Expansion of CMV-mediated NKG2C+ NK cells associates with the development of specific de novo malignancies in liver-transplanted patients.

Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV(+) patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.

Nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients with alcohol-associated cirrhosis awaiting liver transplants.

BACKGROUND & AIMS: Many patients with alcohol-associated cirrhosis also have diabetes, obesity, or insulin resistance-mediated steatosis, but little is known about how these disorders affect the severity of liver disease. We analyzed the prevalence and prognostic implications of metabolic risk factors (MRFs) such as overweight, diabetes, dyslipidemia, and hypertension in patients with alcohol-associated cirrhosis awaiting liver transplants. METHODS: We performed a retrospective study of 110 patients with alcohol-associated cirrhosis (77% male; mean age, 55 y; 71% with >6 mo of abstinence) who received liver transplants at a single center in Paris, France, from 2000 through 2013. We collected data on previous exposure to MRFs, steatosis (>10% in the explant), and histologically confirmed hepatocellular carcinoma (HCC). RESULTS: HCC was detected in explants from 29 patients (26%). Steatosis was detected in explants from 47 patients (70% were abstinent for ≥6 mo); 50% had a history of overweight or type 2 diabetes. Fifty-two patients (47%) had a history of MRFs and therefore were at risk for nonalcoholic fatty liver disease. A higher proportion of patients with MRF had HCC than those without MRF (46% vs 9%; P < .001). A previous history of overweight or type 2 diabetes significantly increased the risk for HCC (odds ratio, 6.23; 95% confidence interval [CI], 2.47-15.76, and odds ratio, 4.63; 95% CI, 1.87-11.47, respectively; P < .001). MRF, but not steatosis, was associated with the development of HCC (odds ratio, 11.76; 95% CI, 2.60-53; P = .001) independent of age, sex, amount of alcohol intake, or severity of liver disease. CONCLUSIONS: Patients with alcohol-associated cirrhosis who received transplants frequently also had nonalcoholic fatty liver disease. MRFs, particularly overweight, obesity, and type 2 diabetes, significantly increase the risk of HCC.

First experience of liver transplantation with type 2 donation after cardiac death in France.

Organ donation after unexpected cardiac death [type 2 donation after cardiac death (DCD)] is currently authorized in France and has been since 2006. Following the Spanish experience, a national protocol was established to perform liver transplantation (LT) with type 2 DCD donors. After the declaration of death, abdominal normothermic oxygenated recirculation was used to perfuse and oxygenate the abdominal organs until harvesting and cold storage. Such grafts were proposed to consenting patients < 65 years old with liver cancer and without any hepatic insufficiency. Between 2010 and 2013, 13 LTs were performed in 3 French centers. Six patients had a rapid and uneventful postoperative recovery. However, primary nonfunction occurred in 3 patients, with each requiring urgent retransplantation, and 4 early allograft dysfunctions were observed. One patient developed a nonanastomotic biliary stricture after 3 months, whereas 8 patients showed no sign of ischemic cholangiopathy at their 1-year follow-up. In comparison with a control group of patients receiving grafts from brain-dead donors (n = 41), donor age and cold ischemia time were significantly lower in the type 2 DCD group. Time spent on the national organ wait list tended to be shorter in the type 2 DCD group: 7.5 months [interquartile range (IQR), 4.0-11.0 months] versus 12.0 months (IQR, 6.8-16.7 months; P = 0.08. The 1-year patient survival rates were similar (85% in the type 2 DCD group versus 93% in the control group), but the 1-year graft survival rate was significantly lower in the type 2 DCD group (69% versus 93%; P = 0.03). In conclusion, to treat borderline hepatocellular carcinoma, LT with type 2 DCD donors is possible as long as strict donor selection is observed.

Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria.

