Publications by authors named "Emilie Grégoire"

38 Publications

The white test for intraoperative screening of bile leakage: a potential trigger factor for acute pancreatitis after liver resection-a case series.

BMC Surg 2021 Oct 2;21(1):356. Epub 2021 Oct 2.

Department of Digestive Surgery and Liver Transplantation, Hôpital la Timone, 264 rue Saint-Pierre, 13385, Marseille Cedex 05, France.

Background: Acute pancreatitis after liver resection is a rare but serious complication, and few cases have been described in the literature. Extended lymphadenectomy, and long ischemia due to the Pringle maneuver could be responsible of post-liver resection acute pancreatitis, but the exact causes of AP after hepatectomy remain unclear.

Cases Presentation: We report here three cases of AP after hepatectomy and we strongly hypothesize that this is due to the bile leakage white test. 502 hepatectomy were performed at our center and 3 patients (0.6%) experienced acute pancreatitis after LR and all of these three patients underwent the white test at the end of the liver resection. None underwent additionally lymphadenectomy to the liver resection. All patient had a white-test during the liver surgery. We identified distal implantation of the cystic duct in these three patients as a potential cause for acute pancreatitis.

Conclusion: The white test is useful for detection of bile leakage after liver resection, but we do not recommend a systematic use after LR, because severe acute pancreatitis can be lethal for the patient, especially in case of distal cystic implantation which may facilitate reflux in the main pancreatic duct.
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http://dx.doi.org/10.1186/s12893-021-01354-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487543PMC
October 2021

Peri-operative risk factors of chronic kidney disease after liver transplantation.

J Nephrol 2021 Aug 23. Epub 2021 Aug 23.

Department of Digestive Surgery and Liver Transplantation, Hôpital la Timone, 264 Rue Saint-Pierre, 13385, Marseille Cedex 05, France.

Background: Chronic kidney disease (CKD) is a frequent long-term complication after liver transplantation (LT) and is associated with poor long-term survival. The aim of our study was to identify the risk factors of developing post-transplant CKD at 1 year, during the pre-operative, peri-operative, and post-LT phases.

Methods: All consecutive patients who underwent primary LT between July 2013 and February 2018 were analyzed. To assess the impact of peri- and post-operative factors on renal function at 1 year we performed a propensity score matching on gender, age of the recipient, Model for End-Stage Liver Disease (MELD) score, etiology of the hepatic disease, and estimated Glomerular Filtration Rate (eGFR) at baseline.

Results: Among the 245 patients who underwent LT, 215 had available data at one year (Y1), and 46% of them had CKD. Eighty-three patients in the CKD group and 83 in the normal renal function group were then matched. The median follow-up was 35 months (27-77). Patients with CKD at Y1 had a decreased 5-year survival compared to patients with normal renal function at one year: figures were 62% and 90%, respectively, p = 0.001. The independent predictors of CKD at Y1 were major complications (OR = 2.2, 95% CI [1.2-4.2]), p = 0.015, intensive care unit (ICU) stay > 5 days (OR = 2.2, 95% CI [1.3-5.1]), p = 0.046, ICU serum lactate level at 24 h ≥ 2.5 mmol/L (OR = 3.8 95% CI [1.1-8]), p = 0.034, need for post-LT renal replacement therapy (OR = 6.4 95% CI [1.4-25]), and MELD score ≥ 20 (OR = 2.1 95% CI [1.1-3.9]), p = 0.019.

Conclusions: The peri-operative period has a major impact on CKD incidence. Early recognition of patients at high risk of CKD may be critical for implementation of nephroprotective measures.
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http://dx.doi.org/10.1007/s40620-021-01127-6DOI Listing
August 2021

Predicting Intraoperative Difficulty of Open Liver Resections: The DIFF-scOR Study, An Analysis of 1393 Consecutive Hepatectomies From a French Multicenter Cohort.

Ann Surg 2021 11;274(5):805-813

University Lille, CHU Lille, Service de Chirurgie Digestive et Transplantations, Lille, France.

Objective: The aim of this study was to build a predictive model of operative difficulty in open liver resections (LRs).

Summary Background Data: Recent attempts at classifying open-LR have been focused on postoperative outcomes and were based on predefined anatomical schemes without taking into account other anatomical/technical factors.

Methods: Four intraoperative variables were perceived by the authors as to reflect operative difficulty: operation and transection times, blood loss, and number of Pringle maneuvers. A hierarchical ascendant classification (HAC) was used to identify homogeneous groups of operative difficulty, based on these variables. Predefined technical/anatomical factors were then selected to build a multivariable logistic regression model (DIFF-scOR), to predict the probability of pertaining to the highest difficulty group. Its discrimination/calibration was assessed. Missing data were handled using multiple imputation.

Results: HAC identified 2 clusters of operative difficulty. In the "Difficult LR" group (20.8% of the procedures), operation time (401 min vs 243 min), transection time (150 vs.63 minute), blood loss (900 vs 400 mL), and number of Pringle maneuvers (3 vs 1) were higher than in the "Standard LR" group. Determinants of operative difficulty were body weight, number and size of nodules, biliary drainage, anatomical or combined LR, transection planes between segments 2 and 4, 4, and 8 or 7 and 8, nonanatomical resections in segments 2, 7, or 8, caval resection, bilioentric anastomosis and number of specimens. The c-statistic of the DIFF-scOR was 0.822. By contrast, the discrimination of the DIFF-scOR to predict 90-day mortality and severe morbidity was poor (c-statistic: 0.616 and 0.634, respectively).

Conclusion: The DIFF-scOR accurately predicts open-LR difficulty and may be used for various purposes in clinical practice and research.
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http://dx.doi.org/10.1097/SLA.0000000000005133DOI Listing
November 2021

Oncological relevance of major hepatectomy with inferior vena cava resection for intrahepatic cholangiocarcinoma.

