Preclinical validation of a customized circuit for ex situ uninterrupted cold-to-warm prolonged perfusion of the liver.

CONTEXT: Clinical adoption of ex situ liver perfusion is growing. While hypothermic perfusion protects against ischemia-reperfusion injury in marginal grafts, normothermic perfusion enables organ viability assessment and therefore selection of borderline grafts. The combination of hypothermic and normothermic perfusion, known as "cold-to-warm," may be the optimal sequence for organ preservation, but is difficult to achieve with most commercial perfusion systems. We developed an adaptable customized circuit allowing uninterrupted "cold-to-warm" perfusion and conducted preclinical studies on healthy porcine livers and discarded human livers to demonstrate the circuit's efficacy. METHODS: In collaboration with bioengineers, we developed a customized circuit that adapts to extracorporeal circulation consoles used in cardiovascular surgery and includes a proprietary reservoir enabling easy perfusate change without interrupting perfusion. This preclinical study was conducted on porcine and human livers. Perfusion parameters (pressures, flows, oxygenation) and organ viability were monitored. RESULTS: The customized circuit was adapted to a LivaNova S5® console, and the perfusions were flow-driven with real-time pressure monitoring. Ten porcine liver and 12 discarded human liver perfusions were performed during 14 to 18 h and 7 to 25 h, respectively. No hyperpressure was observed (porcine and human portal pressure 2-6 and 2-8 mm Hg; arterial pressure 10-65 and 20-65 mm Hg, respectively). No severe histological tissue injury was observed (Suzuki score ≤ 3 at the end of perfusion). Seven (70%) porcine livers and five (42%) human livers met the UK viability criteria. CONCLUSION: The customized circuit and system design enables smooth uninterrupted "cold-to-warm" perfusion not present in current commercial perfusion systems.

European validation of the classification for the anticipated difficulty of liver transplantation.

BACKGROUND: Appropriate risk stratification for the difficulty of liver transplantation (LT) is essential to guide the selection and acceptance of grafts and avoid morbidity and mortality. METHODS: Based on 987 LTs collected from 5 centers, perioperative outcomes were analyzed across the 3 difficulty levels. Each LT was retrospectively scored from 0 to 10. Scores of 0-2, 3-5 and 6-10 were then translated into respective difficulty levels: low, moderate and high. Complications were reported according to the comprehensive complication index (CCI). RESULTS: The difficulty level of LT in 524 (53%), 323 (32%), and 140 (14%) patients was classified as low, moderate and high, respectively. The values of major intraoperative outcomes, such as cold ischemia time (p = 0.04) and operative time (p < 0.0001) increased gradually with statistically significant values among difficulty levels. There was a corresponding increase in CCI (p = 0.04), severe complication rates (p = 0.05) and length of ICU (p = 0.01) and hospital (p = 0.004) stays across the different difficulty levels. CONCLUSION: The LT difficulty classification has been validated.

Open Versus Laparoscopic Right Hepatectomy for Hepatocellular Carcinoma Following Sequential TACE-PVE: A Multicentric Comparative Study.

BACKGROUND: Right hepatectomy (RH) for hepatocellular carcinoma (HCC) is ideally preceded by transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE). Laparoscopic approach improves short-term outcome and textbook outcome (TO), which reflects the "ideal" surgical outcome, after RH. However, laparoscopic RH on an underlying diseased liver and after TACE/PVE remains a challenging procedure. The aim of this study was to compare the outcomes in patients who underwent laparoscopic liver resection (LLR) or open liver resection (OLR) following TACE/PVE. PATIENTS AND METHODS: All patients with HCC who underwent RH after TACE/PVE in five French centers were retrospectively included. Outcomes were compared between the LLR group and the OLR group using propensity score matching (PSM). Quality of surgical care was defined by TO. RESULTS: Between 2005 and 2019, 117 patients were included (41 in LLR group, 76 in OLR group). Overall morbidity was comparable (51% versus 53%, p = 0.24). In LLR group, TO was completed in 66% versus 37% in OLR group (p = 0.02). LLR and absence of clamping were the only factors associated with TO completion [hazard ratio (HR) 4.27, [1.77-10.28], p = 0.001]. After PSM, 5-year overall survival (OS) and progression-free survival (PFS) were 55% in matched LLR versus 77% in matched OLR, p = 0.35, and 13% in matched LLR versus 17% in matched OLR, p = 0.97. TO completion was independently associated with a better 5-year OS (65.2% versus 42.5%, p = 0.007). CONCLUSION: Major LLR after TACE/PVE should be considered as a valuable option in expert centers to increase the chance of TO, the latter being associated with a better 5-year OS.