In France, decisions regarding superurgent (SU) liver transplantation (LT) for patients with acute liver failure (ALF) are principally based on the Clichy-Villejuif (CV) criteria. The aims of the present study were to study the outcomes of patients registered for SU LT and the factors that were predictive of spontaneous improvement and to determine the usefulness of the CV criteria. All patients listed in France for SU LT between 1997 and 2010 who were 15 years old or older with ALF were included. In all, 808 patients were listed for SU transplantation: 22% with paracetamol-induced ALF and 78% with non-paracetamol-induced ALF. Of these 808 patients, 112 improved spontaneously, 587 underwent LT, and 109 died or left the waiting list because of a worsening condition. The 1-year survival rate according to an intention-to-treat analysis and the survival after LT were 66.3% [interquartile range (IQR), 62.7%-69.7%] and 74.2% (IQR, 70.5%-77.6%), respectively. The factors that were predictive of a spontaneous recovery with ALF-related paracetamol hepatotoxicity were as follows: hepatic encephalopathy grade 0, 1, or 2 [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.99-11.6]; creatinine clearance≥60 mL/minute/1.73 m2 (OR, 4.77; 95% CI, 1.96-11.63), a bilirubin level<200 µmol/L (OR, 21.64; 95% CI, 1.76-265.7); and a factor V level>20% (OR, 5.79; 95% CI, 1.66-20.29). For ALF-related nonparacetamol hepatotoxicity, the factor that was predictive of a spontaneous recovery was a bilirubin level<200 µmol/L (OR, 10.38; 95% CI, 4.71-22.86). The sensitivity, specificity, and positive and negative predictive values for the CV criteria were 75%, 56%, 50%, and 79%, respectively, for ALF due to paracetamol and 69%, 50%, 64%, and 55%, respectively, for ALF not related to paracetamol. The performance of current criteria for SU transplantation could be improved if paracetamol-induced ALF and non-paracetamol-induced ALF were split and 2 other items were included in this model: the bilirubin level and creatinine clearance.

Surgery for secondary aorto-enteric fistula or erosion (SAEFE) complicating aortic graft replacement: a retrospective analysis of 32 patients with particular focus on digestive management.

BACKGROUND: Optimal management of patients with abdominal secondary aorto-enteric fistula or erosion (SAEFE) complicating aortic graft replacement is controversial. OBJECTIVE: The aim of the present study was to report on the postoperative and long-term outcomes of patients operated on for SAEFE. METHODS: From 2002 to 2012, consecutive patients operated on for SAEFE were identified. All were managed with in situ revascularization by cryopreserved allograft associated with the treatment of the digestive tract involved. Postoperative and long-term outcomes were collected prospectively and analysed retrospectively. RESULTS: A total of 32 patients (median age 65 years) underwent an aortic replacement for SAEFE after a median of 5 years after the initial aortic surgery. Fistula location was duodenal (n = 20), small bowel (n = 6), colonic (n = 5), or gastric (n = 1). Digestive treatment included suture (n = 16), resection with anastomosis (n = 13), and Hartmann's procedure (n = 3). An omentoplasty was performed in 18 patients (56 %), and 17 patients (53 %) had a feeding jejunostomy. Postoperative mortality was 25 %. Among perioperative risk factors, preoperative shock was associated with postoperative mortality (p = 0.009). Among the 24 patients who survived, 15 patients developed 27 postoperative complications (overall morbidity rate of 62.5 %), including six (25 %) patients with severe morbidity (Dindo III-IV). Reoperation was required in five (21 %) patients. During follow-up (median 31 months), no patient developed a recurrent aorto-enteric fistula. CONCLUSIONS: Surgery for SAEFE is a major undertaking, with high mortality and morbidity. Excision of the prosthetic graft with cryopreserved allograft replacement and management in a tertiary referral centre with expertise in both vascular and digestive surgery allows good long-term results.

Interest of preoperative immunonutrition in liver resection for cancer: study protocol of the PROPILS trial, a multicenter randomized controlled phase IV trial.