HPB (Oxford) 2021 Sep 24;23(9):1439-1447. Epub 2021 Feb 24.

Department of General Surgery and Liver Transplantation, La Timone Hospital, Aix Marseille University, Marseille, France.

Background: This study aimed to investigate the short- and long-terms outcomes of patients undergoing major hepatectomy (MH) with inferior vena cava (IVC) resection for intrahepatic cholangiocarcinoma (ICC).

Methods: Data from all patients who underwent MH for ICC with or without IVC resection between 2010 and 2018 were analysed retrospectively. Postoperative outcomes, overall survival (OS), and recurrence-free survival (RFS) were compared in the whole population. A propensity score matching (PSM) analysis and an inverse probability weighting analysis (IPW) were performed to assess the influence of IVC resection on short- and long-terms outcomes.

Results: Among the 78 patients who underwent MH, 20 had IVC resection (IVC patients). Overall, the mortality and severe complication rate were 8% and 20%, respectively. IVC patients required more extended hepatectomies (p = 0.001) and had increased rates of transfusions (p = 0.001), however they did not experience increased postoperative morbidity, even after PSM. The 1-, 3- and 5-years OS and DFS were 78%, 45%, and 32% and 48%, 20%, and 16%, respectively. IVC was not associated with decreased OS (p = 0.52) and/or RFS (p = 0.85), even after IPW.

Conclusion: MH with IVC resection for ICC seems to provide acceptable short- and long-term results in a selected population of patients.
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http://dx.doi.org/10.1016/j.hpb.2021.02.007DOI Listing
September 2021

Acute severe hepatitis in adult-onset Still's disease: case report and comprehensive review of a life-threatening manifestation.

Clin Rheumatol 2021 Jun 21;40(6):2467-2476. Epub 2020 Sep 21.

Service de médecine interne, Aix Marseille Université, APHM, Hôpital La Timone, Marseille, France.

Acute severe hepatitis is a rare complication of adult-onset Still's disease (AOSD). This condition is poorly characterized. We performed a review of the medical literature to describe clinical, biological, pathological, and treatment characteristics from AOSD patients with acute severe hepatitis. Their characteristics were compared with AOSD patients without severe hepatitis. Twenty-one cases were collected including a new case reported here. Patients with severe hepatitis were mostly young adults with a median age of 28 years (range: 20 to 55 years). Overall, patients with severe hepatitis had less arthritis, macular rash, sore throat, lymphadenopathy, or splenomegaly than patients without severe hepatitis. Cytopenia was more frequent in case of severe hepatitis. Most patients were treated with steroids, and the use of biotherapies has increased over the last decade. Despite treatment, 49% of patients required liver transplantation and 24% died. Key Points • Acute severe hepatitis in adult-onset Still's disease (AOSD) is associated with liver transplantation and/or death in, respectively, 43% and 24% of cases. • Severe hepatitis is the inaugural manifestation of AOSD in half of cases. Diagnosis is difficult when extra-hepatic clinical manifestations are lacking. • The mechanism of hepatic necrosis in AOSD with severe hepatitis is unknown. Liver biopsy is not specific and should not delay treatment initiation.
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http://dx.doi.org/10.1007/s10067-020-05383-yDOI Listing
June 2021

Liver transplantation for hepatocellular carcinoma after down staging with sorafenib: a monocentric case-matched series.

J Gastrointestin Liver Dis 2020 03 13;29(1):120-121. Epub 2020 Mar 13.

Aix Marseille University, Department of General Surgery and Liver Transplantation, Hopital la Timone, Marseille, France.

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http://dx.doi.org/10.15403/jgld-748DOI Listing
March 2020

The technique and outcomes of central hepatectomy by the Glissonian suprahilar approach.

Eur J Surg Oncol 2019 Dec 12;45(12):2369-2374. Epub 2019 Sep 12.

Department of General Surgery and Liver Transplantation, Hôpital de la Timone, Marseille, France; Aix-Marseille University, 27 boulevard Jean Moulin, 13385, Marseille, France.

Introduction: Central hepatectomy (CH) is technically challenging and seldom-used to treat centrally located tumors. However, CH is a parenchyma-sparing resection that may decrease the risk of postoperative liver failure. This retrospective study presents our technique of CH and assesses the outcomes.

Methods: All CH performed in our department over two decades (1997-2017) were identified. Indications and short-term outcomes were compared between the two decades. Long-term outcomes were assessed.

Results: Sixty-four patients underwent CH using a suprahilar approach for hepatocellular carcinoma (HCC: n = 30), metastasis (n = 23), intrahepatic cholangiocarcinoma (IHCCA: n = 9) or other diseases (n = 2). CH represented 6% of 1004 major hepatectomies, (7.4% (n = 35) before 2007 vs 5.4% (n = 29) after 2007). The mean operating time was 219 ± 56 min. A perioperative blood transfusion was required in 14 patients (22%). Intraoperative bile duct injuries occurred in 5 patients (8%), and they were repaired. One patient died postoperatively (1,5%). Ten patients (16%) experienced a major complication. Nine patients (14%) suffered from bile leakage, of which 6 healed spontaneously. Only one patient had low grade liver failure. The R0-resection rate was 69%. After 2007, there were no bile duct injuries (0/29 vs 5/35, p < 0.05), and the average hospital stay was shorter but not significantly (11 vs 14 days). Actuarial 5-year survival was 56% for HCC patients and 34% for those with colorectal metastasis CONCLUSIONS: CH is associated with significant biliary morbidity and may increase positive surgical margins. Nevertheless, it should be recommended in selected patients to avoid the risk of postoperative liver failure.
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http://dx.doi.org/10.1016/j.ejso.2019.09.010DOI Listing
December 2019

Liver transplantation in patients with liver failure related to exertional heatstroke.

