential as an additional outcome predictor in the early phase after OLT, as in our subanalysis of IRI patients, PCT values < 15 mcg/l were associated with impaired outcome.

Proceedings of the 26th Annual Virtual Congress of the International Liver Transplantation Society.

After a 1-y absence due to the coronavirus disease 2019 pandemic, the 26th Annual Congress of the International Liver Transplantation Society was held from May 15 to 18, 2021, in a virtual format. Clinicians and researchers from all over the world came together to share their knowledge on all the aspects of liver transplantation (LT). Apart from a focus on LT in times of coronavirus disease 2019, featured topics of this year's conference included infectious diseases in LT, living donation, machine perfusion, oncology, predictive scoring systems and updates in anesthesia/critical care, immunology, radiology, pathology, and pediatrics. This report presents highlights from invited lectures and a review of the select abstracts. The aim of this report, generated by the Vanguard Committee of International Liver Transplantation Society, is to provide a summary of the most recent developments in clinical practice and research in LT.

Morbidity and mortality of iatrogenic hemothorax occurring in a cohort of liver transplantation recipients: a multicenter observational study.

Hemothorax (HT) is a life-threatening condition, mainly iatrogenic and poorly explored in Liver Transplantation (LT) recipients. The aim of this study is to report and analyze for the first time incidence and outcomes of HT in LT recipients, as well as to suggest a management strategy. Data concerning 7130 consecutive adult liver and liver-kidney transplant recipients were retrospectively collected from ten Transplantation Centers' institutional databases, over a 10-year period. Clinical parameters, management strategies and survival data about post-operative HT were analyzed and reported. Thirty patients developed HT during hospitalization (0.42%). Thoracentesis was found to be the most common cause of HT (16 patients). A non-surgical management was performed in 17 patients, while 13 patients underwent surgery. 19 patients developed thoracic complications after HT treatment, with an overall mortality rate of 50%. The median length of stay in Intensive Care Units was 22 days (IQR25-75 5-66.5). Postoperative hemothorax is mainly due to iatrogenic causes in LT recipients. Despite rare, it represents a serious complication with a high mortality rate and a challenging medical and surgical management. Its occurrence should always be prevented.

Intention to treat outcomes among patients with pancreatic cancer treated using International Study Group on Pancreatic Surgery recommended pathways for resectable and borderline resectable disease.

BACKGROUND: The International Study Group on Pancreatic Surgery recommends upfront surgery for resectable pancreatic cancer or borderline resectable-venous (BR-V) disease and neoadjuvant therapy (NAT) among those with arterial involvement (BR-A or locally advanced, LA). Though neoadjuvant therapy (NAT) is a promising strategy, outcomes are rarely reported on intention-to-treat (ITT) basis. This study presents ITT outcomes where pathways to surgery were in line with International Study Group on Pancreatic Surgery guidelines. METHODS: Patients recommended for potentially curative treatment with PDAC between 2012 and 2017 (n = 345) were classified as resectable, BR-A/BR-V or LA, according to NCCN criteria. The primary outcome was overall survival. Secondary outcomes were resection rates, positive margins and toxicity among patients receiving NAT. RESULTS: At surgery, the resection rates were 78% (172/221), 65% (35/54) and 54% (21/39) for those with resectable, BR-V and BR-A/LA disease, respectively (P < 0.0001). The median survival of those resected in the BR-A/LA cohort was 31 months. However, on an ITT basis, there was no significant difference in survival between resectable, BR-V and BR-A/LA disease (median: 19 versus 15 versus 19 months; P = 0.585). On review, some 31 (44%) patients of the BR-A/LA cohort either did not receive or did not complete NAT. CONCLUSION: To realize benefits of NAT, more patients need to complete NAT and to undergo resection. Upfront resection for BR-V disease is associated with equivalent outcomes to upfront surgery for resectable disease or NAT for BR-A/LA disease. Strategies to increase the proportion of patients who complete NAT and undergo resection are needed.

Hypothermic Oxygenated Liver Perfusion (HOPE) Prevents Tumor Recurrence in Liver Transplantation From Donation After Circulatory Death.