Auxiliary Liver Transplantation for Cirrhosis: From APOLT to RAPID: A Scoping Review.

OBJECTIVE: To survey the available literature regarding the use of auxiliary liver transplantation (ALT) in the setting of cirrhosis. SUMMARY OF BACKGROUND: ALT is a type of liver transplantation (LT) procedure in which part of the cirrhotic liver is resected and part of the liver graft is transplanted. The cirrhotic liver left in situ acts as an auxiliary liver until the graft has reached sufficient volume. Recently, a 2-stage concept named RAPID (Resection and Partial Liver segment 2/3 transplantation with Delayed total hepatectomy) was developed, which combines hypertrophy of the small graft followed by delayed removal of the native liver. METHODS: A scoping review of the literature on ALT for cirrhosis was performed, focusing on the historical background of RAPID and the status of RAPID for this indication. The new comprehensive nomenclature for hepatectomy ("New World" terminology) was used in this review. RESULTS: A total of 72 cirrhotic patients underwent ALT [heterotopic (n = 34), orthotopic (Auxiliary partial orthotopic liver transplantation, n = 34 including 5 followed by resection of the native liver at the second stage) and RAPID (n = 4)]. Among the 9 2-stage LTs (APOLT, n = 5; RAPID, n = 4), portal blood flow modulation was performed in 6 patients by deportalization of the native liver (n = 4), portosystemic shunt creation (n = 1), splenic artery ligation (n = 3) or splenectomy (n = 1). The delay between the first and second stages ranged from 18 to 90 days. This procedure led to an increase in the graft-to-recipient weight ratio between 33% and 156%. Eight patients were alive at the last follow-up. CONCLUSIONS: Two-stage LT and, more recently, the RAPID procedure are viable options for increasing the number of transplantations for cirrhotic patients by using small grafts.

Cytoreductive Surgery and Intraperitoneal Chemotherapy in Advanced Serous Epithelial Ovarian Cancer: A 14-Year French Retrospective Single-Center Study of 124 Patients.

INTRODUCTION: Ovarian cancer (OC) is the most lethal gynecological cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy appears to increase survival, and normothermic intraperitoneal chemotherapy (IPC) could improve overall survival (OS). Furthermore, intraperitoneal epinephrine could decrease the toxicity of chemotherapy by decreasing the systemic absorption of chemotherapy. The goal of this study was to assess the effects of CRS and IPC with intraperitoneal epinephrine, as first-line therapy, on the survival of patients with serous epithelial OC (EOC) with peritoneal metastases. METHODS: A prospective monocentric database was retrospectively searched for all patients with advanced serous EOC treated by interval or consolidative CRS plus IPC with intraperitoneal epinephrine after neoadjuvant chemotherapy. OS and disease-free survival (DFS), postoperative complications, and prognostic factors were analyzed. RESULTS: From January 2003 to December 2017, 124 patients with serous EOC were treated with interval (n = 58) or consolidative (n = 66) complete CRS plus IPC with intraperitoneal epinephrine. The median follow-up was 77.8 months, the median OS was 60.8 months, and the median DFS was 21.2 months. In our multivariate analysis, a higher Peritoneal Cancer Index (PCI) and positive lymph node status resulted in worse OS, while higher World Health Organization score, higher PCI score, and positive lymph node status were risk factors for worse DFS. Grade 3 or higher surgical morbidity occurred in 27.42% of cases; only 3.2% had grade 3 renal toxicity and mortality was 0.8%. CONCLUSION: CRS and IPC with intraperitoneal epinephrine in stage III EOC offer good OS and DFS with acceptable morbidity and mortality rates.

