Pancreatic head cancer in patients with chronic pancreatitis

International audienceBACKGROUND: Chronic pancreatitis (CP) is a risk factor of pancreatic adenocarcinoma (PA). The discovery of a pancreatic head lesion in CP frequently leads to a pancreaticoduodenectomy (PD) which preceded by a multidisciplinary meeting (MM). The aim of this study was to evaluate the relevance between this indication of PD and the definitive pathological results. METHODS: Between 2000 and 2010, all patients with CP who underwent PD for suspicion of PA without any histological proof were retrospectively analyzed. The operative decision has always been made at an MM. The definitive pathological finding was retrospectively confronted with the decision made at an MM, and patients were classified in two groups according to this concordance (group 1) or not (group 2). Clinical and biological parameters were analyzed, preoperative imaging were reread, and confronted to pathological findings in order to identify predictive factors of malignant degeneration. RESULTS: During the study period, five of 18 (group 1) patients with CP had PD were histologically confirmed to have PA, and the other 13 (group 2) did not have PA. The median age was 52.5+/-8.2 years (gender ratio 3.5). The main symptoms were pain (94.4%) and weight loss (72.2%). There was no patient's death. Six (33.3%) patients had a major complication (Clavien-Dindo classification ≥ 3). There was no statistical difference in clinical and biological parameters between the two groups. The rereading of imaging data could not detect efficiently all patients with PA. CONCLUSIONS: Our results confirmed the difficulty in detecting malignant transformation in patients with CP before surgery and therefore an elevated rate of unnecessary PD was found. A uniform imaging protocol is necessary to avoid PD as a less invasive treatment could be proposed

Oxygenated versus non-oxygenated flush out and storage of donor livers:An experimental study

Background: During donor organ procurement and subsequent static cold storage (SCS), hepatic adenosine triphosphate (ATP) levels are progressively depleted, which contributes to ischemia-reperfusion injury (IRI). We sought to investigate a simple approach to prevent ATP depletion and IRI using a porcine donation after circulatory death (DCD) liver reperfusion model. Methods: After 30 min warm ischemia, porcine livers were flushed via the portal vein with cold (4 degrees C) non-oxygenated University of Wisconsin (UW) preservation solution (n = 6, control group) or with oxygenated UW (n = 6, OxyFlush group). Livers were then subjected to 4 h SCS in non-oxygenated (control) or oxygenated (OxyFlush) UW, followed by 4 h normothermic reperfusion using whole blood. Hepatic ATP levels were compared, and hepatobiliary function and injury were assessed. Results: At the end of SCS, ATP was higher in the OxyFlush group compared to controls (delta ATP of +0.26 vs. -0.68 mu mol/g protein, p = 0.04). All livers produced bile and metabolized lactate, and there were no differences between the groups. Grafts in the OxyFlush group had lower blood glucose levels after reperfusion (p = 0.04). Biliary pH, glucose and bicarbonate were not different between the groups. Injury markers including liver transaminases, lactate dehydrogenase, malondialdehyde, cell-free DNA and flavin mononucleotide in the SCS solution and during reperfusion were also similar. Histological assessment of the parenchyma and bile ducts did not reveal differences between the groups. Conclusion: Oxygenated flush out and storage of DCD porcine livers prevents ATP depletion during ischemia, but this does not seem sufficient to mitigate early signs of IRI

Prolonged dual hypothermic oxygenated machine preservation (DHOPE-PRO) in liver transplantation:study protocol for a stage 2, prospective, dual-arm, safety and feasibility clinical trial

INTRODUCTION: End-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally. METHODS AND ANALYSIS: This is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00–3:59 hour) or to the control arm (4:00–15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation. TRIAL REGISTRATION NUMBER: NL8740

Comparison of reconstruction methods used during liver transplantation in case of a graft with replaced or accessory right hepatic artery:A retrospective study