BACKGROUND: Malnutrition is an independent risk factor of postoperative morbidity and mortality and it's observed in 20 to 50% of surgical patients. Preoperative interventions to optimize the nutritional status, reduce postoperative complications and enteral nutrition has proven to be superior to the parenteral one. Moreover, regardless of the nutritional status of the patient, surgery impairs the immunological response, thus increasing the risk of postoperative sepsis. Immunonutrition has been developed to improve the immunometabolic host response in perioperative period and it has been proven to reduce significantly postoperative infectious complications and length of hospital stay in patients undergoing elective gastrointestinal surgery for tumors. We hypothesize that a preoperative oral immunonutrition (ORAL IMPACT®) can reduce postoperative morbidity in liver resection for cancer. METHODS/DESIGN: Prospective multicenter randomized placebo-controlled double-blind phase IV trial with two parallel treatment groups receiving either study product (ORAL IMPACT®) or control supplement (isocaloric isonitrogenous supplement--IMPACT CONTROL®) for 7 days before liver resection for cancer. A total of 400 patients will be enrolled. Patients will be stratified according to the type of hepatectomy, the presence of chronic liver disease and the investigator center. The main end-point is to evaluate in intention-to-treat analysis the overall 30-day morbidity. Secondary end-points are to assess the 30-day infectious and non-infectious morbidity, length of antibiotic treatment and hospital stay, modifications on total food intake, compliance to treatment, side-effects of immunonutrition, impact on liver regeneration and sarcopenia, and to perform a medico-economic analysis. DISCUSSION: The overall morbidity rate after liver resection is 22% to 42%. Infectious post-operative complications (12% to 23%) increase the length of hospital stay and costs and are responsible for a quarter of 30-day mortality. Various methods have been advocated to decrease the rate of postoperative complications but there is no evidence to support or refute the use of any treatment and further trials are required. The effects of preoperative oral immunonutrition in non-cirrhotic patients undergoing liver resection for cancer are unknown. The present trial is designed to evaluate whether the administration of a short-term preoperative oral immunonutrition can reduce postoperative morbidity in non-cirrhotic patients undergoing liver resection for cancer. TRIAL REGISTRATION: Clinicaltrial.gov: NCT02041871.

Efficient replication of primary or culture hepatitis C virus isolates in human liver slices: a relevant ex vivo model of liver infection.

UNLABELLED: The development of human cultured hepatitis C virus (HCV) replication-permissive hepatocarcinoma cell lines has provided important new virological tools to study the mechanisms of HCV infection; however, this experimental model remains distantly related to physiological and pathological conditions. Here, we report the development of a new ex vivo model using human adult liver slices culture, demonstrating, for the first time, the ability of primary isolates to undergo de novo viral replication with the production of high-titer infectious virus as well as Japanese fulminant hepatitis type 1, H77/C3, and Con1/C3. This experimental model was employed to demonstrate HCV neutralization or HCV inhibition, in a dose-dependent manner, either by cluster of differentiation 81 or envelope protein 2-specific antibodies or convalescent serum from a recovered HCV patient or by antiviral drugs. CONCLUSION: This new ex vivo model represents a powerful tool for studying the viral life cycle and dynamics of virus spread in native tissue and also allows one to evaluate the efficacy of new antiviral drugs.

Postoperative and long-term outcomes after redo surgery for failed colorectal or coloanal anastomosis: retrospective analysis of 50 patients and review of the literature.

