Control of warm ischemia (WI) lesions that occur with donation after circulatory death (DCD) would significantly increase the donor pool for liver transplantation. We aimed to determine whether a ...novel, oxygenated and hypothermic machine perfusion device (HMP Airdrive system) improves the quality of livers derived from DCDs using a large animal model.
Cardiac arrest was induced in female large white pigs by intravenous injection of potassium chloride. After 60 minutes of WI, livers were flushed in situ with histidine-tryptophan-ketoglutarate and subsequently preserved either by simple cold storage (WI-SCS group) or HMP (WI-HMP group) using Belzer-MPS solution. Liver grafts procured from heart-beating donors and preserved by SCS served as controls. After 4 hours of preservation, all livers were transplanted.
All recipients in WI-SCS group died within 6 hours after transplantation. In contrast, the HMP device fully protected the liver against lethal ischemia/reperfusion injury, allowing 100% survival rate. A postreperfusion syndrome was observed in all animals of the WI-SCS group but none of the control or WI-HMP groups. After reperfusion, HMP-preserved livers functioned better and showed less hepatocellular and endothelial cell injury, in agreement with better-preserved liver histology relative to WI-SCS group. In addition to improved energy metabolism, this protective effect was associated with an attenuation of inflammatory response, oxidative load, endoplasmic reticulum stress, mitochondrial damage, and apoptosis.
This study demonstrates for the first time the efficacy of the HMP Airdrive system to protect liver grafts from lethal ischemic damage before transplantation in a clinically relevant DCD model.
Background
The French transplant governing system defined “Rescue” (the so-called “
Hors Tour
”) livers as those livers which were declined for the five top-listed patients. This study compares the ...outcomes following liver transplantation (LT) in patients who received a donor liver through a rescue allocation (RA) procedure or according to MELD score priority (standard allocation, SA) and evaluates the impact on the graft pool of a proactive policy to accept RA grafts.
Methods
Data from all consecutive patients who underwent LT with SA or RA grafts from 2011 to 2015 were compared in terms of short- and long-term outcomes.
Results
The 249 elective first LTs were performed with 64 (25.7%) RA and 185 (74.3%) SA grafts. RA grafts were obtained from older donors and were associated with a longer cold ischemia time. Recipients of RA livers were older and had lower MELD scores. The rates of delayed graft function, primary nonfunction, retransplantation, complications, and mortality were similar between the RA and SA groups. At 1 and 3 and 5 years, graft and patient survival rates were similar between the groups. These results were maintained after matching on recipient characteristics. Our proactive policy to accept RA grafts increased the liver pool for elective first transplantation by 25%.
Conclusions
RA livers can be safely transplanted into selected recipients and significantly expand the liver pool.
Background
Cirrhosis is not recognised as one of the main risk factors of invasive pulmonary aspergillosis (IPA), although its prevalence is increasing. The aim of our study was to identify factors ...for IPA in such patients with a positive
Aspergillus
sp. culture in respiratory samples and to evaluate its impact on outcome.
Methods
We conducted a monocentric retrospective study between January 2005 and December 2015. All cirrhotic patients hospitalised in our liver ICU with a positive
Aspergillus
sp. respiratory sample were included. These patients were case-matched with cirrhotic patients without positive Aspergillus respiratory sample. Finally, the patients were classified as having putative aspergillosis or colonisation according to the criteria described previously.
Results
In total, 986 cirrhotic patients were admitted to ICU during the study period. Among these, sixty patients had a positive
Aspergillus
sp. respiratory sample. Chronic obstructive pulmonary disease (COPD) comorbidity and organ supports were significantly associated with
Aspergillus
colonisation. Seventeen patients (28%) were diagnosed as proven or putative IPA and 43 were considered as colonised by
Aspergillus
sp. The median delay between ICU admission and an IPA diagnosis was 2 2–24 days. Only COPD was predictive of the presence of IPA (OR 6.44; 95% CI 1.43–28.92;
p
= 0.0151) in patients with a positive
Aspergillus
sp. culture. The probability of in-hospital mortality was 71% in the IPA group versus 19% in the colonisation group (
p
= 0.0001).