Variations in graft arterial anatomy can increase the risk of postoperative hepatic arterial thrombosis (HAT), especially in presence of a replaced or accessory right hepatic artery (RHA). We retrospectively analyzed 223 cases of liver transplantations with the presence of an RHA on the graft. Patient outcomes were compared according to the four different reconstruction methods used: (i) the re-implantation of the RHA into the splenic or gastroduodenal artery (n = 106); (ii) the interposition of the superior mesenteric artery (SMA) (n = 83); (iii) dual anastomosis (n = 24); (iv) use of an aortic patch including the origins of both the SMA and the coeliac trunk (n = 10). A competing risk analysis and Inverse Probability Weighting (IPW) were used. We found that the interposition of the SMA method was associated with a significantly lower incidence of HAT, at 4.8% compared to the re-implantation method at 17.9%, dual anastomosis at 12.5%, and aortic patch at 20%, p =.03. In the competing risk analysis with IPW, the only risk factor for RHA thrombosis was the type of reconstruction. Taking the SMA interposition group as the reference, the sub-hazard ratio (sHR) was 5.05 (CI 95 [1.72; 14.78], p &lt;.01) for the re-implantation group, sHR = 2.37 (CI 95 [0.51; 11.09], p =.27) for the dual anastomosis group and sHR = 2.24 (CI 95 [0.35; 14.33], p =.40) for the aortic patch group. There were no differences for intraoperative transfusion, hospitalization duration (p =.37) or incidence of severe complications (p =.1). The long-term graft (p =.69) and patient (p =.52) survival was not different. In conclusion, the SMA interposition method was associated with a lower incidence of RHA thrombosis.</p

Comparison of reconstruction methods used during liver transplantation in case of a graft with replaced or accessory right hepatic artery:A retrospective study

Variations in graft arterial anatomy can increase the risk of postoperative hepatic arterial thrombosis (HAT), especially in presence of a replaced or accessory right hepatic artery (RHA). We retrospectively analyzed 223 cases of liver transplantations with the presence of an RHA on the graft. Patient outcomes were compared according to the four different reconstruction methods used: (i) the re-implantation of the RHA into the splenic or gastroduodenal artery (n = 106); (ii) the interposition of the superior mesenteric artery (SMA) (n = 83); (iii) dual anastomosis (n = 24); (iv) use of an aortic patch including the origins of both the SMA and the coeliac trunk (n = 10). A competing risk analysis and Inverse Probability Weighting (IPW) were used. We found that the interposition of the SMA method was associated with a significantly lower incidence of HAT, at 4.8% compared to the re-implantation method at 17.9%, dual anastomosis at 12.5%, and aortic patch at 20%, p =.03. In the competing risk analysis with IPW, the only risk factor for RHA thrombosis was the type of reconstruction. Taking the SMA interposition group as the reference, the sub-hazard ratio (sHR) was 5.05 (CI 95 [1.72; 14.78], p &lt;.01) for the re-implantation group, sHR = 2.37 (CI 95 [0.51; 11.09], p =.27) for the dual anastomosis group and sHR = 2.24 (CI 95 [0.35; 14.33], p =.40) for the aortic patch group. There were no differences for intraoperative transfusion, hospitalization duration (p =.37) or incidence of severe complications (p =.1). The long-term graft (p =.69) and patient (p =.52) survival was not different. In conclusion, the SMA interposition method was associated with a lower incidence of RHA thrombosis.</p

Therapeutic anticoagulation after liver transplantation is not useful among patients with pre-transplant Yerdel-grade I/II portal vein thrombosis:A two-center retrospective study

BACKGROUND: Portal vein thrombosis (PVT) is no longer a contraindication for liver transplantation (LT). While therapeutic anticoagulation (tAC) is recommended during the waiting period, there is no evidence for its usefulness in the prevention of PVT recurrence after LT. OBJECTIVES: The aim of our study was to evaluate the role of tAC post-LT in the prevention of PVT recurrence. PATIENTS/METHODS: All adult LTs performed in 2 high volume centres between 2003 and 2018, were retrospectively analysed. Only patients with PVT classified as Yerdel grade I or II and with standard portal reconstruction were included. PVT recurrence and tAC-associated morbidity within 1 year were compared between patients receiving tAC or not. RESULTS: During the study period, out of 2612 LTs performed, 235 (9%) patients with PVT were included. 113 patients (48.1%) received post-LT tAC (tAC group) while 122 (51.9%) did not (non-tAC group). The incidence of bleeding events was significantly higher in the tAC group (26 (23%) vs. 5 (4.1%), p<0.01) and the initial hospitalization duration was longer (21 vs. 17.5 days, p<0.01). Within the first year, PVT recurrence was observed for 9 (3.8%) patients without any difference between the tAC and non-tAC groups (6 (5.1%) vs. 3 (2.5%), p=0.39). The only identified risk factor for PVT recurrence was the recipients' age (OR=0.94, p=0.03). Graft (p=0.11) and patient (p=0.44) survival were similar between the 2 groups. CONCLUSION: Therapeutic anticoagulation is not necessary in the prevention of grade I/II PVT recurrence and is associated with higher morbidity and longer hospital stay

Waitlist mortality of young patients with biliary atresia:Impact of allocation policy and living donor liver transplantation