INTRODUCTION: Redo surgery for failed colorectal or coloanal anastomosis is a surgical challenge, but despite its technical difficulties and the high associated morbidity risk, it may represent the only valuable option to improve patients' quality of life by avoiding a permanent stoma and decreasing chronic pelvic symptoms. OBJECTIVES: This study aimed to analyze postoperative and long-term outcomes, with particular focus on functional results, in patients undergoing redo surgery in comparison with previously published studies. DESIGN: This was a retrospective review of prospectively collected data in an institutional database. SETTING: The study was conducted in the colorectal unit of a tertiary referral teaching hospital in France. PATIENTS: Consecutive patients who underwent redo surgery for failed colorectal or coloanal anastomosis from 1998 to 2011 were included. RESULTS: A total of 50 patients (23 men, 27 women) were included. The median age at redo surgery was 62 years (range, 40-84). Twenty-six patients (52%) underwent a redo colorectal anastomosis and 24 patients a redo coloanal anastomosis (48%). Indications were anastomotic stricture (n = 20), chronic pelvic sepsis (n = 14), rectovaginal fistula (n = 3), prior Hartmann's procedure for complication of initial anastomosis (n = 8), and anastomotic cancer recurrence (n = 5). The median operative time was 435 minutes. Postoperative mortality was 0% and morbidity was 26%. No anastomotic leakage occurred. After a median follow-up of 21 (range, 1-137) months, 44 patients (88%) were evaluated for functional results. The median number of bowel movements per day was 2 (range, 1-10), with 70% of patients having fewer than 3 per day. LIMITATION: The study was limited by its retrospective nature and lack of data on quality of life. CONCLUSIONS: Redo surgery for failed colorectal or coloanal anastomosis is a valuable surgical option which allows avoidance of a permanent stoma in nearly 90% of patients. It remains a major undertaking with high intraoperative and postoperative morbidity.

Best temperature for static liver graft storage is 1°C.

BACKGROUND: The best storage temperature in liver transplantation remains an unsolved question. METHODS: After storage for 24h in University of Wisconsin solution at +4°C, +1°C, or -0.5°C, rat livers were subjected, or not, to 15min of warm ischemia, rinsed with Ringer lactate, and subsequently reperfused with oxygenated Krebs-Henseleit buffer. RESULTS: In the presence of warm ischemia, for livers stored at +4°C, creatine kinase (CK) peaked at 21±5IUg(-1)h(-1), hepatic resistance at 34,700±1500dynscm(-5), bile flow reached 18±4µLg(-1)h(-1) after 10min, and oxygen consumption stabilized at about 25µmolg(-1)h(-1) after 20min. When livers were stored at +1°C, CK and hepatic resistance were lowered, bile production was 33±6µLg(-1)h(-1) (P<0.05 versus +4°C), and oxygen consumption was 105±10µmolg(-1)h(-1) (P<0.001). For livers stored at-0.5°C, results were not statistically different from those of the +1°C group except for bile flow, which was significantly lower. Without warm ischemia, the peak of CK (P=0.015) and the peak hepatic resistance (P<0.001) of the +4°C group were significantly increased compared with the +1°C or -0.5°C groups. However, no difference in bile flow or oxygen consumption was observed. The number of trypan blue-positive nonparenchymal cells (P=0.003) and the gain in liver weight during the reperfusion (P=0.015) were minimal after storage at +1°C. CONCLUSIONS: Static storage at +1°C improved liver function compared with +4°C or -0.5°C. Main beneficial effect was observed with parameters reflecting sinusoidal cells injury.

[Abdominal secondary aorto-enteric fistulae complicating aortic graft replacement: postoperative and long-term outcomes in 32 patients]. / Fistules aorto-intestinales après remplacement prothétique de l'aorte abdominale : résultats chirurgicaux et suivi à long terme chez 32 patients.

Management of patients with abdominal secondary aorto-entericfistulae (SAEF) complicating aortic graft replacement is controversial. We retrospectively analyzed the postope- rative and long-term outcomes of all consecutive patients operated on for SAEF betwveen 2002 and2012. All were managed by in situ replacement with a cryopreserved allograft and treatment of the affected digestive tract. Thirty-two patients (median age 65 years) underwent aortic replacement for SAEFa median of 5 years after initial aortic surgery. The fistulae were located in the duodenum (n = 20), small bowel (n = 6), colon (n = 5) or stomach (n = 1). Treatment of the digestive tract included suture (n = 16), resection with anastomosis (n = 12) covered by a defunctioning stoma (n = 1), and Hartmann's procedure (n = 3). Omentoplasty was performed in 18 patients (56 %), and 17 patients (53 %) had afeedingjejunostomy. Eight patients (25 %) died post-operatively, 3 with a recurrent aorto-enteric fistula. Fifteen (62.5 %) of the remaining patients developed 27 complications, including 6 patients (19 %) with severe morbidity (Dindo III-IV). The reoperation rate was 21 %. The median hospital stay was 33 days. During follow-up (median 15 months), no further patients had a recurrent aorto-enteric fistula. We conclude that surgery for SAEF is a major procedure associated with high mortality and morbidity. Good long-term results can be obtained by excision of the prosthetic graft with cryopreserved allograft replacement, and by management in a tertialy referral center with expertise in both vascular and digestive surgery.