Conclusion
Patients with cirrhosis can be at risk of IPA, especially with COPD. Antifungal agents should be given as soon as possible mainly in cirrhotic patients with COPD.
Abstract Background Acute kidney injury (AKI) following hepatectomy remains understudied in terms of diagnosis, severity, recovery and prognostic value. The aim of this study was to assess the risk ...factors and prognostic value of AKI on short- and long-term outcomes following hepatectomy for hepatocellular carcinoma (HCC). Method This is a retrospective analysis of a single-center cohort of 457 consecutive patients who underwent hepatectomy for HCC. The KDIGO criteria were used for AKI diagnosis. The incidence, risk factors, and prognostic value of AKI were investigated. Results AKI occurred in 67 patients (15%). The mortality and major morbidity rates were significantly higher in patients with AKI (37% and 69%) than in those without (6% and 22%; p < 0.001). Renal recovery was complete in 35 (52%), partial in 25 (37%), and absent in 7 (11%) patients. Advanced age, an increased MELD score, major hepatectomy and prolonged duration of operation were identified as independent predictors of AKI. AKI was identified as the strongest independent predictor of postoperative mortality but did not impact survival. Conclusion AKI is a common complication after hepatectomy for HCC. Although its development is associated with poor short-term outcomes, it does not appear to be predictive of impaired long-term survival.
Primary sclerosing cholangitis (PSC) is a probable autoimmune liver disease characterized by persistent and progressive biliary inflammation that leads to biliary infection, cirrhosis, or ...cholangiocarcinoma. Genome-wide omics data are scarce regarding this severe disease.
MEDLINE database gene prioritization by text mining (biliary inflammation, biliary fibrosis, biliary stasis) was integrated in distinct omics data: (1) PSC liver transcriptome training and validation cohorts, (2) farnesoid X receptor (FXR) mice liver transcriptome subjected to an FXR agonist or FXR knockout mice; (3) liver single-cell transcriptome of the Abcb4−/− mice model of PSC.
A liver molecular network highlighted the involvement of nuclear receptor subfamily 0 group B member 2 (NR0B2) and its associated nuclear receptor FXR in a metabolic cascade that may influence the immune response. NR0B2 upregulation in PSC liver was independent of gender, age, body mass index, liver fibrosis, and PSC complications. Heterogeneity of NR0B2 upregulation was found in cholangiocyte cell types in which the NR0B2-based cell fate decision revealed the involvement of several metabolic pathways for detoxification (sulfur, glutathione derivative, and monocarboxylic acid metabolisms). Genes potentially implicated in carcinogenesis were also discovered on this cholangiocyte trajectory: GSTA3, inhibitor of DNA binding 2, and above all, TMEM45A, a transmembrane molecule from the Golgi apparatus considered as oncogenic in several cancers.
By revisiting PSC through PubMed data mining, we evidenced the early cholangiocyte deregulation of NR0B2, highlighting a metabolic and premalignant reprogramming of the cholangiocyte cell type. The therapeutic targeting of NR0B2 could potentiate that of FXR and enable action on early events of the disease and prevent its progression.
Background
The outcomes of liver resection (LR) with a narrow margin in patients with transplantable hepatocellular carcinoma (HCC) have not been studied. The aim was to assess whether narrow margin ...following up-front LR impacts the incidence, timing, pattern, and transplantability of tumor recurrence in patients with initially transplantable HCC.
Methods
All initially transplantable HCC patients undergoing hepatectomy with either narrow (<10 mm) or wide (≥10 mm) margins from 2007 to 2016 at four Western university centers were compared in terms of recurrence, transplantability of recurrence, recurrence-free survival (RFS), and intention-to-treat overall survival (ITT-OS). Independent predictors of non-transplantability of recurrence were assessed.