J Hepatol 2019 03 4;70(3):431-439. Epub 2018 Dec 4.

AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Liver Intensive Care Unit, Villejuif F-94800, France; INSERM, Unité 1193, Université Paris-Saclay, Villejuif F-94800, France; DHU Hepatinov, Villejuif F-94800, France.

Background & Aims: Severe acute liver injury is a grave complication of exertional heatstroke. Liver transplantation (LT) may be a therapeutic option, but the criteria for LT and the optimal timing of LT have not been clearly established. The aim of this study was to define the profile of patients who require transplantation in this context.

Methods: This was a multicentre, retrospective study of patients admitted with a diagnosis of exertional heatstroke-related severe acute liver injury with a prothrombin time (PT) of less than 50%. A total of 24 male patients were studied.

Results: Fifteen of the 24 patients (median nadir PT: 35% [29.5-40.5]) improved under medical therapy alone and survived. Nine of the 24 were listed for emergency LT. At the time of registration, the median PT was 10% (5-12) and all had numerous dysfunctional organs. Five patients (nadir PT: 12% [9-12]) were withdrawn from the list because of an elevation of PT values that mainly occurred between day 2 and day 3. Ultimately, 4 patients underwent transplantation as their PT persisted at <10%, 3 days (2.75-3.25) after the onset of exertional heatstroke, and they had more than 3 organ dysfunctions. Of these 4 patients, 3 were still alive 1 year later. Histological analysis of the 4 explanted livers demonstrated massive or sub-massive necrosis, and little potential for effective mitoses, characterised by a "mitonecrotic" appearance.

Conclusion: The first-line treatment for exertional heatstroke-related severe acute liver injury is medical therapy. LT is only a rare alternative and such a decision should not be taken too hastily. A persistence of PT <10%, without any signs of elevation after a median period of 3  days following the onset of heatstroke, was the trigger that prompted LT, was the trigger adopted in order to decide upon LT.

Lay Summary: Acute liver injury due to heatstroke can progress to acute liver failure with organ dysfunction despite medical treatment; in such situations, liver transplantation (LT) may offer a therapeutic option. The classic criteria for LT appear to be poorly adapted to heatstroke-related acute liver failure. We confirmed thatmedication is the first-line therapy acute liver injury caused by heatstroke, with LT only rarely necessary. A decision to perform LT should not be made hastily. Fluctuations in prothrombin time and the patient's clinical status should be considered even in the event of severe liver failure.
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http://dx.doi.org/10.1016/j.jhep.2018.11.024DOI Listing
March 2019

Short-term outcomes after major hepatic resection in patients with cirrhosis: a 75-case unicentric western experience.

HPB (Oxford) 2019 03 16;21(3):352-360. Epub 2018 Aug 16.

Department of Digestive Surgery, Hôpital de la Timone, Marseille, France; Université Aix-Marseille, 27 Boulevard Jean Moulin, 13385, Marseille, France.

Background: The benefit of performing major hepatic resection (MHR) for hepatocellular carcinoma (HCC) in patients with cirrhosis remains controversial because of its high risk of posthepatectomy liver failure (PHLF). This study was conducted to assess the risk of MHR for HCC in patients with cirrhosis.

Methods: Patients with Child-Pugh A or B cirrhosis and HCC who underwent MHR from January 2000 to June 2014 were retrospectively identified. Risk factors for postoperative morbidity and mortality using univariate and multivariate analyses were evaluated.

Results: Seventy patients with Child-Pugh A (93%) and 5 (7%) with Child-Pugh B cirrhosis underwent MHR for HCC. Thirteen (17%) had Barcelona Clinic Liver Cancer (BCLC) stage A, 39 (50%) had BCLC B, and 23 (32%) had BCLC C disease. A perioperative blood transfusion was performed in 18 patients (24%). Ninety-day postoperative mortality was 9% (n=7). Major complications occurred in 16 patients (21%), including PHLF in 9 patients (12%). A multivariate analysis showed that perioperative blood transfusion was the main independent factor associated with mortality (OR= 6.5) and major morbidity (OR=10).

Conclusion: In selected patients with HCC and cirrhosis, MHR is feasible and has acceptable mortality, but careful perioperative management and limiting blood loss are required.
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http://dx.doi.org/10.1016/j.hpb.2018.07.020DOI Listing
March 2019

Morbidity and mortality of hepatic right lobe living donors: systematic review and perspectives.

J Gastrointestin Liver Dis 2018 Jun;27(2):169-178

Aix-Marseille University, Experimental Interventional Imaging Laboratory, European Center for Medical Imaging Research; Aix-Marseille University, Department of General Surgery and Liver Transplantation, Hôpital de la Timone, Marseille, France.

Background And Aims: The main restriction in the development of adult-adult Living Donor Liver Transplantation (LDLT) is the risk of morbidity and mortality for donors, which raises ethical questions. The objectives of this study are to review published studies dealing with morbidity and mortality in LDLT and to identify the proposed management and strategies for preventing donor mortality and morbidity in LDLT.

Methods: The Medline database was searched from 2000 to 2017 using the MeSH terms "liver transplantation" and "morbidity" or "mortality" in combination with keywords "living donor liver transplantation".

Results: Among the 382 articles obtained, 43 articles were relevant for morbidity, 15 for mortality and 6 for both morbidity and mortality. Twenty-three papers reported donor deaths. The major cause of death was sepsis (30%). Morbidity ranged from 10% to 78.3% depending on the studies.