Preoperative prediction of inadvertent enterotomy during adhesive small bowel obstruction surgery using combination of CT features.

OBJECTIVES: The purpose of this study was to identify the preoperative CT features that are associated with inadvertent enterotomy (IE) during adhesive small bowel obstruction (ASBO) surgery. METHODS: From January 2015 to December 2019, all patients with ASBO who underwent an abdominal CT were reviewed. Abdominal CT were retrospectively reviewed by two radiologists with a consensus read in case of disagreement. IE during ASBO surgery was retrospectively recorded. Univariate and multivariate analyses of CT features associated with IE were performed and a simple CT score was built to stratify the risk of IE. This score was validated in an independent retrospective cohort. Abdominal CT of the validation cohort was reviewed by a third independent reader. RESULTS: Among the 368 patients with ASBO during the study period, 169 were surgically treated, including 129 ASBO for single adhesive band and 40 for matted adhesions. Among these, there were 47 IE. By multivariate analysis, angulation of the transitional zone (OR = 4.19, 95% CI [1.10-18.09]), diffuse intestinal adhesions (OR = 4.87, 95% CI [1.37-19.76]), a fat notch sign (OR = 0.32, 95% CI [0.12-0.85]), and mesenteric haziness (OR = 0.13, 95% CI [0.03-0.48]) were independently associated with inadvertent enterotomy occurrence. The simple CT score built to stratify risk of IE displayed an AUC of 0.85 (95% CI [0.80-0.90]) in the study sample and 0.88 (95% CI [0.80-0.96]) in the validation cohort. CONCLUSION: A simple preoperative CT score is able to inform the surgeon about a high risk of IE and therefore influence the surgical procedure. KEY POINTS: • In this retrospective study of 169 patients undergoing abdominal surgery for adhesive small bowel obstruction, 47 (28%) inadvertent enterotomy occurred. • A simple preoperative CT score enables accurate stratification of inadvertent enterotomy risk (area under the curve 0.85). • By multivariable analysis, diffuse intestinal adhesions and angulation of the transitional zone were predictive of inadvertent enterotomy occurrence.

Post-Transplantation Cytomegalovirus Infection Interplays With the Development of Anastomotic Biliary Strictures After Liver Transplantation.

Background: Anastomotic biliary stricture (ABS) remains the most frequent complication after liver transplantation (LT). This study aimed to identify new anastomotic biliary stricture risk factors, with a specific focus on postoperative events. Additionally, ABS management and impact on patient and graft survival were assessed. Methods: All consecutive patients who underwent LT with duct-to-duct anastomosis between 2010 and 2019 were included. All patients who died within 90 days after LT due to non-ABS-related causes were excluded. Results: Among 240 patients, 65 (27.1%) developed ABS after a median time of 142 days (range, 13-1265). Median follow-up was 49 months (7-126). Upon multivariable analysis, donor BMI (OR=0.509, p = 0.037), post-LT CMV primoinfection (OR = 5.244, p < 0.001) or reactivation (OR = 2.421, p = 0.015) and the occurrence of post-LT anastomotic biliary fistula (OR = 2.691, p = 0.021) were associated with ABS. Anastomotic technical difficulty did not independently impact the risk of ABS (OR = 1.923, p = 0.051). First-line ABS treatment was systematically endoscopic (100%), and required a median of 2 (range, 1-11) procedures per patient. Repeat LT was not required in patients developing ABS. The occurrence of ABS was not associated with overall patient survival (p = 0.912) nor graft survival (p = 0.521). Conclusion: The risk of developing ABS after LT seems driven by the occurrence of postoperative events such as CMV infection and anastomotic fistula. In this regard, the role of CMV prophylaxis warrants further investigations.

Delayed return of gastrointestinal function after hepatectomy in an ERAS program: incidence and risk factors.