Results
This study included 187 patients (narrow group,
n
= 107 vs. wide group,
n
= 80). Recurrence was significantly more frequent in the narrow margin group (44% vs. 26%;
p
= 0.01) with a shorter RFS (
p
= 0.03). The transplantability of recurrence and ITT-OS were, however, not different between the two groups. The presence of satellite nodules on the resected specimens emerged as the sole independent predictor of non-transplantability of tumor recurrence. The stratification of the analysis according to the presence of cirrhosis achieved essentially the same results as in the whole study population.
Conclusions
Narrow margin was associated with a higher tumor recurrence rate and a shorter RFS for patients with initially transplantable HCC. However, transplantability of recurrence and long-term ITT-OS were not impaired.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients show lower humoral vaccine responsiveness than immunocompetent individuals. HLA diversity, measured by the HLA evolutionary ...divergence (HED) metrics, reflects the diversity of the antigenic repertoire presented to T cells, and has been shown to predict response to cancer immunotherapy. We retrospectively investigated the association of HED with humoral response to SARS-CoV-2 vaccine in allo-HSCT recipients. HED was calculated as pairwise genetic distance between alleles at HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 loci in recipients and their donors. Low anti-spike IgG levels (<30 BAU/mL) were associated with short time from allo-SCT and low donor DPB1-HED, mostly related to donor DPB1 homozygosity. The diversity of donor HLA-DP molecules, assessed by heterozygosity or sequence divergence, may thus impact the efficacy of donor-derived CD4 T cells to sustain vaccine-mediated antibody response in allo-HSCT recipients.
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•Hematopoietic stem cell transplant recipients have impaired response to SARS-CoV-2 vaccine•HLA-DPB1 divergence in the donor is associated with low levels of anti-spike IgG•Donor HLA-DPB1 homozygosity is associated with no SARS-CoV-2 vaccine response
Immunology; Virology Highlights Hematopoietic stem cell transplant recipients have impaired response to SARS-CoV-2 vaccine HLA-DPB1 divergence in the donor is associated with low levels of anti-spike IgG Donor HLA-DPB1 homozygosity is associated with no SARS-CoV-2 vaccine response
This study assessed the prognostic value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in the prediction of MVI and early recurrence following ...resection.
This prospective study (ClinicalTrials.gov ID: NCT02145013) included 78 consecutive HCC patients who underwent 18F-FDG PET/CT before curative-intent resection from 2014 to 2017. Prognostic factors available before surgery for predicting MVI and early recurrence (≤2 years) were identified by univariate and multivariate analyses.
The 18F-FDG PET/CT result was positive in 30 (38%) patients. MVI was present in 33% (26/78) of specimens. Early recurrence occurred in 19% (14/74) of surviving patients. PET/CT positivity was the sole independent predictor of MVI (odds ratio OR = 3.6, 95% confidence interval CI = 1.1–11.2; p = 0.03), with a specificity and sensitivity for predicting MVI of 73% and 62%, respectively. Analysis of variables available before surgery showed that PET/CT positivity (hazard ratio HR = 5.8, 95% CI = 1.6–20.4; p = 0.006) and the male sex (HR = 6.6; 95% CI = 1.8–24.2; p = 0.005) were independent predictors of early recurrence.
18F-FDG PET/CT predicts MVI and early recurrence after surgery for HCC and could be used to select patients for neoadjuvant treatment.
The shortage of liver grafts continues to worsen. Because the expanded use of small-for-size grafts (SFSGs) would substantially alleviate this shortage, we aimed to analyse the available knowledge on ...auxiliary liver transplantation (ALT) with SFSGs in patients with chronic liver disease (CLD) to identify opportunities to develop ALT with SFSGs in patients with CLD.
This is a systematic review on ALT using SFSGs in patients with CLD. The review was completed by updates obtained from the authors of the retained reports.