Conclusions: The living donors' morbidity and mortality is high, currently representing the main restriction in the development of LDLT. Some promising techniques, such as the donor portal vein flow modulation could lead to the further development of LDLT.
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http://dx.doi.org/10.15403/jgld.2014.1121.272.morDOI Listing
June 2018

Authors' Reply: Postoperative Bleeding After Laparoscopic Pancreaticoduodenectomy: The Achilles' Heel?

World J Surg 2018 09;42(9):3060-3061

Department of Digestive Disease, Institut Mutualiste Montsouris, Université Paris-Descartes, 42 Boulevard Jourdan, 75014, Paris, France.

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http://dx.doi.org/10.1007/s00268-018-4583-0DOI Listing
September 2018

Portal vein stenosis preconditioning of living donor liver in swine: early mechanisms of liver regeneration and gain of hepatic functional mass.

Am J Physiol Gastrointest Liver Physiol 2018 07 22;315(1):G117-G125. Epub 2018 Feb 22.

Experimental Interventional Imaging Laboratory EA-4264, European Centre for Medical Imaging Research, Aix-Marseille University , Marseille , France.

To reduce the morbidity and mortality risk for the donor in living donor liver transplantation (LDLT), we previously identified 20% left portal vein (LPV) stenosis as an effective preconditioning method to induce cell proliferation in the contralateral lobe without downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours after preconditioning and investigate the changes in liver volume and function. Fourteen pigs were used this study. Five pigs were used to study the genetic, cellular and molecular mechanisms set up in the early hours following the establishment of our preconditioning. The remaining nine pigs were equally divided into three groups: sham-operated animals, 20% LPV stenosis, and 100% LPV stenosis. Volumetric scanning and 99 mTc-Mebrofenin hepatobiliary scintigraphy were performed before preconditioning and 14 days after to study morphological and functional changes in the liver. We demonstrated that liver regeneration triggered by 20% LPV stenosis in the contralateral lobe involves TNF-α, IL-6, and inducible nitric oxide synthase 2 by means of STAT3 and hepatocyte growth factor. We confirmed that our preconditioning was responsible for an increase in the total liver volume. Finally, we demonstrated that this volumetric gain was associated with an increase in hepatic functional capacity. NEW & NOTEWORTHY We describe a new preconditioning method for major hepatectomy that is applicable to hepatectomy for donation. We identified 20% left portal vein stenosis as effective preconditioning that is capable of inducing cell proliferation in the contralateral lobe without the downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours following preconditioning, and we confirm that 20% left portal vein stenosis is responsible for an increase in the functional capacity and total liver volume in a porcine model.
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http://dx.doi.org/10.1152/ajpgi.00390.2017DOI Listing
July 2018

Indocyanine Green Retention Rates at 15 min Predicted Hepatic Decompensation in a Western Population.

World J Surg 2018 08;42(8):2570-2578

Centre Hépato-biliaire, Hôpital Paul Brousse, 12 Avenue Paul Vaillant Couturier, 94800, Villejuif, France.

Background: ICGR15 is widely used in Asia to evaluate the liver reserve before hepatectomy, but not in Western countries where patients are selected using the MELD score and/or platelet count. Postoperative liver failure is rare nowadays, but hepatic decompensation (HD), defined by 3-month postoperative ascites, impairs quality of life and survival. The aim of this study was to evaluate the relevance of indocyanine green retention rate at 15 min (ICGR15) before liver resection in Western countries, in order to predict HD.

Methods: This prospectively designed study included consecutive adult patients undergoing hepatectomy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in three French HPB centres.

Results: Between 2012 and 2014, 147 patients were included (80% of HCC and 20% of ICC). The Child-Pugh status was grade A for all patients. In the overall population and in F3/F4 patients (n = 83), ICGR15 (P = 0.02) and platelet counts (P = 0.02) were predictive of HD under multivariate analysis. Among F3/F4 patients undergoing minor hepatectomy with preoperative ICGR15 > 15%, the rate of HD was 36%. In the overall population, ICGR15 was predictive of HD (P = 0.02) and postoperative ascites (P = 0.03). The ROC curve identified a cut-off point of 15% as being associated with increased HD, with good accuracy for ICGR15 in the study population (AUROC 0.73), mainly before minor hepatectomy (AUROC 0.79).

Conclusions: In patients with HCC and ICC selected using the MELD score and platelet rate, an ICGR15 > 15% is a relevant, non-invasive and clearly accurate method to predict HD specially before minor hepatectomy.
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http://dx.doi.org/10.1007/s00268-018-4464-6DOI Listing
August 2018

Postoperative Bleeding After Laparoscopic Pancreaticoduodenectomy: the Achilles' Heel?

World J Surg 2018 04;42(4):1138-1146

Department of Digestive Disease, Institut Mutualiste Montsouris, Université Paris-Descartes, 42 Boulevard Jourdan, 75014, Paris, France.

Background: Laparoscopic pancreaticoduodenectomy (LPD) is technically demanding, and its impact on postoperative outcomes remains controversial.

Objective: To compare short-term outcomes between laparoscopic versus open pancreaticoduodenectomy (OPD) in order to assess the safety of LPD.

Methods: From 2002 to 2014, all consecutive patients undergoing LPD or OPD at two tertiary centers were retrospectively analyzed. Patients were matched for demographics, comorbidities, pathological diagnosis, and pancreatic texture. Results for the two groups were compared for postoperative outcomes.

