Biliary atresia

Biliary atresia (BA) is a rare disease characterised by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most frequent surgical cause of cholestatic jaundice in this age group. BA occurs in approximately 1/18,000 live births in Western Europe. In the world, the reported incidence varies from 5/100,000 to 32/100,000 live births, and is highest in Asia and the Pacific region. Females are affected slightly more often than males. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. BA is not known to be a hereditary condition. No primary medical treatment is relevant for the management of BA. Once BA suspected, surgical intervention (Kasai portoenterostomy) should be performed as soon as possible as operations performed early in life is more likely to be successful. Liver transplantation may be needed later if the Kasai operation fails to restore the biliary flow or if cirrhotic complications occur. At present, approximately 90% of BA patients survive and the majority have normal quality of life

Local immunostimulation leading to rejection of accepted male skin grafts by female mice as a model for cancer immunotherapy

The introduction is a review of the literature covering the different immunotherapeutic protocols tested within clinical trial for human practice. It has been shown that many cancer patients are able to mount a spontaneous T lymphocyte response against their tumor. In metastatic progressing patients, this response has evidently been incomplete. An increasing number of data on human tumors and tumor infiltrating lymphocytes support the scenario of an immunosuppressive environment that appears to be present within the tumor. This immunosuppressive environment seems to be a major factor preventing the success of immunotherapies, especially for anti-cancer vaccination. Our working hypothesis is that reversing focally the immunosuppressive environment to an immunostimulating environment could potentiate the effect of anti-cancer vaccination and other immunotherapeutic approaches such as immunostimulating antibodies (as anti CTLA-4). Stalled immune responses are occasionally observed in the area of tissue transplantation where a small number of recipients can be withdrawn from treatment with immunosuppressive agents without deleterious effects on the grafted organ. In a mouse strain named CBA, this phenomenon is observed when male skin is grafted onto females. Female of this mice strain do not reject syngeneic male skin grafts even though they mount a T cell response against the male-specific HY antigen. This experimental model was used to test our working hypothesis. In our skin graft model we have tested several agents that, when applied locally, may relieve the immunosuppression and reactivate the immune response leading to graft rejection. Some cytokine combinations, locally administered, are effective in promoting the rejection of these skin grafts. Local immunostimulation performed by injecting a combination of cytokines and Toll-like receptor ligands in close vicinity to the graft promoted rejection. This approach was then tested in a few tumor-bearing human patients in combination with anti-tumor vaccination. A clinical phase I/II trial based on the combination discovered was conducted, with encouraging preliminary results. These data suggest that a therapeutic approach using local injections of the combination described in this work might contribute to boost the efficacy of various cancer immunotherapy modalities. Relief of intratumor immunosuppression may increase considerably the fraction of patients who respond to vaccination directed against tumor antigens recognized by T cells.L’introduction est une revue de la littérature reprenant les différentes méthodes d’immunothérapie du cancer qui ont été utilisées dans le cadre d’essais en clinique. Il est actuellement bien démontré que la plupart des patients atteints de cancer sont capables de développer spontanément une réponse lymphocytaire cytotoxique dirigée contre leur tumeur. Cette réponse est évidemment incomplète chez les patients en progression métastatique. De plus en plus d’observations basées sur l’analyse des tumeurs humaines et des lymphocytes infiltrant ces tumeurs supportent l’idée qu’un environnement immunosuppresseur est présent au sein même de la tumeur. Cet environnement immunosuppresseur serait un facteur essentiel du manque d’efficacité des vaccinations anti-cancer. Notre hypothèse de travail est qu’en agissant localement sur l’environnement immunosuppresseur présent dans les tumeurs et en le rendant plutôt stimulant, cela permettrait de réactiver les lymphocytes infiltrant les tumeurs, et de potentialiser l’effet des vaccinations anti cancer. L’absence de réponse immunitaire efficace est également observée occasionnellement en transplantation d’organe où quelques patients présentent une tolérance opérationnelle à l’organe greffé sans qu’aucune immunosuppression ne soit nécessaire. Dans une race de souris appelée CBA, ce phénomène est observé quand on réalise une greffe de peau de mâle sur une femelle. Les femelles de cette race de souris ne rejettent pas les greffons cutanés mâle syngéniques, malgré qu’elles soient capables de monter une réponse immunitaire cytotoxique dirigée contre l’antigène mâle-spécifique (HY). Nous avons utilisé ce modèle expérimental, proche de la situation observée dans les tumeurs humaines, pour tester nos hypothèses. Dans ce modèle murin de greffe de peau nous avons testé différents agents qui, injectés localement, pourraient atténuer l’immunosuppression locale et réactiver la réponse immunitaire, ce phénomène menant à un rejet des greffes. Nos expériences nous ont permis d’identifier une combinaison originale de cytokines et de ligands des Toll-Like récepteurs, qui, injectés au contact de la greffe, induisent un rejet du greffon dans 100% des cas. Cette approche a par la suite été testée chez des patients atteints de cancer en combinaison avec une vaccination anti-tumorale. Un essai clinique de Phase I/II a été initié sur base de la combinaison découverte dans notre modèle expérimental. Les résultats préliminaires obtenus sur trois patients sont encourageants. Une approche thérapeutique par injections locales de la combinaison décrite ici pourrait augmenter l’efficacité de l’immunothérapie du cancer, particulièrement celle des vaccinations anti-tumorales.(MED - Sciences médicales) -- UCL, 201

The immunological monitoring of kidney and liver transplants in adult and pediatric recipients.