[Medical treatment of sigmoid diverticulitis]. / Traitement médical des diverticulites sigmoïdiennes.

Acute diverticulitis is defined by diverticular and peridiverticular inflammation and infection and is efficiently treated medically in most of the cases. For most patients, outpatient treatment is possible and hospitalization is only indicated if the patient is unable to eat, suffers from an acute attack, has diverticulitis related complications or if symptoms fail to improve despite adequate outpatient therapy The treatment of acute uncomplicated diverticulitis usually consists of broad-spectrum antibiotics covering both aerobic and anaerobic bacteria. Antibiotic therapy is usually administrated for 7 to 10 days but its duration can be longer if any complications occur. If there is no clinical improvement within 2 or 3 days, repeat CT imaging is needed, as this may reveal an abscess, phlegmon or fistula, which may require percutaneous drainage or surgery. The published literature does not support the recommendation of any prophylactic diet or medical treatment for reducing the risk of first or recurrent diverticulitis in patients with diverticulosis.

[Surgical treatment of sigmoid diverticulitis]. / Traitement chirurgical de a diverticulite sigmoïdienne.

Surgery for diverticulitis is usually discussed in two situations: in emergency to treat a diverticulitis related complication or electively to prevent the risk of diverticulitis recurrence (prophylactic colonic resection). Surgical treatment of complicated diverticulitis has gone to changes during the last decade thanks to advances in laparoscopic surgery and interventional radiology (drainage, embolization). Emergency surgery for diverticulitis is mainly indicated (90%) for infectious related complications and more rarely for bleeding or stenosis. Surgery is the standard treatment of peritonitis complicating diverticulitis (Hinchey 3 or 4) and is recommended in Hinchey 1 or 2 diverticulitis after failure of a well conducted medical treatment with or without radiological drainage (for abscesses >or= 5cm). Indications for prophylactic surgery after an episode of uncomplicated diverticulitis is not systematic and should be discussed case by case according to the baseline characteristics of patients. Prophylactic surgery consists in sigmoid resection including the sigmoido-rectal junction with colorectal anastomosis and should be performed under laparoscopy.

Comparative outcomes of rectal cancer surgery between elderly and non-elderly patients: a systematic review.

Elderly people represent almost all patients diagnosed with and treated for rectal cancer, and this trend is likely to become more apparent in the future. Surgical management and treatment decisions for this disease are becoming increasingly complex, but only a few reports deal specifically with older patients. In this systematic review, we provide an overview of published studies of outcomes after curative surgery for rectal cancer in elderly people (>70 years). We identified 48 studies providing information about postoperative results, survival, surgical approach, stoma formation, functional results, and quality of life after rectal resection for cancer. We found that advanced chronological age should not, by itself, exclude patients from curative rectal surgery or from other surgical options that are available for younger patients. Although overall survival is lower in elderly patients than in younger patients, cancer-specific survival does not decrease with age. However, the level of evidence for most studies was weak, emphasising the need for high-quality clinical trials for this population.

Liver biopsy analysis has a low level of performance for diagnosis of intermediate stages of fibrosis.