BACKGROUND: Delayed return of gastrointestinal function (DGIF) after hepatectomy can involve increased morbidity and prolonged hospital stay. Yet, data on incidence and risks factors are lacking. METHODS: All consecutive patients who underwent hepatectomy between June 2018 and December 2020 were included. All patients were included in an enhanced recovery after surgery (ERAS) program. DGIF was defined by the need for nasogastric tube (NGT) insertion after surgery. DGIF risk factors were identified. RESULTS: Overall, 206 patients underwent hepatectomy. DGIF occurred in 41 patients (19.9%) after a median time of 2 days (range, 1-14). Among them, 6 patients (14.6%) developed aspiration pneumonia, of which one required ICU for mechanical ventilation. DGIF developed along with an intraabdominal complication in 7 patients (biliary fistula, n = 5; anastomotic fistula, n = 1; adhesive small bowel obstruction, n = 1). DGIF was associated with significantly increased severe morbidity rate (p = 0.001), prolonged time to normal food intake (p < 0.001) and hospital stay (p < 0.001) and significantly decreased overall compliance rate (p = 0.001). Independent risk factors of DGIF were age (p < 0.001), vascular reconstruction (p = 0.007), anaesthetic induction using volatiles (p = 0.003) and epidural analgesia (p = 0.004). Using these 4 variables, a simple DGIF risk score has been developed allowing patient stratification in low-, intermediate- and high-risk groups. CONCLUSION: DGIF after hepatectomy was frequently observed and significantly impacted postoperative outcomes. Identifying risk factors remains critical for preventing its occurrence.

Fluorescence-based pancreas stump perfusion is associated with postoperative acute pancreatitis after pancreatoduodenectomy a prospective cohort study.

BACKGROUND: Postoperative acute pancreatitis (POAP) emerges as a distinct pancreas-specific complication increasing both the risk and the burden of POPF after pancreatoduodenectomy. Among various risk factors, pancreas stump (PS) hypoperfusion might play a role in POAP occurrence but has never been investigated. The current study aimed at evaluating the feasibility of intraoperative fluorescence angiography (IOFA) of the PS using ICG and its association with POAP. METHODS: Consecutive patients who underwent pancreatoduodenectomy for a periampullary tumor with pancreatojejunostomy and PS perfusion assessment using IOFA between January 2020 and November 2020 were prospectively included. Perioperative management and surgical strategy were standardized. IOFA of the pancreas stump was performed before fashioning pancreatojejunostomy. POAP was defined according to the Connor definition and was confirmed upon radiological blind review. Outcomes between patients with normally perfused and hypoperfused PS were compared. POAP was the primary endpoint. RESULTS: Among 30 patients, nine patients (30%) developed POAP according to the Connor definition, and six patients (20%) had CT-confirmed POAP. Upon IOFA, six patients (20%) presented PS hypoperfusion; of which one patient underwent extended pancreatectomy further to the left. PS hypoperfusion was statistically associated with the occurrence of POAP (80% vs. 16%; p = 0.011) and CT-confirmed POAP (60% vs. 12%; p = 0.041). Clinically relevant POPF rate was 40% in case of PS hypoperfusion and 4% in case of normal PS perfusion (p = 0.064). CONCLUSIONS: PS perfusion assessment using IOFA seems safe and reliable to anticipate POAP. PS IOFA could be considered as a potential tool for perioperative assessment of surgical risk after pancreatoduodenectomy.

Investigating new serological and tissue markers for the follow-up of patients operated for alveolar echinococcosis.

AIMS: Alveolar echinococcosis (AE) is characterized by a chronically progressing hepatic injury caused by Echinococcus multilocularis. Surgery presently remains the best curative option. Currently, biological predictive features derived from the resected specimens are not suitable to assess surgery efficacy. The present study was designed to investigate whether a selection of markers measured on the resected specimens exhibits predictive features related to parasite viability, or to a total elimination of the parasite, in addition to serological markers. METHODS AND RESULTS: In a collaboration between two centres, one in France (Besançon), and one in Switzerland (Bern), samples from 40 AE patients were analysed by microarray and serology techniques, individually. Paired serum samples before and after surgery were obtained for 26 patients. In the sera, a significant decrease in PD-L1 levels was observed after surgery, in addition to anti-Em18 levels. In the liver tissue, low levels of Cluster of Differentiation (CD)-3 were correlated with the absence of serum anti-Em18 after surgery. CONCLUSION: This study showed PD-L1 is promising as a potential serological marker and further confirmed the performance of anti-Em18 serology. Further studies on a larger cohort are needed to confirm the utility of performing systematically microarray on resected liver tissue.

