Rationale for the potential use of mesenchymal stromal cells in liver transplantation.

Mesenchymal stromal cells (MSCs) are multipotent and self-renewing cells that reside essentially in the bone marrow as a non-hematopoietic cell population, but may also be isolated from the connective tissues of most organs. MSCs represent a heterogeneous population of adult, fibroblast-like cells characterized by their ability to differentiate into tissues of mesodermal lineages including adipocytes, chondrocytes and osteocytes. For several years now, MSCs have been evaluated for their in vivo and in vitro immunomodulatory and 'tissue reconstruction' properties, which could make them interesting in various clinical settings, and particularly in organ transplantation. This paper aims to review current knowledge on the properties of MSCs and their use in pre-clinical and clinical studies in solid organ transplantation, and particularly in the field of liver transplantation. The first available clinical data seem to show that MSCs are safe to use, at least in the medium-term, but more time is needed to evaluate the potential adverse effects of long-term use. Many issues must be resolved on the correct use of MSCs. Intensive in vitro and pre-clinical research are the keys to a better understanding of the way that MSCs act, and to eventually lead to clinical success

Aorto-duodenal fistula secondary to aortic graft replacement.

peer reviewedSecondary aorto-duodenal fistula (SADF) is a rare and serious event occurring in up to 45% of aortic prosthesis infections. The clinical manifestations are variable ranging from isolated signs of graft infection such as fever to massive gastrointestinal bleeding. The diagnosis is based on CT scan and is generally oriented by an inconstant association of indirect signs. Despite a high early severe postoperative morbidity and mortality, especially in presence of a preoperative shock, emergency surgery allows for the diagnosis and treatment of SADF with multidisciplinary management allowing favorable midterm outcomes among surviving patients. The images that we present in this manuscript highlight some indirect signs of SADF on CT scan that should alert clinicians to warrant on time surgical management with an illustration of per operative diagnosis of the fistula

Mesenchymal stromal cells combined with everolimus promote Treg expansion but do not synergize in a rat liver transplant rejection model

peer reviewedBackground: Mesenchymal stromal cells (MSCs) have particular properties that can be of interest in organ transplantation, including expansion of regulatory T cells (Tregs), a key factor in graft tolerance induction. The immunosuppression to be associated with MSCs has not yet been defined. Additionally, the impact of the association of everolimus with MSCs on Treg expansion and on induction of liver graft tolerance has never been studied. The aim of this study was to evaluate the effects of MSCs combined, or not, with everolimus, on Treg expansion and in a model of liver transplantation (LT) rejection in the rat. Methods: Firstly, Lewis rats received intravenous MSCs at D9 with/without subcutaneous everolimus from D0 to D14. Analysis of circulating Tregs was performed at D0, D14 and D28. Secondly, 48 h after LT with a Dark Agouti rat liver, 30 Lewis rats were randomized in 3 groups: everolimus (subcutaneous for 14 days), MSCs (intravenous injection at D2 and D9), or both everolimus and MSCs. Rejection of the liver graft was assessed by liver tests, histology and survival. Results: Individually, MSC infusion and everolimus promoted Treg expansion in rats, and everolimus had no negative impact on Treg expansion when combined with MSCs. However, in the LT model, injections of MSCs 2 and 9 days following LT were not effective at preventing acute rejection, and the combination of MSCs with everolimus failed to show any synergistic effect when compared to everolimus alone. Conclusion: Everolimus may be used in association with MSCs. However, in our model of LT in the rat, post-transplant MSC injections did not prevent acute rejection, and the association of MSCs with everolimus did not show any synergistic effect

Infusion of third-party mesenchymal stem cells after liver transplantation: a phase-1, open-label, clinical study

peer reviewedBackground: Mesenchymal stromal cells (MSC) are multipotent bone mar- row progenitors that have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aimed to be the first evaluation of the safety and tolerability of MSC infusion after liver transplantation in a prospective, controlled phase-1 study. Methods: 10 liver transplant recipients under standard immunosuppression (TAC-MMF-low dose steroids until day 30) received 1.5–3 9 106/kg third party MSC on post-operative day 3 ` 2. These patients were prospectively compared to a group of 10 control liver recipients. Primary endpoints were MSC infusion toxicity, and incidence of cancer and opportunistic infections at month 6. Secondary endpoints were patient and graft survivals and rejection at month 6, as well as the effects of MSC on recipients’ immune function and on immunohistology of at month 6 graft biopsies. Results: No MSC infusional toxicity was observed. Both groups were comparable in terms of donor and recipient characteristics. There was no difference in primary end-points between control and MSC groups. No patient developed de novo cancer. There was no statistical difference in patient and graft survivals or in rejection rates. There was no graft rejection in the MSC group. Month-6 graft biopsies were not different according to Banff and fibrosis scores. Discussion: This phase 1 study showed excellent tolerability and safety of a single infusion of third-party MSC after liver transplantation. There were no graft safety issues and no excess of immunosuppression after MSC injection. Further analyses of consequences of MSC injection on the immune profile are needed. The possibility of avoiding calcineurin-inhibitors with repeated MSC injections as main immunosuppressive therapy and/of tolerance induction by MSC infusion should be investigated by further studies. This study is in part supported by an ESOT Senior Clinical Research Grant and by the University of Liege