BACKGROUND & AIMS: There is controversy about the performance of noninvasive tests such as FibroTest in diagnosing intermediate stages of fibrosis. We investigated whether this controversy results from limitations of biopsy analysis for intermediate-stage fibrosis and inappropriate determination of the standard area under the receiver-operator characteristic curve (AUROC). METHODS: To determine whether biopsy has a lower diagnostic performance for fibrosis stage F2 (few septa) vs F1 (fibrosis without septa), compared with its performance for F1 vs F0 or F4 vs F3, we determined the fibrotic areas of large surgical samples collected from 20 consecutive patients with chronic liver disease or normal liver tissue that surrounded tumors. We analyzed digitized images of 27,869 virtual biopsies of increasing length and also analyzed data from 6500 patients with interpretable FibroTest results who also underwent biopsy analysis. RESULTS: The overall performance of biopsy analysis (by Obuchowski measure) increased with biopsy length from 0.885 for 5-mm to 0.912 for 30-mm samples (P < .0001). The performance of biopsy was lower for the diagnosis of F2 vs F1 samples (weighted AUROC [wAUROC] = 0.505) than for F1 vs F0 (wAUROC = 0.773; 53% difference; P < .0001) or F4 vs F3 (wAUROC = 0.700; 39% difference; P < .0001), even when 30-mm biopsy samples were used. The performance of FibroTest was also lower for the diagnosis of F2 vs F1 samples (wAUROC = 0.512) than for F1 vs F0 samples (wAUROC = 0.626; 22% difference; P < .0001) or F4 vs F3 (wAUROC = 0.628; 23% difference; P < .0001). However, the FibroTest had smaller percentage differences among wAUROC values than biopsy. CONCLUSIONS: Biopsy has a low level of diagnostic performance for fibrosis stages F2 and F1. The recommendation for biopsy analysis, instead of a validated biomarker panel such as FibroTest, for the diagnosis of intermediate stages of fibrosis is therefore misleading.

Thrombocytopenia, splenomegaly, and portal blood flow in patients who have undergone liver transplantation for cirrhosis.

The platelet count (PC), the spleen size (SS), and the portal blood flow (PBF) have been independently studied in the perioperative period after orthotopic liver transplantation (OLT) for cirrhosis, but these parameters have not been described and analyzed in combination. We analyzed PC data and Doppler sonography measurements of SS and PBF from 125 adult patients before OLT and 1, 3, 6, 9, and 12 months after transplantation. A linear mixed model with fixed subject random intercepts was used. PCs increased significantly from 101.5 ± 68.5 × 10(9) /L before OLT to 162.4 ± 86 × 10(9) /L 1 month after OLT and remained stable for 1 year after the operation. PBF increased significantly from 619 ± 239 mL/minute before OLT to 1379 ± 491 mL/minute after OLT and remained stable during the first year. SS slowly decreased after OLT, but the decrease became significant only 9 months after the operation (13.8 ± 4.2 cm before OLT versus 11.7 ± 3.7 cm at 9 months, P < 0.05). The cirrhosis etiology did not influence the evolution of the parameters. With or without replication or interferon treatment before OLT, the hepatitis C group viruses did not influence PCs postoperatively. The evolution of SS was correlated to the evolution of PCs in the year after transplantation. In conclusion, PCs and PBF increase rapidly after OLT, whereas SS slowly decreases. The cirrhosis etiology does not influence the evolution of PCs. Thrombocytopenia and splenomegaly are 2 results of portal hypertension, but the rapid normalization of PBF does not completely or rapidly reverse these 2 phenomena.

Right colon to rectal anastomosis (Deloyers procedure) as a salvage technique for low colorectal or coloanal anastomosis: postoperative and long-term outcomes.