Results: Sixty-five LPD were performed and compared to 290 OPD. In the whole population, postoperative pancreatic fistula (PF) was higher in the LPD group, but the proportion of ampullary adénocarcinoma (25 vs. 10%, p = 0.004) and soft pancreatic parenchyma (52 vs. 38%, p = 0.001) were higher in the LDP group. After matching (n = 65), LPD was associated with longer operative time (429 vs. 328 min, p < 0.001) and lower blood loss (370 vs. 515 mL, p = 0.047). The PF rate and its severity were similar (33 vs. 27%, p = 0.439, p = 0.083) in the two groups. However, both complications (78 vs. 71%, p = 0.030) and major complications (40 vs. 23%, p = 0.033) were more frequent in the LPD group. LPD patients experience more postoperative bleeding (21 vs. 14%, p = 0.025) compared to their open counterparts. In multivariate analysis, perioperative transfusion (OR = 5 IC 95% (1.5-16), p = 0.008), soft pancreas (OR = 2.5 IC 95% (1.4-4.6), p = 0.001), and ampullary adenocarcinoma (OR = 2.6 IC 95% (1.2-5.6), p = 0.015) were independent risks factors of major complications.

Conclusion: Despite lower blood loss and lower intraoperative transfusion, LPD leads to higher rate of postoperative complications with postoperative bleeding in particular.
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http://dx.doi.org/10.1007/s00268-017-4269-zDOI Listing
April 2018

Sensitizing Surgeons to Their Outcome Has No Measurable Short-term Benefit.

Ann Surg 2017 11;266(5):884-889

*Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, Université Paris 7, Clichy, France †Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Paul Brousse, Villejuif, France ‡Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Claude Huriez, Lille, France §Department of Hepatobiliopancreatic Surgery, Hôpital Nord, Amiens, France ¶Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Croix Rousse, Lyon, France ||Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Saint Antoine, Paris, France **Department of Hepatobiliopancreatic Surgery, Hôpital Edouard Herriot, Lyon, France ††Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Saint André, Bordeaux, France ‡‡Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital de la Conception, Marseille, France §§Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France ¶¶Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France.

Objective: Investigate if involving surgeons in outcome prediction-research and having them use a dedicated Electronic-Health-Record that provides feedback, improves patients' outcome.

Background: Improvement of clinical outcome mainly relies on the declaration of adverse events, identification of their predictors, self-assessment, and feedback.

Methods: Thirteen French Hepato-Pancreato-Biliary-centers made commitment to include all patients undergoing elective hepatectomies in an observational study. Each center was given access to a dedicated website, where perioperative data were prospectively collected. The website provided real-time individual and comparative feedback of outcome and was also intended to perform prognostication studies. The hypothesis was that by using this strategy, the length-of-stay would be reduced by 10%. Power-calculation implied the inclusion of 1720 patients. Secondary endpoints were 90-day mortality, severe morbidity, and the comprehensive-complication index.

Results: Only 5 of the 13 participating centers were fully compliant in enrolling their patients and the inclusion period was extended by 1-year (October 2012-October 2015) to meet the objective. During this period, the collaborative group published 9 studies based on the study data (median impact factor = 8.327) that identified quantitative clinical variables, qualitative clinical variables, and nonclinical variables influencing outcome. For patients enrolled by the 5 active centers (n = 1752), there was no improvement in length of stay (13.3 vs 12.4 days, P = 0.287), severe complications (23.6 vs 20.5%, P = 0.134), the complication comprehensive index (24.0 vs 24.9, P = 0.448), mortality (4.1 vs 3.9%, P = 0.903), or unplanned readmissions (7.2 vs 8.4%, P = 0.665), even after adjusting for confounders.

Conclusion: Simply sensitizing surgeons to their outcome has no measurable short-term clinical benefit.
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http://dx.doi.org/10.1097/SLA.0000000000002403DOI Listing
November 2017

Comparison of different feeding regimes after pancreatoduodenectomy - a retrospective cohort analysis.

Nutr J 2017 Jul 4;16(1):42. Epub 2017 Jul 4.

Department of Digestive Surgery, Hôpital Nord, Aix-Marseille University, Chemin des Bourrely 13915, cedex 20, Marseille, France.

Background: Delayed gastric emptying (DGE) is the most frequent pancreatic specific complication (PSC) after pancreaticoduodenectomy (PD). Several gastric decompression systems exist to manage DGE. Patients with a pancreatic tumor require prolonged nutrition; however, controversies exist concerning nutrition protocol after PD. The aim of the study was to assess the safety and efficacy of nasogastric (NG), gastrostomy (GT), and gastrojejunostomy (GJ) tubes with different feeding systems on postoperative courses.

Methods: Between January 2013 and March 2016, 86 patients underwent PD with pancreaticogastrostomy. Patients were divided into three groups: GJ group with enteral nutrition (EN, n = 12, 14%), NG (n = 31, 36%) and GT groups (n = 43, 50%), both with total parenteral nutrition (TPN).

Results: Patients in the GJ (n = 9, 75%) and GT (n = 18, 42%) groups had an American Society of Anesthesiologists (ASA) score of 3 more often than those in the NG group (n = 5, 16%, p ≤ 0.01). Multivariate analysis identified the GT tube with TPN as an independent risk factor of severe morbidity (p = 0.02) and DGE (p < 0.01). An ASA score of 3, jaundice, common pancreatic duct size ≤3 mm and soft pancreatic gland texture (p < 0.05) were found as independent risk factors of PSCs. Use of a GJ tube with EN, GT tube with TPN, jaundice, and PSCs were identified as independent risk factors for greater postoperative length of hospital stay (p < 0.01). Mean global hospitalization cost did not differ between groups.

Conclusion: GT tube insertion with TPN was associated with increased severe postoperative morbidity and DGE and should not be recommended. EN through a GJ tube after PD is feasible but does not have clear advantages on postoperative courses compared to an NG tube.
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http://dx.doi.org/10.1186/s12937-017-0265-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496601PMC
July 2017

Intensive Early Rehabilitation in the Intensive Care Unit for Liver Transplant Recipients: A Randomized Controlled Trial.

Arch Phys Med Rehabil 2017 08 6;98(8):1518-1525. Epub 2017 Mar 6.