Heterotopic ALT was performed in 26 cases between 1980 and 2017, none for SFGS stricto sensu, and auxiliary partial orthotopic liver transplantation (APOLT) in 27 cases (from 1999 to 2021), all for SFSG. In APOLT cases, partial native liver resection was performed in most of cases, whereas the second-stage remnant native liver hepatectomy was performed in 9 cases only. The median graft-to-body weight ratio was 0.55, requiring perioperative or intraoperative portal modulation in 16 cases. At least 1 complication occurred in 24 patients following the transplant procedure (morbidity rate, 89%). Four patients (4/27, 15%) died after the APOLT procedure. At the long term, 19 (70%) patients were alive and well at 13 months to 24 years (median, 4.5 years) including 18 with the APOLT graft in place and 1 following retransplantation.
Despite high postoperative morbidity, and highly reported technical variability, the APOLT technique is a promising technique to use SFSGs in patients with CLD, achieving satisfactory long-term results. The results need to be confirmed on a larger scale, and a standardised technique could lead to even better results.
At the cost of a high postoperative morbidity, the long-term results of APOLT for small-for-size grafts are good. Standardisation of the procedure and of portal modulation remain needed.
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•Using a small-for-size graft is a risk factor of small-for-size syndrome.•Auxiliary liver transplantation can be orthotopic or heterotopic.•In auxiliary transplantation, the remnant native liver prevents small-for-size syndrome.•Transplantation with a small-for-size graft requires individually tailored portal modulation.•Auxiliary liver transplantation might substantially increase the number of available grafts.
Retrospective studies have reported good results with liver transplantation (LTx) for acute-on-chronic liver failure (ACLF) in selected patients. The aim of this study was to evaluate the selection ...process for LTx in patients with ACLF admitted to the intensive care unit (ICU) and to assess outcomes.
This prospective, non-interventional, single high-volume center study collected data on patients with ACLF admitted to the ICU between 2017-2020.
Among 200 patients (mean age: 55.0 ± 11.2 years and 74% male), 96 patients (48%) were considered potential candidates for LTx. Unfavourable addictology criteria (n = 76) was the main reason for LTx ineligibility. Overall, 69 patients were listed for LTx (34.5%) and 50 were transplanted (25% of the whole population). The 1-year survival in the LTx group was significantly higher than in the non-transplanted group (94% vs. 15%, p <0.0001). Among patients eligible for LTx, mechanical ventilation during the first 7 days of ICU stay and an increase in the number of organ failures at day 3 were associated with the absence of LTx or death (odds ratio 9.58; 95% CI 3.29–27.89; p <0.0001 for mechanical ventilation and odds ratio 1.87; 95% CI 1.08–3.24; p <0.027 for increasing organ failures). The probability of not being transplanted in patients with ACLF under mechanical ventilation is >85.4% in those experiencing an increase of 2 organ failures since admission or >91% if experiencing an increase >2 organ failures, at which point futility could be considered.
This prospective analysis of outcomes of patients with ACLF admitted to the ICU highlights the drastic nature of selection in this setting. Unfavourable addictology criteria, mechanical ventilation and increasing number of organ failures since admission were predictive of absence of LTx, futility and death.
Liver transplantation (LT) is the best therapeutic option in selected cirrhotic patients admitted to the ICU with acute on chronic liver failure. However, the selection criteria are poorly described and based on retrospective studies. This is the first prospective study that aimed to describe the selection process for LT in a transplant center. Patients with ACLF should be admitted to the ICU and evaluated within a short period of time for LT. In the context of organ shortage, eligibility for LT and either absence of LT, futility of care or death are better clarified in our study. These are mainly determined by prolonged respiratory failure and worsening of organ failures since ICU admission. Considering worldwide variations in the etiology and definition of ACLF, transplant availability and a narrow therapeutic window for transplant further prospective studies are awaited.
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•Among 200 patients with ACLF admitted to the ICU, half were considered eligible for LTx and a quarter were transplanted.•Reasons for LTx ineligibility were active alcohol consumption (73%), uncontrolled infections (12.5%) and severe malnutrition (12.5%).•In eligible patients, the main cause of death during evaluation or on the waitlist was sepsis (66%).•Mechanical ventilation within 7 days of ICU admission and additional organ failures between admission and day 3 predicted absence of LTx and death.•We established an equation to determine the probability of not being transplanted in eligible patients.
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