OBJECTIVE: The aim of this study was to investigate tumor recurrence after liver transplantation for hepatocellular carcinoma (HCC), with and without hypothermic oxygenated liver perfusion (HOPE) before transplantation. PATIENTS AND METHODS: We analyzed all liver recipients with HCC, transplanted between January 2012 and September 2019 with donation after circulatory death (DCD) livers after previous end-ischemic HOPE-treatment (n = 70, Center A). Tumor parameters and key confounders were compared to consecutive recipients with HCC, transplanted during the same observation period with an unperfused DBD liver (n = 70). In a next step, we analyzed unperfused DCD (n = 70) and DBD liver recipients (n = 70), transplanted for HCC at an external center (Center B). RESULTS: Tumor parameters were not significantly different between HOPE-treated DCD and unperfused DBD liver recipients at Center A. One-third of patients were outside established tumor thresholds, for example, Milan criteria, in both groups. Despite no difference in tumor load, we found a 4-fold higher tumor recurrence rate in unperfused DBD livers (25.7%, 18/70), compared to only 5.7% (n = 4/70) recipients with tumor recurrence in the HOPE-treated DCD cohort (P = 0.002) in Center A. The tumor recurrence rate was also twice higher in unperfused DCD and DBD recipients at the external Center B, despite significant less cases outside Milan. HOPE-treatment of DCD livers resulted therefore in a 5-year tumor-free survival of 92% in HCC recipients, compared to 73%, 82.7%, and 81.2% in patients receiving unperfused DBD or DCD livers, from both centers. CONCLUSION: We suggest that a simple machine liver perfusion approach appears advantageous to protect from HCC recurrence after liver transplantation, despite extended tumor criteria.

Effect of time to surgery in resectable pancreatic cancer: a systematic review and meta-analysis.

PURPOSE: Achieving surgical resection is essential if patients with pancreatic ductal adenocarcinoma (PDAC) have a chance for cure. The objective of this study was to evaluate the effect of time to surgery on resection rates in patients with resectable PDAC. METHODS: A systematic literature search was performed to identify studies reporting times to surgery and resection rates. Meta-regression models were then produced to assess the relationship between time to surgery and resection rates, using both intra- and inter-study comparisons. RESULTS: A total of 21 studies were included, comprising n = 2171 patients, with a pooled resection rate of 76%. Intra-study meta-analysis of the five studies that reported comparisons between patients with vs. without preoperative biliary drainage (PBD) or with long vs. short delays to surgery found earlier surgery to be associated with a significantly higher rate of resection (pooled odds ratio 1.93, 95% CI: 1.25-2.97, P = 0.003). Inter-study meta-regression across all studies found a tendency for resection rates to decline with increasing time from CT or ERCP to surgery (gradient - 0.13 log-odds per week, 95% CI - 0.28, 0.03, P = 0.100), although this did not reach statistical significance, in part due to considerable heterogeneity between studies. CONCLUSION: Pathways to reduce the time to surgery, primarily by avoiding PBD, demonstrate significantly greater resection rates. Early surgery, including avoidance of PBD, not only provides patients with the benefit of avoiding harm associated with PBD but also with a greater chance of undergoing resection.

Recurrence patterns of pancreatic cancer after pancreatoduodenectomy: systematic review and a single-centre retrospective study.

BACKGROUND: Positive margins in pancreatoduodenectomy (PD) for pancreatic cancer, specifically the superior mesenteric artery (SMA) margin, are associated with worse outcomes. Local therapies targeting these margins could impact on recurrence. This study analysed recurrence-patterns to identify whether strategies to control local disease could have a meaningful impact. METHODS: (I) Systematic review to define recurrence patterns and resection margin status. (II) Additional retrospective study of PD performed at our centre. RESULTS: In the systematic review, 23/617 evaluated studies were included (n = 3815). Local recurrence was observed in 7-69%. SMA margin (6 studies) was positive in 15-35%. In the retrospective study (n = 204), local recurrence was more frequently observed with a positive SMA margin (66 vs.45%; p = 0.005). Furthermore, in a multivariate cox-proportional hazard model, only a positive SMA margin was associated with disease recurrence (HR 1.615; 95%CI 1.127-2.315; p = 0.009). Interestingly, median overall survival was 20 months and similar for patients who developed local only, metastases only or simultaneous recurrence (p = 0.124). CONCLUSION: Local recurrence of pancreatic cancer is common and associated with similar mortality rates as those who present with simultaneous or metastatic recurrence. Involvement of the SMA margin is an independent predictor for disease progression and should be the target of future adjuvant local therapies.