BACKGROUND: After extended left colectomy, it may be difficult to take down a well-vascularized colon into the pelvis and perform a tension-free colorectal or coloanal anastomosis. The Deloyers procedure comprising complete mobilization and rotation of the right colon while maintaining the ileocolic artery may be used in this circumstance. OBJECTIVE: The aim of this study is to report postoperative and long-term outcomes after the Deloyers procedure as a salvage technique for colorectal anastomosis or coloanal anastomosis. DESIGN: From a prospective database, we retrospectively reviewed all patients who underwent a Deloyers procedure. SETTING: This study was conducted at the Colorectal Unit in a tertiary referral teaching hospital. PATIENTS: Between 1998 and 2011, 48 consecutive patients underwent a Deloyers procedure. Indications were as following: Hartmann reversal (n = 17), previous colorectal anastomosis-related complications (n = 11), diverticular disease (n = 6), left colon cancer (n = 6), ischemic colitis (n = 3), iterative colectomy for cancer (n = 3), rectal cancer local recurrence (n = 1), and synchronous colon cancer (n = 1). RESULTS: There were 38 men and 10 women (median age at surgery, 67 years). Colorectal anastomosis and coloanal anastomosis were performed in 38 and 10 patients. Thirty-one patients had defunctioning stoma. Mortality and early morbidity rate was 2% and 23%. Three patients (6%) had severe complications (Dindo ≥ 3). There was no anastomotic leakage. Reoperation was required in 2 patients for intra-abdominal hemorrhage. The median hospital stay was 12 days. The median follow-up was 26 months. All patients had their ileostomy closed. Twenty-three percent of patients developed late complications. The median number of bowel movements per day was 3 (range, 1-7), but 67% of patients had fewer than 3. One patient required an ileostomy refashioning because of poor functional results, and 23% of patients routinely take loperamide-based medication. LIMITATION: The retrospective nature of the study was a limitation. CONCLUSIONS: The Deloyers procedure is safe, associated with low morbidity and good long-term functional results. It represents a safe alternative to total colectomy and ileorectal anastomosis.

Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity.

Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and first invade the liver of the mammalian host, as an obligatory step of the life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic forms and merozoites that subsequently infect erythrocytes and cause the malaria disease. Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface. Still, the molecular mechanisms underlying sporozoite entry and differentiation within hepatocytes are largely unknown. Here we show that the tetraspanin CD81, a putative receptor for hepatitis C virus, is required on hepatocytes for human Plasmodium falciparum and rodent Plasmodium yoelii sporozoite infectivity. P. yoelii sporozoites fail to infect CD81-deficient mouse hepatocytes, in vivo and in vitro, and antibodies against mouse and human CD81 inhibit in vitro the hepatic development of P. yoelii and P. falciparum, respectively. We further demonstrate that the requirement for CD81 is linked to sporozoite entry into hepatocytes by formation of a parasitophorous vacuole, which is essential for parasite differentiation into exoerythrocytic forms.

Extracorporeal membrane oxygenation as a bridge to liver transplantation for acute respiratory distress syndrome-induced life-threatening hypoxaemia aggravated by hepatopulmonary syndrome.

INTRODUCTION: Combined with massive lung aeration loss resulting from acute respiratory distress syndrome, hepatopulmonary syndrome, a liver-induced vascular lung disorder characterized by diffuse or localized dilated pulmonary capillaries, may induce hypoxaemia and death in patients with end-stage liver disease. METHODS: The case of such a patient presenting with both disorders and in whom an extracorporeal membrane oxygenation was used is described. RESULTS: A 51-year-old man with a five-year history of alcoholic cirrhosis was admitted for acute respiratory failure, platypnoea and severe hypoxaemia requiring emergency tracheal intubation. Following mechanical ventilation, hypoxaemia remained refractory to positive end-expiratory pressure, 100% of inspired oxygen and inhaled nitric oxide. Two-dimensional contrast-enhanced (agitated saline) transthoracic echocardiography disclosed a massive right-to-left extracardiac shunt, without patent foramen ovale. Contrast computed tomography (CT) of the thorax using quantitative analysis and colour encoding system established the diagnosis of acute respiratory distress syndrome aggravated by hepatopulmonary syndrome. According to the severity of the respiratory condition, a veno-venous extracorporeal membrane oxygenation was implemented and the patient was listed for emergency liver transplantation. Orthotopic liver transplantation was performed at Day 13. At the end of the surgical procedure, the improvement in oxygenation allowed removal of extracorporeal membrane oxygenation (Day 5). The patient was discharged from hospital at Day 48. Three months after hospital discharge, the patient recovered a correct physical autonomy status without supplemental O2. CONCLUSIONS: In a cirrhotic patient, acute respiratory distress syndrome was aggravated by hepatopulmonary syndrome causing life-threatening hypoxaemia not controlled by standard supportive measures. The use of extracorporeal membrane oxygenation, by controlling gas exchange, allowed the performing of a successful liver transplantation and final recovery.