Transmural Bowel Necrosis From Acute Mesenteric Ischemia and Strangulated Small-Bowel Obstruction: Distinctive CT Features.

OBJECTIVE. The purpose of this study was to assess whether transmural bowel necrosis has distinct CT features based on the three main causes: occlusive acute mesenteric ischemia (AMI), nonocclusive AMI, and strangulated small-bowel obstruction (SBO). MATERIALS AND METHODS. From January 2010 to December 2017, the records of all patients with a pathologic diagnosis of transmural bowel necrosis were extracted from the pathology department database of a university hospital. The inclusion criteria for the study were presence of transmural bowel necrosis at pathologic examination and available contrast-enhanced CT images obtained within the 24 hours before surgery. Seventy-seven patients were finally included. The CT scans were retrospectively independently reviewed by two abdominal radiologists to identify the classic CT findings of transmural bowel necrosis. Statistical analyses were performed. RESULTS. Pneumatosis intestinalis was statistically more frequent in nonocclusive AMI (59%) than in occlusive AMI (29%) and strangulated SBO (7%) (p < 0.01), as were superior mesenteric venous gas (55%, 29%, and 0%; p < 0.01) and portal venous gas (48%, 10%, and 0%; p < 0.01). Decreased or absent bowel wall enhancement was more frequent in AMI than in SBO (nonocclusive AMI, 83%; occlusive AMI, 81%; SBO, 56%; p = 0.02), as was thinned bowel wall (nonocclusive AMI, 52%; occlusive AMI, 48%; SBO, 18%; p = 0.02). Spontaneous hyperattenuation of the bowel wall was more frequent in strangulated SBO (41%) than in nonocclusive AMI (10%) and occlusive AMI (14%) (p < 0.01). CONCLUSION. Transmural bowel necrosis has distinct CT findings according to its three main causes. Occlusive AMI is characterized by an absence of bowel wall enhancement and less mesenteric fat stranding, nonocclusive AMI by a high prevalence of pneumatosis intestinalis and portal venous gas, and strangulated SBO by spontaneous hyperattenuation of the bowel wall and an absence of pneumatosis intestinalis and portal venous gas.

CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin.

Immune checkpoint blockade has proven its efficacy in hypermutated subtypes of metastatic colorectal cancers (mCRC). Immunogenic potential can also be observed with conventional chemotherapies, but this property has never been explored thoroughly in CRC patients. The CRC therapeutic arsenal includes oxaliplatin, a well-characterized platinum drug already described as immunogenic. Here, we investigated the impact of the oxaliplatin-based treatment on mCRC immunopeptidome. We demonstrated that oxaliplatin-resistant CRC cell lines overexpressed telomerase reverse transcriptase (TERT), colorectal-associated-tumor antigen-1 (COA-1) and mesothelin tumor-associated antigens. We identified new HLA class-II-restricted and promiscuous peptides derived from COA-1 and mesothelin. The two naturally processed peptides COA-1331-345 and Meso366-380 appear to be the most immunogenic in mCRC patients. A prospective cohort of 162 mCRC patients enabled us to explore the impact of oxaliplatin exposure on the antitumor-specific immune response. Interestingly, chemotherapy-naive mCRC patients present high immune CD4 T-cell responses directed against TERT, COA-1 and mesothelin-derived peptides. These antitumor T-cell responses were maintained after 3 months of oxaliplatin-based treatment. Altogether, these findings highlight the interest of immunostimulatory agents to improve the management of chemoresistant mCRC patients. Finally, the high frequency of immune responses targeting the new immunogenic peptides derived from COA-1 and mesothelin support their use in immunomonitoring strategies.