Patients with biliary atresia (BA) below 2 years of age in need of a transplantation largely rely on partial grafts from deceased donors (deceased donor liver transplantation [DDLT]) or living donors (living donor liver transplantation [LDLT]). Because of high waitlist mortality in especially young patients with BA, the Eurotransplant Liver Intestine Advisory Committee (ELIAC) has further prioritized patients with BA listed before their second birthday for allocation of a deceased donor liver since 2014. We evaluated whether this Eurotransplant (ET) allocation prioritization changed the waitlist mortality of young patients with BA. We used a pre-post cohort study design with the implementation of the new allocation rule between the two periods. Participants were patients with BA younger than 2 years who were listed for liver transplantation in the ET database between 2001 and 2018. Competing risk analyses were performed to assess waitlist mortality in the first 2 years after listing. We analyzed a total of 1055 patients with BA, of which 882 had been listed in the preimplementation phase (PRE) and 173 in the postimplementation phase (POST). Waitlist mortality decreased from 6.7% in PRE to 2.3% in POST (p = 0.03). Interestingly, the proportion of young patients with BA undergoing DDLT decreased from 32% to 18% after ET allocation prioritization (p = 0.001), whereas LDLT increased from 55% to 74% (p = 0.001). The proportional increase in LDLT decreased the median waitlist duration of transplanted patients from 1.5 months in PRE to 0.85 months in POST (p = 0.003). Since 2014, waitlist mortality in young patients with BA has strongly decreased in the ET region. Rather than associated with prioritized allocation of deceased donor organs, the decreased waitlist mortality was related to a higher proportion of patients undergoing LDLT.</p

Optimisation of tacrolimus utilization in liver transplanted patients

L’efficacité des traitements immunosuppresseurs a permis l’essor et le succès de la transplantation hépatique. Ainsi, l’utilisation des inhibiteurs de la calcineurine, dont le tacrolimus est le représentant principal, a permis une diminution drastique de la fréquence des complications immunologiques. En revanche, les effets indésirables liés à son utilisation représentent aujourd’hui une part importante de la morbidité posttransplantation. Partant de ce constat, l’objectif de notre travail était d’optimiser l’utilisation du tacrolimus chez les patients transplantés hépatiques à l’aide de méthodes pharmacologiques innovantes et d’explorer les mécanismes physiopathologiques de sa toxicité. Un premier axe de recherche a été d’évaluer une stratégie de minimisation extrême de la cible de concentration résiduelle sanguine du tacrolimus permettant ainsi de conforter cette attitude thérapeutique. Une seconde piste a permis de mettre en évidence l’importance de la variabilité intra-individuelle des concentrations de tacrolimus durant la phase précoce comme marqueur de la survenue de ses effets indésirables et de la survie à long terme des patients. Enfin, l’étude de la mesure des concentrations de tacrolimus dans la bile nous a permis d’apporter des pistes sur les mécanismes potentiels de sa toxicité. Les résultats de ces différents travaux nous ont donc permis d’améliorer notre pratique clinique et d’ouvrir plusieurs pistes dans la compréhension des mécanismes de la toxicité du tacrolimus.The efficacy of immunosuppressive drugs has led to the development and success of liver transplantation. Indeed, use of calcineurin inhibitors, of which tacrolimus is the main drug, has allowed an important decrease in the frequency of immunological complications. On the other hand, the adverse effects associated with its use now represent a significant proportion of post-transplant morbidity. Based on this observation, the objective of our work was to optimize the use of tacrolimus in liver transplant recipient using innovative pharmacological methods and to explore the mechanisms of its toxicity. A first way of research was to evaluate a policy of extreme minimization of tacrolimus target blood trough concentration, thus confirming this therapeutic policy. The second part highlights the importance of the intra-patient variability of tacrolimus trough concentrations during the early phase as a marker of the occurrence of its adverse effects and of patient’s the long-term survival. Finally, the measurement of tacrolimus concentrations in bile provides us new hypotheses on the mechanisms of its toxicity. The results of these studies helped us to improve our clinical practice and to explore the mechanisms of tacrolimus toxicity