Aix-Marseille University, Assistance Publique des Hôpitaux de Marseille, Department of General Surgery and Liver Transplantation, Hôpital de la Conception, Marseille, France. Electronic address:

Objective: To validate the feasibility and tolerance of an intensive rehabilitation protocol initiated during the postoperative period in an intensive care unit (ICU) in liver transplant recipients.

Design: Prospective randomized study.

Setting: ICU.

Participants: Liver transplant recipients over a period of 1 year (N=40).

Interventions: The "usual treatment group" (n=20), which benefited from the usual treatment applied in the ICU (based on physician prescription for the physiotherapist, with one session a day), and the experimental group (n=20), which followed a protocol of early and intensive rehabilitation (based on a written protocol validated by physicians and an evaluation by physiotherapist, with 2 sessions a day), were compared.

Main Outcome Measures: Our primary aims were tolerance, assessed from the number of adverse events during rehabilitation sessions, and feasibility, assessed from the number of sessions discontinued.

Results: The results revealed a small percentage of adverse events (1.5% in the usual treatment group vs 1.06% in the experimental group) that were considered to be of low intensity. Patients in the experimental group sat on the edge of their beds sooner (2.6 vs 9.7d; P=.048) and their intestinal transit resumed earlier (5.6 vs 3.7d; P=.015) than patients in the usual treatment group. There was no significant difference between the 2 arms regarding length of stay (LOS), despite a decrease in duration in the experimental group.

Conclusions: The introduction of an intensive early rehabilitation program for liver transplant recipients was well tolerated and feasible in the ICU. We noted that the different activities proposed were introduced sooner in the experimental group. Moreover, there is a tendency to decreased LOS in the ICU for the experimental group. These results now need to be confirmed by studies on a larger scale.
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http://dx.doi.org/10.1016/j.apmr.2017.01.028DOI Listing
August 2017

Parenchymal-sparing hepatectomies (PSH) for bilobar colorectal liver metastases are associated with a lower morbidity and similar oncological results: a propensity score matching analysis.

HPB (Oxford) 2016 09 5;18(9):781-90. Epub 2016 Jul 5.

Institut Hospitalo-Universitaire (IHU), Institute for Minimally Invasive Hybrid Image-Guided Surgery, Université de Strasbourg, Strasbourg, France; Institut de Recherche Contre les Cancers de l'Appareil Digestif (IRCAD), Strasbourg, France; General, Digestive, and Endocrine Surgery, Nouvel Hôpital Civil, Strasbourg, France. Electronic address:

Objective: The aim of this study is to evaluate whether a parenchymal-sparing strategy provides similar results in terms of morbidity, mortality, and oncological outcome of non-PSH hepatectomies in a propensity score matched population (PSMP) in case of multiple (>3) bilobar colorectal liver metastases (CLM).

Background: The surgical treatment of bilobar liver metastasis is challenging due to the necessity to achieve complete resection margins and a sufficient future remnant liver. Two approaches are adaptable as follows: parenchymal-sparing hepatectomies (PSH) and extended hepatectomies (NON-PSH).

Methods: A total of 3036 hepatectomies were analyzed from a multicentric retrospective cohort of hepatectomies. Patients were matched in a 1:1 propensity score analysis in order to compare PSH versus NON-PSH resections.

Results: PSH was associated with a lower number of complications (≥1) (25% vs. 34%, p = 0.04) and a lower grade of Dindo-Clavien III and IV (10 vs. 16%, p = 0.03). Liver failure was less present in PSH (2 vs. 7%, p = 0.006), with a shorter ICU stay (0 day vs. 1 day, p = 0.004). No differences were demonstrated in overall and disease-free survival.

Conclusion: In conclusion, PSH resection for bilobar multiple CLMs represents a valid alternative to NON-PSH resection in selected patients with a reduced morbidity and comparable oncological results.
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http://dx.doi.org/10.1016/j.hpb.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011081PMC
September 2016

Successful liver transplantation for hepatocellular carcinoma following down-staging using sorafenib single therapy.

Liver Int 2016 09 8;36(9):1393. Epub 2016 Jul 8.

Department of Hepato-Gastroenterology, Hôpital de la Timone, Aix-Marseille Université, Marseille Cedex 5, France.

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http://dx.doi.org/10.1111/liv.13190DOI Listing
September 2016

Influence of Depression on Recovery After Major Noncardiac Surgery: A Prospective Cohort Study.

Ann Surg 2015 Nov;262(5):882-9; discussion 889-90

*INSERM-U1178, Paris, France †Université Paris Sud, Université Paris Descartes, Paris, France ‡Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Beaujon, Assistance-Publique Hôpitaux de Paris, Clichy, France §Université de la Picardie Jules Vernes, Département de Psychologie, CRP-CPO, Amiens, France ¶Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Claude Huriez, Lille, France ||Department of Digestive Surgery, Amiens University Hospital, Amiens, France **Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital de la Conception, Marseille, France ††Department of Visceral Surgery and Transplantation, Hautepierre Hospital, University Hospitals of Strasbourg, Strasbourg, France ‡‡Department of Hepatobiliary and Liver Transplantation Surgery, Hôpital Pitié-Salpêtrière, Paris, France §§Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Croix Rousse, Lyon, France ¶¶Department of Hepatobiliopancreatic Surgery, Hôpital Edouard Herriot, Lyon, France ||||Department of Hepatobiliopancreatic Surgery and Liver Transplantation, Hôpital Paul Brousse, Villejuif, France ***Center de Soins Psychothérapeutiques de Transition pour Adolescents, Hôpital d'Argenteuil, Argenteuil, France. †††Université Paris Diderot, Paris, France.

Objectives: To determine the influence of patient depression (and anxiety) on postoperative outcome and surgeons' consideration of it.