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) incidence is increasing worldwide. Several studies have shown that lymphopenia was correlated with a poor prognosis but the potential interest to measure lymphopenia in the pre and post-operative setting as well as its added value among conventional prognostic factors was never investigated. METHODS: Data from two independent cohorts in whom patients underwent resection for pancreatic carcinoma were retrospectively recorded. We examined the association between perioperative findings, pre and post-operative lymphocyte counts and overall survival (OS) in univariate and multivariate analyses. Performance assessment and internal validation of the final model were evaluated with Harrell's C-index, calibration plot and bootstrap sample procedures. RESULTS: Three hundred ninety patients were included in the analysis between 2000 and 2011. Pre and post-operative lymphocyte counts were independent prognostic factors associated with OS in multivariate analysis (p = 0.0128 and p = 0.0764, respectively). The addition of lymphocyte count variable to the conventional parameters identified in multivariate analysis (metastatic lymph node ratio, veinous emboli and adjuvant chemotherapy) significantly improved the model discrimination capacity (bootstrap mean difference = 0.04; 95 % CI, 0.01-0.06). The use of a threshold and combining the categorical (≥1000; <1000) information in pre and post lymphocyte counts permitted the identification of 4 subgroups of patients with different prognosis (p < 0.0001). Finally, the description of patients in long-term remission showed that only 3 of 65 (4.6 %) patients with post-operative lymphocyte count under 1000/mm3 were alive 4 years after surgery contrary to 54 of 236 (22.8 %) patients with a post-operative lymphocyte count above 1000/mm3. CONCLUSION: Pre and post-operative lymphopenia are independent prognostic factors for OS and they have an additive value regarding conventional prognostic factors for death-risk stratification and to predict long-term survival. Lymphopenia should be included as stratification factors in future clinical trial assessing overall survival in pancreatic cancer patients.

Should we perform decompressive laparotomy during severe acute pancreatitis with intra-abdominal hypertension below 25 mmHg: Only the gut knows.

We suggest that during severe acute pancreatitis (SAP) with intra-abdominal hypertension, practitioners should consider decompressive laparotomy, even with intra-abdominal pressure (IAP) below 25 mmHg. Indeed, in this setting, non-occlusive mesenteric ischemia (NOMI) may occur even with IAP below this cutoff and lead to transmural necrosis if abdominal perfusion pressure is not promptly restored. We report our experience of 18 critically ill patients with SAP having undergone decompressive laparotomy of which one third had NOMI while IAP was mostly below 25 mmHg.

Perceptions of surgical difficulty in liver transplantation: A European survey and development of the Pitié-Salpêtrière classification.

BACKGROUND: Significant variations exist regarding the definition of difficult liver transplantation. The study goals were to investigate how liver transplant surgeons evaluate the surgical difficulty of liver transplantation and to use the identified factors to classify liver transplantation difficulty. METHODS: A Web-based online European survey was presented to liver transplant surgeons. The survey was divided into 3 parts: (1) participant demographics and practices; (2) various situations based on recipient, liver disease, tumor treatment, and technical factors; and (3) 8 real-life clinical vignettes with different levels of complexity. In part 3 of the survey, respondents were asked whether they would perform liver transplantation but were not aware that these patients eventually underwent liver transplantation. RESULTS: A total of 143 invites were sent out, and 97 (67.8%) participants completed the survey. Most participants considered previous spontaneous bacterial peritonitis, previous supra-mesocolic surgery, hypertrophy of segment I, and obesity to be recipient factors for high-difficulty liver transplantation. Most participants considered liver transplantation to be challenging in patients with Budd-Chiari syndrome, Kasai surgery, polycystic liver disease, diffuse portal vein thrombosis, and a history of open hepatectomy. The proportion of participants indicating that liver transplantation was warranted varied across the 8 cases, from 69% to 100%. Our classification of the surgical difficulty of liver transplantation employed these recipient-related, surgical history-related, and liver disease-related variables and 3 difficulty groups were identified: low, intermediate, and high difficulty groups. CONCLUSION: This survey provides an overview of the surgical difficulty of various situations in liver transplantation that could be useful for further benchmark and textbook outcome studies.

Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review.