Over the last half century, kidney and liver transplantation have been recognized as the treatment of choice for adult and children with end-stage renal or liver failure. Infants present a relative naïve immune system, but they are capable of mounting both cellular and humoral immune responses to the foreign antigens presented by the allograft. Immune monitoring is a way of measuring functional and molecular correlates of immune reactivity which may provide clinically useful information for identifying patients who have an increase risk of acute rejection prior to clinical symptoms or develop transplant tolerance. However, although numerous assays have been shown to predict rejection, to date no assays have been demonstrated to detect or predict transplantation tolerance. This is a summary of the published literature on promising antigen-specific and non-antigen-specific assays used for immunological monitoring in solid organ transplantation. This work also attempts to review their applicability to pediatric transplantation, specifically, pediatric kidney and liver recipients

First lessons of the Toulouse ammonium nitrate disaster, 21st september 2001, AZF plant, France

International audienceA terrible explosion of ammonium nitrate, killing 30 people, occurred on 21st September 2001, in Toulouse, in AZF plant belonging to Grande Paroisse Company, TotalFinaElf Group. The manufactured chemicals in the plant were mainly ammonium nitrate, ammonium nitrate-based fertilisers and other chemicals including chlorinated compounds. The origins of the accident haven't found yet an agreement among investigators (company, justice). The aim of this paper is to provide abroad an overview of some lessons learnt on that accident, from many perspectives, following the national debates and parliamentary enquiry as well as the various technical accident investigations

Monitoring tolerance after human liver transplantation

The validation of reliable, non-invasive immunological assays evaluating anti-donor responsiveness in allograft recipients would provide a clinically relevant tool for the early detection of ongoing rejection process as well as for the identification of operational tolerance in the long term. A sequential approach towards immunological monitoring of allografts is proposed in this review: (i) investigations exploring the initial donor-recipient alloresponses, including the analysis of the cytokine network; (ii) investigations regarding graft acceptance and operational tolerance in long-term transplant patients, consisting in the analysis of regulatory T cells and of circulating precursors of dendritic cells, in the measurement of T cell alloreactivity as well as in the study of T cell receptor repertoires. Beside the conventional in vivo and in vitro immunological techniques, the potential applications of molecular imaging in transplantation also deserve further exploration, with particular respect to allograft immune monitoring. Enforced collaboration between transplant clinicians and immunologists will be required to develop the translational research protocols required for the development of immunological monitoring, within an international multicentric network. © 2006 Elsevier B.V. All rights reserved

A comparison of laparoscopic resection of posterior segments with formal laparoscopic right hepatectomy for colorectal liver metastases: a single-institution study

INTRODUCTION: The benefit of by laparoscopic resection for lesions located in postero-superior segments is unclear. The present series aimed at comparing intraoperative and post-operative results in patients undergoing either laparoscopic RPS or laparoscopic RH for colorectal liver metastases located in the right postero-superior segments. METHODS: From 2000 to 2015, patients who underwent laparoscopic resection of segment 6 and/or 7 (RPS group) were compared with those with right hepatectomy (RH group) in terms of tumour characteristics, surgical treatment, and short-term outcomes. RESULTS: Among the 177 selected patients, 78 (44.1 %) had laparoscopic RPS and 99 (55.9 %) a laparoscopic RH. Among RPS patients, 26 (33.3 %) underwent anatomical resection of either segment 7, 8 or both. Three (3 %) patients undergoing RH died in the post-operative course and none in the RPS group. Sixty-three (35.5 %) patients experienced post-operative complications, including major complications in 24 (13.5 %) patients. Liver failure (17.1 vs. 0 %, p = 000.1), biliary leakage (6.0 vs. 1.2 %, p = 00.1), intra-abdominal collection (19.1 vs. 2.5 %, p = 000.1), and pulmonary complication (16.1 vs. 1.2 %, p = 000.1) were significantly increased in the RH group. CONCLUSION: The present series suggests that patients who underwent laparoscopic resection of CRLM located in the postero-superior segments developed significantly less complications than patients undergoing formal RH

Liver retransplantation in children. A 21-year single-center experience*

In this study, the epidemiology and outcome of graft loss following primary pediatric liver transplantation (LT) were analysed, with the hypothesis that early retransplantation (reLT) might be associated with lower immunologic risks when compared with late reLT. Between March 1984 and December 2005, 745 liver grafts were transplanted to 638 children at Saint-Luc University Hospital, Brussels. Among them, a total of 90 children (14%) underwent 107 reLT, and were categorized into two groups (early reLT, n = 58; late reLT, n = 32), according to the interval between either transplant procedures (30 days). Ten-year patient survival rate was 85% in recipients with a single LT, vs. 61% in recipients requiring reLT (P < 0.001). Ten-year patient survival rates were 59% and 66% for early and late reLT, respectively (P = 0.423), the corresponding graft survival rates being 51% and 63% (P = 0.231). Along the successive eras, the rate of reLT decreased from 17% to 10%, whereas progressive improvement of outcome post-reLT was observed. No recurrence of chronic rejection (CR) was observed after reLT for CR (0 of 19). Two children developed a positive cross-match at reLT (two of 10, 20%), both retransplanted lately for CR secondary to immunosuppression withdrawal following a post-transplant lymphoproliferative disease. In summary, the results presented could not evidence better results for late reLT when compared with early reLT. The former did not seem to be associated with higher immunologic risk, except for children having withdrawal of immunosuppression following the first graft