Background: Patients' mental state influences the course of nonpsychiatric diseases. Evidence in the surgical setting comes mainly from cardiac-surgery patients and no predictive-model of postoperative outcome considers this dimension.

Methods: This prospective multicenter study included patients undergoing liver resections, a model of major abdominal surgery, between September 2013 and September 2014 in 8 centers. The primary outcome was postoperative morbidity or mortality (assessed by the Clavien-Dindo grade and the Comprehensive Complication Index) and the postoperative length of stay (LOS). Depression and anxiety were assessed preoperatively with the Hospital Anxiety and Depression Scale and a validated cutoff. Surgeons were preoperatively asked to predict outcome. Multivariable mixed-effects Cox models were fitted to evaluate the influence of depression on actual and surgeon-anticipated outcome and on the difference between actual and surgeon-anticipated LOS.

Results: Hospital Anxiety and Depression Scale identified 142 of 591 patients (24.0%) as depressed and 40.3% as anxious. Neither condition was independently correlated with morbidity or mortality, but depression was an independent risk factor for prolonged LOS (adjusted hazard ratio 0.65, 95% confidence interval 0.50-0.83, P = 0.001). Depression was not correlated with anticipated LOS. Three variables explained the gap between anticipated and actual LOS: depression (P = 0.003), associated surgical procedures in addition to liver resection (P = 0.007), and postoperative morbidity (P < 0.001).

Conclusions: Nearly 1 quarter of patients undergoing major abdominal surgery are depressed preoperatively. This depression is a strong independent predictor of prolonged LOS and partly explains surgeons' failure to predict outcome accurately.
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http://dx.doi.org/10.1097/SLA.0000000000001448DOI Listing
November 2015

Invasive Listeria monocytogenes infection after liver transplantation: a life-threatening condition.

Lancet 2015 Jan;385(9963):200

Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, Aix-Marseille Université, Marseille, France; Comité de Lutte Contre Les Infections Nosocomiales, Hôpital Sainte-Marguerite, Marseille, France.

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http://dx.doi.org/10.1016/S0140-6736(14)61831-6DOI Listing
January 2015

Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression.

J Clin Invest 2014 Dec 10;124(12):5337-51. Epub 2014 Nov 10.

It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.
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http://dx.doi.org/10.1172/JCI72415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348942PMC
December 2014

Transjugular intrahepatic porto-systemic shunt is a risk factor for liver dysplasia but not hepatocellular carcinoma: a retrospective study of explanted livers.

Dig Liver Dis 2015 Jan 11;47(1):57-61. Epub 2014 Oct 11.

Department of Hepato-Gastroenterology, Hôpital de la Conception, Marseille, France; UMR 911, Université de la Méditerranée, Marseille, France.

Background: Conflicting data exist regarding the risk for hepatocellular carcinoma after transjugular intrahepatic porto-systemic shunt (TIPS) insertion in cirrhotic patients.

Methods: We retrospectively analysed histopathological data from 214 patients who were transplanted in our Institution including 68 patients who underwent TIPS placement before transplantation. Pathological lesions from explanted livers, including incidental hepatocellular carcinoma, small cell dysplasia and large cell dysplasia were recorded.

Results: Pathological lesions were found in 36.4% of explanted livers. TIPS insertion was an independent risk factor for pathological lesion (HR = 2.11, p < 0.05), concurrently with age (HR = 1.10 per year, p < 0.001) and viral aetiology of cirrhosis (HR = 3.05, p < 0.001). When considering the different type of lesions, TIPS insertion was not associated with an increased risk for hepatocellular carcinoma but was an independent risk factor for liver dysplasia (HR = 2.15, p = 0.042).

Conclusion: Although a direct relationship between TIPS insertion and hepatocellular carcinoma risk was not demonstrated in this study, the increased frequency of liver dysplasia observed in TIPS-bearing explanted livers deserves further prospective investigations with adequate follow-up.
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http://dx.doi.org/10.1016/j.dld.2014.09.009DOI Listing
January 2015

Lymphoepithelial cyst of the pancreas: an analysis of 117 patients.

Pancreas 2014 Oct;43(7):987-95

From the *Aix-Marseille Université; †Assistance Publique des Hôpitaux de Marseille (APHM), Service de Chirurgie Digestive, Hôpital La Conception; and ‡APHM, Service d'Anatomie Pathologique, Hôpital La Timone, Marseille, France.

Objectives: Lymphoepithelial cyst (LEC) of the pancreas is an unusual and benign cystic tumor. Accurate preoperative diagnosis is difficult; hence, most of pancreatic LECs are resected. The aim was to describe clinicopathological features of pancreatic LEC to guide appropriate management.

Methods: We retrospectively collected data about LEC patients treated in our department between 1987 and 2012 and added cases from review of the literature during the same period.

Results: One hundred seventeen cases (3 from our institution and 114 from literature review) were identified. Most patients were men (78%). The discovery was generally fortuitous. Serum CA19-9 was elevated in half of the cases. No specific radiological feature was identified. Fine needle aspiration and cytologic analysis allowed a correct preoperative diagnosis in 21% of the patients, showing presence of squamous cells, lymphocytes, and keratinous debris. Half of them were treated conservatively, whereas other patients underwent surgery. Neither malignant transformation nor recurrence after resection was observed.

Conclusions: The LEC of the pancreas is a rare benign tumor that could be treated conservatively. Fine needle aspiration is the only tool that can achieve a diagnosis without resection. If no certain diagnosis can be made, surgery is warranted to rule out a malignant differential diagnosis.
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http://dx.doi.org/10.1097/MPA.0000000000000167DOI Listing
October 2014

Successful treatment with sofosbuvir of fibrosing cholestatic hepatitis C after liver transplantation in an HIV-HCV-coinfected patient.

Antivir Ther 2015 8;20(3):353-6. Epub 2014 Aug 8.