Liver failure includes distinct subgroups of diseases: Acute liver failure (ALF) without preexisting cirrhosis, acute-on-chronic liver failure (ACLF) (severe form of cirrhosis associated with organ failures and excess mortality), and liver fibrosis (LF). Inflammation plays a key role in ALF, LF, and more specifically in ACLF for which we have currently no treatment other than liver transplantation (LT). The increasing incidence of marginal liver grafts and the shortage of liver grafts require us to consider strategies to increase the quantity and quality of available liver grafts. Mesenchymal stromal cells (MSCs) have shown beneficial pleiotropic properties with limited translational potential due to the pitfalls associated with their cellular nature. MSC-derived extracellular vesicles (MSC-EVs) are innovative cell-free therapeutics for immunomodulation and regenerative purposes. MSC-EVs encompass further advantages: pleiotropic effects, low immunogenicity, storage stability, good safety profile, and possibility of bioengineering. Currently, no human studies explored the impact of MSC-EVs on liver disease, but several preclinical studies highlighted their beneficial effects. In ALF and ACLF, data showed that MSC-EVs attenuate hepatic stellate cells activation, exert antioxidant, anti-inflammatory, anti-apoptosis, anti-ferroptosis properties, and promote regeneration of the liver, autophagy, and improve metabolism through mitochondrial function recovery. In LF, MSC-EVs demonstrated anti-fibrotic properties associated with liver tissue regeneration. Normothermic-machine perfusion (NMP) combined with MSC-EVs represents an attractive therapy to improve liver regeneration before LT. Our review suggests a growing interest in MSC-EVs in liver failure and gives an appealing insight into their development to rehabilitate marginal liver grafts through NMP.

CD8+ CD226high T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery.

CD226 has been reported to participate in the rescue of CD8+ T cell dysfunction. In this study, we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes (TILs) derived from colorectal cancer (CRC) liver metastases treated with chemotherapy and radical surgery. TILs from 43 metastases were isolated and analyzed ex vivo using flow cytometry. CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry. Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets. CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors. CD226 on CD8+ T cells was not specifically coexpressed with other immune checkpoints, such as PD1, TIGIT, and TIM3, in liver metastases. Multivariate Cox regression analysis revealed CD226 expression on CD8+ T cells to be an independent prognostic factor (p = 0.003), along with CD3 density at invasion margins (p = 0.003) and TIGIT expression on CD4+ T cells (p = 0.019). CD155 was not associated with the prognostic value of CD226. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors. Downregulation of CD226 on CD8+ TILs in the liver microenvironment was restored by IL15 treatment. Overall, CD226 expression on liver metastasis-infiltrating CD8+ T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.

Liver Transplantation Using Allografts With Recent Liver Blunt Trauma: A Nationwide Audit From the French CRISTAL Biomedicine Agency Registry.

BACKGROUND: In the current setting of organ shortage, brain-dead liver donors with recent liver trauma (RLT) represent a potential pool of donors. Yet, data on feasibility and safety of liver transplantation (LT) using grafts with RLT are lacking. METHODS: All liver grafts from brain-dead donors with RLT proposed for LT between 2010 and 2018 were identified from the nationwide CRISTAL registry of the Biomedicine Agency. The current study aimed at evaluating 1-y survival as the primary endpoint. RESULTS: Among 11 073 LTs, 142 LTs (1.3%) using grafts with RLT were performed. These 142 LTs, including 23 split LTs, were performed from 131 donors (46.1%) of 284 donors with RLT proposed for LT. Transplanted grafts were procured from donors with lower liver enzymes levels ( P < 0.001) and less advanced liver trauma according to the American Association for the Surgery of Trauma liver grading system ( P < 0.001) compared with not transplanted grafts. Before allocation procedures, 20 (7%) of 284 donors underwent damage control intervention. During transplantation, specific liver trauma management was needed in 19 patients (13%), consisting of local hemostatic control (n = 15), partial hepatic resection on back-table (n = 3), or perihepatic packing (n = 1). Ninety-day mortality and severe morbidity rates were 8.5% (n = 12) and 29.5% (n = 42), respectively. One-year overall and graft survival rates were 85% and 81%, and corresponding 5-y rates were 77% and 72%, respectively. CONCLUSIONS: Using liver grafts from donors with RLT seems safe with acceptable long-term outcomes. All brain-dead patients with multiorgan trauma, including liver injury, should be considered for organ allocation.