Temperature shift and host cell contact up-regulate sporozoite expression of Plasmodium falciparum genes involved in hepatocyte infection.

Plasmodium sporozoites are deposited in the skin by Anopheles mosquitoes. They then find their way to the liver, where they specifically invade hepatocytes in which they develop to yield merozoites infective to red blood cells. Relatively little is known of the molecular interactions during these initial obligatory phases of the infection. Recent data suggested that many of the inoculated sporozoites invade hepatocytes an hour or more after the infective bite. We hypothesised that this pre-invasive period in the mammalian host prepares sporozoites for successful hepatocyte infection. Therefore, the genes whose expression becomes modified prior to hepatocyte invasion would be those likely to code for proteins implicated in the subsequent events of invasion and development. We have used P. falciparum sporozoites and their natural host cells, primary human hepatocytes, in in vitro co-culture system as a model for the pre-invasive period. We first established that under co-culture conditions, sporozoites maintain infectivity for an hour or more, in contrast to a drastic loss in infectivity when hepatocytes were not included. Thus, a differential transcriptome of salivary gland sporozoites versus sporozoites co-cultured with hepatocytes was established using a pan-genomic P. falciparum microarray. The expression of 532 genes was found to have been up-regulated following co-culture. A fifth of these genes had no orthologues in the genomes of Plasmodium species used in rodent models of malaria. Quantitative RT-PCR analysis of a selection of 21 genes confirmed the reliability of the microarray data. Time-course analysis further indicated two patterns of up-regulation following sporozoite co-culture, one transient and the other sustained, suggesting roles in hepatocyte invasion and liver stage development, respectively. This was supported by functional studies of four hitherto uncharacterized proteins of which two were shown to be sporozoite surface proteins involved in hepatocyte invasion, while the other two were predominantly expressed during hepatic parasite development. The genome-wide up-regulation of expression observed supports the hypothesis that the shift from the mosquito to the mammalian host contributes to activate quiescent salivary gland sporozoites into a state of readiness for the hepatic stages. Functional studies on four of the up-regulated genes validated our approach as one means to determine the repertoire of proteins implicated during the early events of the Plasmodium infection, and in this case that of P. falciparum, the species responsible for the severest forms of malaria.

Intractable ascites without mechanical vascular obstruction after orthotopic liver transplantation: etiology and clinical outcome of sinusoidal obstruction syndrome.

Intractable ascites after orthotopic liver transplantation (OLT) is a relatively rare complication. However, it often takes a life threatening course, which requires re-transplantation. In previous studies, several reports gave hepatic sinusoidal obstruction syndrome (SOS) as one of the causes of refractory ascites. However, the detailed etiology of SOS after OLT and its association with clinical consequences remain unclear because there have been few studies to date. We report two recent cases with rapidly progressive refractory ascites associated with SOS, following completely different clinical courses. In case 1, the first episode of acute allograft rejection triggered SOS and subsequent intractable ascites, while the second acute rejection worsened his clinical status. A transjugular intrahepatic portosystemic stent-shunt (TIPS) was placed and this procedure resulted in complete disappearance of ascites and of renal dysfunction. In contrast, refractory ascites in case 2, who had neither rejection nor mechanical outlet obstruction, worsened despite TIPS stent placement, and re-transplantation was necessary. We speculate that the pre-existing diseased liver of the cadaver donor caused this serious complication, necessitating a second graft.