Service d'Hépato-Gastroentérologie, Centre Hospitalo-Universitaire Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.

Fibrosing cholestatic hepatitis is a severe form of post-liver transplantation HCV recurrence. Fibrosing cholestatic hepatitis is characterized by its early onset and severe prognosis in HIV-infected patients. We report the case of an HIV-HCV genotype-4 coinfected patient successfully treated with a combination of sofosbuvir and ribavirin. After 4 weeks of treatment we observed a resolution of HCV recurrence related symptoms associated with a normalization of liver biochemistry and dramatic decrease of HCV viral load. This case illustrates the efficiency and tolerance of a sofosbuvir-based anti-HCV interferon-free regimen in post-liver HCV recurrence. Because of the absence of drug interactions between sofosbuvir and antiretroviral treatment or calcineurin inhibitors, its administration in HIV-HCV-coinfected liver transplanted patients is very promising.
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http://dx.doi.org/10.3851/IMP2841DOI Listing
February 2016

Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.

Ann Surg 2013 May;257(5):807-15

Hôpital La Conception, Marseille, France.

Objective: The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period.

Background: LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases.

Methods: This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1-149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures.

Results: Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT.

Conclusions: LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.
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http://dx.doi.org/10.1097/SLA.0b013e31828ee17cDOI Listing
May 2013

Mapping of NKp46(+) Cells in Healthy Human Lymphoid and Non-Lymphoid Tissues.

Front Immunol 2012 20;3:344. Epub 2012 Nov 20.

Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM2 Marseille, France ; Institut National de la Santé et de la Recherche Medicale, UMR 1104 Marseille, France ; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 7280 Marseille, France.

Understanding Natural Killer (NK) cell anatomical distribution is key to dissect the role of these unconventional lymphocytes in physiological and disease conditions. In mouse, NK cells have been detected in various lymphoid and non-lymphoid organs, while in humans the current knowledge of NK cell distribution at steady state is mainly restricted to lymphoid tissues. The translation to humans of findings obtained in mice is facilitated by the identification of NK cell markers conserved between these two species. The Natural Cytotoxicity Receptor (NCR) NKp46 is a marker of the NK cell lineage evolutionary conserved in mammals. In mice, NKp46 is also present on rare T cell subsets and on a subset of gut Innate Lymphoid Cells (ILCs) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) transcription factor. Here, we documented the distribution and the phenotype of human NKp46(+) cells in lymphoid and non-lymphoid tissues isolated from healthy donors. Human NKp46(+) cells were found in splenic red pulp, in lymph nodes, in lungs, and gut lamina propria, thus mirroring mouse NKp46(+) cell distribution. We also identified a novel cell subset of CD56(dim)NKp46(low) cells that includes RORγt(+) ILCs with a lineage(-)CD94(-)CD117(bright)CD127(bright) phenotype. The use of NKp46 thus contributes to establish the basis for analyzing quantitative and qualitative changes of NK cell and ILC subsets in human diseases.
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http://dx.doi.org/10.3389/fimmu.2012.00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501723PMC
November 2012

Primary small bowel volvulus in adult.

J Emerg Med 2013 Apr 11;44(4):e329-30. Epub 2012 Oct 11.

University de la Mediterranée and Assistance-Publique Hôpitaux de Marseille, Department of General Surgery and Liver Transplantation, Hospital la Conception, Marseille, France.

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http://dx.doi.org/10.1016/j.jemermed.2012.08.023DOI Listing
April 2013

Salvage liver transplantation for hepatic gas gangrene.

J Gastrointest Surg 2012 Sep 6;16(9):1802-4. Epub 2012 Jun 6.

Aix-Marseille Univ 13284 Marseille, & Assistance-Publique Hôpitaux de Marseille, Department of Digestive Surgery and Liver Transplantation, Hopital de La Conception, 13005 Marseille, France.

Hepatic gas gangrene is an uncommon situation mainly due to bacterial infection by Clostridium perfringens. It remains a life-threatening condition associated with a high mortality rate. Quick diagnosis and aggressive therapy including liver transplantation should be proposed to improve the outcome. This report describes a rare case of hepatic gas gangrene on native liver, secondary to iatrogenic hepatic artery thrombosis and instrumental biliary tree infection, which was successfully treated by liver transplantation.
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http://dx.doi.org/10.1007/s11605-012-1917-3DOI Listing
September 2012

Cannabis body packing: two case reports.

Clin Toxicol (Phila) 2011 Nov;49(9):862-4

CEIP-Addictovigilance, Hôpital Timone, 264 Rue Saint-Pierre, Marseille, 13005 France.

Introduction: Body packing is a well-known means of narcotic carriage across international borders. The most common drugs carried are cocaine and heroin.

Case Descriptions: We describe 2 cases of cannabis body packing which occurred the same year in the South of France, one with complications: a 45-year-old male went to emergency for abdominal pain. A plain abdominal x-ray revealed multiple foreign bodies in the gastrointestinal tract. It was confirmed by abdominal CT. The laparatomy confirmed peritonitis secondary to colonic perforation, and 34 filled condoms packages were extracted. After calling poison centre, toxicological analysis was performed on one package. The resin wrapped in cellophane contained 15% tetrahydrocannabinol (THC). The patient was discharged on day 12.

Discussion/conclusion: Cannabis body packing is rarely reported, and the only known complications have a mechanic etiology. Plain abdominal x-ray is the best method for detection and it can be confirmed by abdominal CT and toxicological analysis. Cannabis is the most important illicit drug used in the word. Also cannabis body packing is probably underestimated. Health care practitioners should be aware of the possibility of body packing when someone coming back from abroad complains of abdominal pain.
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http://dx.doi.org/10.3109/15563650.2011.623679DOI Listing
November 2011
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