Future liver remnant portal or hepatic vein reconstruction at stage I of ALPPS-How far can we push the boundaries?

Preservation of the future liver remnant (FLR) vascular integrity has always been considered crucial to achieving successful liver growths after major hepatectomies. Most surgeons appeared therefore reluctant to combine stage I of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) with vascular reconstructions. Here we describe a case series, where we combine parenchymal transection and venous in- or outflow reconstruction of the FLR at stage I of ALPPS. In addition, the cold flush of the FLR or delayed portal vein embolization is applied in selected cases.

Benchmarks in Pancreatic Surgery: A Novel Tool for Unbiased Outcome Comparisons.

OBJECTIVE: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). BACKGROUND: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. METHODS: This multicenter study analyzes consecutive patients (2012-2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. RESULTS: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%-93%) and minimally invasive (11%-62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. CONCLUSION: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.

Retrieval Practice or Overall Donor and Recipient Risk: What Impacts on Outcomes After Donation After Circulatory Death Liver Transplantation in the United Kingdom?

Parameters of retrieval surgery are meticulously documented in the United Kingdom, where up to 40% of livers are donation after circulatory death (DCD) donations. This retrospective analysis focuses on outcomes after transplantation of DCD livers, retrieved by different UK centers between 2011 and 2016. Donor and recipient risk factors and the donor retrieval technique were assessed. A total of 236 DCD livers from 9 retrieval centers with a median UK DCD risk score of 5 (low risk) to 7 points (high risk) were compared. The majority used University of Wisconsin solution for aortic flush with a median hepatectomy time of 27-44 minutes. The overall liver injury rate appeared relatively high (27.1%) with an observed tendency toward more retrieval injuries from centers performing a quicker hepatectomy. Among all included risk factors, the UK DCD risk score remained the best predictor for overall graft loss in the multivariate analysis (P < 0.001). In high-risk and futile donor-recipient combinations, the occurrence of liver retrieval injuries had negative impact on graft survival (P = 0.023). Expectedly, more ischemic cholangiopathies (P = 0.003) were found in livers transplanted with a higher cumulative donor-recipient risk. Although more biliary complications with subsequent graft loss were found in high-risk donor-recipient combinations, the impact of the standardized national retrieval practice on outcomes after DCD liver transplantation was minimal.

Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation.

BACKGROUND & AIMS: Donation after circulatory death (DCD) liver transplantation is known for potentially worse outcomes because of higher rates of graft non-function or irreversible cholangiopathy. The impact of machine liver perfusion techniques on these complications remains elusive. We aimed to provide data on 5-year outcomes in patients receiving DCD liver transplants, after donor organs had been treated by hypothermic oxygenated perfusion (HOPE). METHODS: Fifty HOPE-treated DCD liver transplants performed in Zurich between 2012 and 3/2017 were matched with 50 primary donation after brain death (DBD) liver transplants, and with 50 untreated DCD liver transplants in Birmingham. Match factors focussed on short cold ischaemia, comparable recipient age and low recipient laboratory model for end-stage liver disease scores. Primary endpoints were post-transplant complications, and non-tumour-related patient death or graft loss. RESULTS: Despite extended donor warm ischaemia, HOPE-treated DCD liver transplants achieved similar overall graft survival, compared to standard DBD liver transplants. Particularly, graft loss due to any non-tumour-related causes occurred in 8% (4/50) of cases. In contrast, untreated DCD livers resulted in non-tumour-related graft failure in one-third (16/50) of cases (p = 0.005), despite significantly (p <0.001) shorter functional donor warm ischaemia. Five-year graft survival, censored for tumour death, was 94% for HOPE-treated DCD liver transplants vs. 78% in untreated DCD liver transplants (p = 0.024). CONCLUSIONS: The 5-year outcomes of HOPE-treated DCD liver transplants were similar to those of DBD primary transplants and superior to those of untreated DCD liver transplants, despite much higher risk. These results suggest that a simple end-ischaemic perfusion approach is very effective and may open the field for safe utilisation of extended DCD liver grafts. LAY SUMMARY: Machine perfusion techniques are currently being introduced into the clinic, with the aim of optimising injured grafts prior to implantation. While short-term effects of machine liver perfusion have been frequently reported in terms of hepatocellular enzyme release and early graft function, the long-term benefit on irreversible graft loss has been unclear. Herein, we report on 5-year graft survival in donation after cardiac death livers, treated either by conventional cold storage, or by 1-2 h of hypothermic oxygenated perfusion (HOPE) after cold storage. Graft loss was significantly less in HOPE-treated livers, despite longer donor warm ischaemia times. Therefore, HOPE after cold storage appears to be a simple and effective method to treat high-risk livers before implantation.