Infusion of third-party mesenchymal stem cells after liver transplantation: a phase-1, open-label, clinical study

peer reviewedBackground: Mesenchymal stromal cells (MSC) are multipotent bone mar- row progenitors that have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aimed to be the first evaluation of the safety and tolerability of MSC infusion after liver transplantation in a prospective, controlled phase-1 study. Methods: 10 liver transplant recipients under standard immunosuppression (TAC-MMF-low dose steroids until day 30) received 1.5–3 9 106/kg third party MSC on post-operative day 3 ` 2. These patients were prospectively compared to a group of 10 control liver recipients. Primary endpoints were MSC infusion toxicity, and incidence of cancer and opportunistic infections at month 6. Secondary endpoints were patient and graft survivals and rejection at month 6, as well as the effects of MSC on recipients’ immune function and on immunohistology of at month 6 graft biopsies. Results: No MSC infusional toxicity was observed. Both groups were comparable in terms of donor and recipient characteristics. There was no difference in primary end-points between control and MSC groups. No patient developed de novo cancer. There was no statistical difference in patient and graft survivals or in rejection rates. There was no graft rejection in the MSC group. Month-6 graft biopsies were not different according to Banff and fibrosis scores. Discussion: This phase 1 study showed excellent tolerability and safety of a single infusion of third-party MSC after liver transplantation. There were no graft safety issues and no excess of immunosuppression after MSC injection. Further analyses of consequences of MSC injection on the immune profile are needed. The possibility of avoiding calcineurin-inhibitors with repeated MSC injections as main immunosuppressive therapy and/of tolerance induction by MSC infusion should be investigated by further studies. This study is in part supported by an ESOT Senior Clinical Research Grant and by the University of Liege

Impact of donor age over 70 years in donation after circulatory death liver transplantation: a 15 years of experience

peer reviewedBackground: Advanced donor age has been identified as a risk factor in donation after circulatory death (DCD 3) liver transplantation (LT), associated with poor graft function and development of ischemic cholangiopathy. In this study, we evaluated the results after DCD 3 LT using grafts from donors over 70 years compared to younger grafts (<70 years). Methods: We retrospectively analysed outcome after DCD 3 LT (n=228), comparing donors 70 years (n=53) and <70 years (n=175) from our center between 2003 and 2020. The two age groups were compared in terms of graft and patient survivals at 1, 3 and 5 years, in terms of donor and recipient demographics, transplant conditions and labora- tory values. Results: The overall graft survivals at 1, 3 and 5 years were 88, 75, 70 per cent respectively. Graft survival rates were not significantly diffe- rent at 5 years between the two groups (P = 0,536). No difference was noted in incidence of acute rejection, biliary strictures, hepatic artery thrombosis or retransplantation rates between the two groups. The time of cold ischemia was significatively lower in the older group (mean 235 min; SD 72) than in younger donor (mean 258 min; SD 72) (p=0.012). The posttransplant AST peak was significatively higher in the advanced age donor group than the second group with 2201±2703 U/L vs 1561U/L (SD 2151±2151 U/L), respectively (p= 0.04).Conclusions: Results for DCD LT from 70-yr-old grafts were similar to those from younger donors. Advanced donors should not be discarded for liver donation if other donor risk factors (such as cold ischemia time and graft quality) are limited

Proton-Antiproton Annihilation and Meson Spectroscopy with the Crystal Barrel

This report reviews the achievements of the Crystal Barrel experiment at the Low Energy Antiproton Ring (LEAR) at CERN. During seven years of operation Crystal Barrel has collected very large statistical samples in pbarp annihilation, especially at rest and with emphasis on final states with high neutral multiplicity. The measured rates for annihilation into various two-body channels and for electromagnetic processes have been used to test simple models for the annihilation mechanism based on the quark internal structure of hadrons. From three-body annihilations three scalar mesons, a0(1450), f0(1370) and f0(1500) have been established in various decay modes. One of them, f0(1500), may be identified with the expected ground state scalar glueball.Comment: 64 pages, LATEX file, 36 figures are available as ps files at http://afuz01.cern.ch/claude/ Submitted to Reviews of Modern Physic

Laparoscopic management of a traumatic lumbar hernia: about a case

Traumatic Lumbar hernia (TLH) is a very rare clinical entity with about 100 cases reported worldwide. It is a difficult challenge when encountered and there is no consensus on the best management: early or delayed, open or laparoscopic. We report the clinical case of a 28-year-old man who suffered from a TLH after a 6- meter-high fall. The diagnosis was based on CT imaging showing a defect in the postero-lateral abdominal wall by disinsertion of the lumbar origin of transverse, internal and external oblique muscles. A few months after the trauma, it became gradualy more painful, the hernia was clinically increased with a large swelling on the right flank majored by valsalva. CT imaging showed herniation of the right colic flexure through the defect. Eight months after the trauma, we performed an intra-abdominal laparoscopic approach. Herniated structures were reduced and we opened the peritoneum. The defect was repaired by placing a pre-peritoneal polypropylene mesh fixed by laparoscopic staples before closing the peritoneum. The patient had an uneventful recovery. Ten weeks after the surgery the result was clinically very good. The CT scanner showed a good recovery of parietal continuity