Optimisation de l'utilisation du tacrolimus chez le transplanté hépatique

The efficacy of immunosuppressive drugs has led to the development and success of liver transplantation. Indeed, use of calcineurin inhibitors, of which tacrolimus is the main drug, has allowed an important decrease in the frequency of immunological complications. On the other hand, the adverse effects associated with its use now represent a significant proportion of post-transplant morbidity. Based on this observation, the objective of our work was to optimize the use of tacrolimus in liver transplant recipient using innovative pharmacological methods and to explore the mechanisms of its toxicity. A first way of research was to evaluate a policy of extreme minimization of tacrolimus target blood trough concentration, thus confirming this therapeutic policy. The second part highlights the importance of the intra-patient variability of tacrolimus trough concentrations during the early phase as a marker of the occurrence of its adverse effects and of patient’s the long-term survival. Finally, the measurement of tacrolimus concentrations in bile provides us new hypotheses on the mechanisms of its toxicity. The results of these studies helped us to improve our clinical practice and to explore the mechanisms of tacrolimus toxicity.L’efficacité des traitements immunosuppresseurs a permis l’essor et le succès de la transplantation hépatique. Ainsi, l’utilisation des inhibiteurs de la calcineurine, dont le tacrolimus est le représentant principal, a permis une diminution drastique de la fréquence des complications immunologiques. En revanche, les effets indésirables liés à son utilisation représentent aujourd’hui une part importante de la morbidité posttransplantation. Partant de ce constat, l’objectif de notre travail était d’optimiser l’utilisation du tacrolimus chez les patients transplantés hépatiques à l’aide de méthodes pharmacologiques innovantes et d’explorer les mécanismes physiopathologiques de sa toxicité. Un premier axe de recherche a été d’évaluer une stratégie de minimisation extrême de la cible de concentration résiduelle sanguine du tacrolimus permettant ainsi de conforter cette attitude thérapeutique. Une seconde piste a permis de mettre en évidence l’importance de la variabilité intra-individuelle des concentrations de tacrolimus durant la phase précoce comme marqueur de la survenue de ses effets indésirables et de la survie à long terme des patients. Enfin, l’étude de la mesure des concentrations de tacrolimus dans la bile nous a permis d’apporter des pistes sur les mécanismes potentiels de sa toxicité. Les résultats de ces différents travaux nous ont donc permis d’améliorer notre pratique clinique et d’ouvrir plusieurs pistes dans la compréhension des mécanismes de la toxicité du tacrolimus

Optimisation de l'utilisation du tacrolimus chez le transplanté hépatique

The efficacy of immunosuppressive drugs has led to the development and success of liver transplantation. Indeed, use of calcineurin inhibitors, of which tacrolimus is the main drug, has allowed an important decrease in the frequency of immunological complications. On the other hand, the adverse effects associated with its use now represent a significant proportion of post-transplant morbidity. Based on this observation, the objective of our work was to optimize the use of tacrolimus in liver transplant recipient using innovative pharmacological methods and to explore the mechanisms of its toxicity. A first way of research was to evaluate a policy of extreme minimization of tacrolimus target blood trough concentration, thus confirming this therapeutic policy. The second part highlights the importance of the intra-patient variability of tacrolimus trough concentrations during the early phase as a marker of the occurrence of its adverse effects and of patient’s the long-term survival. Finally, the measurement of tacrolimus concentrations in bile provides us new hypotheses on the mechanisms of its toxicity. The results of these studies helped us to improve our clinical practice and to explore the mechanisms of tacrolimus toxicity.L’efficacité des traitements immunosuppresseurs a permis l’essor et le succès de la transplantation hépatique. Ainsi, l’utilisation des inhibiteurs de la calcineurine, dont le tacrolimus est le représentant principal, a permis une diminution drastique de la fréquence des complications immunologiques. En revanche, les effets indésirables liés à son utilisation représentent aujourd’hui une part importante de la morbidité posttransplantation. Partant de ce constat, l’objectif de notre travail était d’optimiser l’utilisation du tacrolimus chez les patients transplantés hépatiques à l’aide de méthodes pharmacologiques innovantes et d’explorer les mécanismes physiopathologiques de sa toxicité. Un premier axe de recherche a été d’évaluer une stratégie de minimisation extrême de la cible de concentration résiduelle sanguine du tacrolimus permettant ainsi de conforter cette attitude thérapeutique. Une seconde piste a permis de mettre en évidence l’importance de la variabilité intra-individuelle des concentrations de tacrolimus durant la phase précoce comme marqueur de la survenue de ses effets indésirables et de la survie à long terme des patients. Enfin, l’étude de la mesure des concentrations de tacrolimus dans la bile nous a permis d’apporter des pistes sur les mécanismes potentiels de sa toxicité. Les résultats de ces différents travaux nous ont donc permis d’améliorer notre pratique clinique et d’ouvrir plusieurs pistes dans la compréhension des mécanismes de la toxicité du tacrolimus