Report of the 24th Annual Congress of the International Liver Transplantation Society.

The 24th Joint Annual Congress of the International Liver Transplantation Society in association with European Liver and Intestine Transplant Association and Liver Intensive Care Group of Europe was held in Lisbon, Portugal from May 23 to 26, 2018. More than 1200 participants from over 60 countries including surgeons, hepatologists, anesthesiologists and critical care intensivists, radiologists, pathologists, organ procurement personnel, and research scientists came together with the common aim of improving care and outcomes for liver transplant recipients. Over 600 scientific abstracts were presented. The principal themes were living donation, use of marginal liver donors, machine preservation, disease-specific immunosuppressive regimen, malignancies, and advances in pediatric liver transplantation and liver transplant anesthesia. This report presents excerpts from invited lectures and select abstracts from scientific sessions, which add to current knowledge, and will drive clinical practice and future research.

Comparison of Postoperative Outcomes Between Donation After Circulatory Death and Donation After Brain Death Liver Transplantation Using the Comprehensive Complication Index.

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: LT is 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.

Value of α-methylacyl-CoA racemase immunochemistry for predicting neoplastic progression in Barrett's oesophagus.

AIM: To investigate the value of α-methylacyl-CoA racemase (AMACR) immunohistochemistry for predicting neoplastic progression in Barrett's oesophagus (BO). METHODS AND RESULTS: We conducted a case-control study within a prospective cohort of 720 BO patients. Patients who developed high-grade dysplasia or oesophageal adenocarcinoma were classified as cases, and patients without neoplastic progression as controls. AMACR expression was determined by immunohistochemistry in 12 127 biopsies from 635 patients, and was scored independently by two expert pathologists. Relative risks adjusted for age, gender, BO length and oesophagitis (RR(a)) were calculated in log-linear models. During a median follow-up of 6.6 years, 49 patients (8%) developed high-grade dysplasia or oesophageal adenocarcinoma. Although mild AMACR expression was associated with a trend towards an increased risk of neoplastic progression (RR(a) 1.6, 95% CI 0.9-3.1), the risk was especially elevated with strong AMACR expression (RR(a) 4.8, 95% CI 1.9-12.6). The positive predictive value of strong AMACR expression was slightly higher than that of low-grade dysplasia (22% versus 15%); the negative predictive value was slightly lower (91% versus 93%). CONCLUSIONS: Strong AMACR expression is associated with an increased risk of neoplastic progression in BO. However, AMACR expression appears to be a less powerful predictor for neoplastic progression than low-grade dysplasia.

Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett's oesophagus.

OBJECTIVE: The value of surveillance for patients with Barrett's oesophagus (BO) is under discussion given the overall low incidence of neoplastic progression and lack of discriminative tests for risk stratification. Histological diagnosis of low-grade dysplasia (LGD) is the only accepted predictor for progression to date, but has a low predictive value. The aim of this study was therefore to evaluate the value of p53 immunohistochemistry for predicting neoplastic progression in patients with BO. DESIGN: We conducted a case-control study within a prospective cohort of 720 patients with BO. Patients who developed high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) were classified as cases and patients without neoplastic progression were classified as controls. P53 protein expression was determined by immunohistochemistry in more than 12 000 biopsies from 635 patients and was scored independently by two expert pathologists who were blinded to long-term outcome. RESULTS: During follow-up, 49 (8%) patients developed HGD or OAC. P53 overexpression was associated with an increased risk of neoplastic progression in patients with BO after adjusting for age, gender, Barrett length and oesophagitis (adjusted relative risks (RR(a)) 5.6; 95% CI 3.1 to 10.3), but the risk was even higher with loss of p53 expression (RR(a) 14.0; 95% CI 5.3 to 37.2). The positive predictive value for neoplastic progression increased from 15% with histological diagnosis of LGD to 33% with LGD and concurrent aberrant p53 expression. CONCLUSIONS: Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with BO and appears to be a more powerful predictor of neoplastic progression than histological diagnosis of LGD.