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Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.

Azathioprine-induced veno-occlusive disease of the liver mainly described after kidney transplantation is as rare as severe with a high mortality due to acute portal hypertension and liver failure. A kidney-transplanted patient with severe azathioprine-induced veno-occlusive disease of the liver and worsening despite drug discontinuation was treated by emergency transjugular intrahepatic portosystemic shunt. Whereas the veno-occlusive disease was controlled, the patient developed severe intractable portosystemic encephalopathy successfully treated by a stent reducer maintaining a certain degree of portal diversion. Twelve months after transjugular intrahepatic portosystemic shunt, liver function was normalized and the stent was thrombosed with a subnormal liver histology. Thirty-six months after transjugular intrahepatic portosystemic shunt the patient is alive with normal liver function tests and kidney graft function. Transjugular intrahepatic portosystemic shunt for treatment of severe veno-occlusive disease of the liver is an alternative to tide the patient over until recovery of liver function.

Cytochrome P-450 3A metabolizes CsA into several metabolites with very limited pharmacological activity and toxicity. In 40 liver donors, the relative concentrations of P-450 3A was assessed by immunoblot analysis using a specific monoclonal antibody exhibited a 10-fold variation (mean = 92 +/- 50 arbitrary units [AU]/mg) in levels. Problems consequent upon CsA usage (nephrotoxicity, neurotoxicity, and hypertension) occurred in 8 of 34 transplant recipients in the immediate postoperative period, and in these 8 patients the problems were always associated with low graft P-4503A levels (mean = 52 +/- 19 A.U./mg, P = 0.0003, cf. patients with no toxicity). Four of these patients had CsA levels that were also high, but 4 had CsA levels in the therapeutic range. Episodes of early graft rejection were related to higher P-450 3A levels (mean = 110 +/- 24 A.U./mg). Cytochrome P-450 3A levels were also found to be inversely related to CsA whole blood levels (assessed with a specific antibody 12 hr after the intravenous infusion of CsA at 1 mg/kg in the recipients (P0.02). Cytochrome P-450 3A can provide information that should allow individualized immunosuppression with CsA maintaining therapeutic levels but avoiding toxicity in susceptible individuals.

The many developments that have occurred and continue to occur have also meant that the quality of life experienced by recipients of a successful graft is excellent, with more than 85% of patients returning to normal life and work (even having children). While long-term survival still occurs more frequently in favorable groups such as children with metabolic abnormalities or biliary atresia, results are still extremely good for adults, with 3-year survival figures after transplantation for cirrhosis in the order of 75%. These figures also continue to improve, and with the skill and enthusiasm that workers in this field display they seem destined to continue unabated.

During the past 3 decades, more than 2,250 liver transplants were performed at Paul Brousse Hospital. Overall patient survival was 82% at one year, 71% at 5 years and 64% at 10 years. Our group has developed a variety of approaches to liver transplantation, including: 1. Anti HBs immunoglobulin prophylaxis for the prevention of HBV recurrence. Combination prophylaxis with lamivudine and anti HBs immunoglobulins reduced the rate of HBV re-infection to 20%. 2. Transplantation of HIV-HCV and HIV-HBV infected patients. These transplants are feasible and we achieved 2- year survival rates of 70% and 90%, respectively. The main problem was HCV recurrence which was more severe in HIV co-infected patients. 3. Transplantation for hepatocellular carcinoma on a cirrhotic liver with a single tumor5 cm or3 tumors3 cm. 4. Transplantation for familial amyloidotic polyneuropathy (FAP). The 5- and 10-year survival rates were 76% and 72%, respectively. More than 100 livers obtained after hepatectomy from FAP patients were transplanted as "domino" living donor livers to patients with unresectable liver cancers with a 5-year survival rate of 64%. In some domino recipients, symptoms of FAP disease occurred more rapidly than expected and this could be an indication for a second transplantation of a non FAP-liver. 5. Split-liver transplantation for pediatric patients. This has increased the number of transplantable livers for children by 28%. 6. Split-liver transplantation for 2 adults. The grafts were prepared by ex-vivo or in-situ splitting and the overall 5-year survival rate was 56%. 7. Adult -to-adult living-related liver transplantation. There has been no mortality nor late complications in donors and the overall 5-year survival rate among recipients was 73%. 8. Liver retransplantation with good results in the elective situation. Retransplantation should be used with discretion in the emergency setting.

During the past 16 years, more than 1,500 liver transplants were performed at Paul Brousse Hospital. The overall patient survival rates were 83% at one year and 65% at 10 years. Our group has pioneered a variety of new approaches to liver transplantation, including: 1. Anti-HBs (HBIG) prophylaxis for the prevention of HBV recurrence. To date more than 270 patients have received long-term treatment and the overall 10-year recurrence rate was 27%. 2. Transplantation for hepatocellular carcinoma of the cirrhotic liver in patients with uni- or binodular HCC (3 cm). Survival for transplanted patients was 83% compared with 18% if the liver was resected. 3. Transplantation for familial amyloidotic polyneuropathy (FAP). More than 60 patients had 5- and 10-year survival rates of 85% and 83%, respectively. Ten livers obtained after hepatectomy from these FAP patients were transplanted as "domino" living donor livers to patients with unresectable liver cancers with satisfactory short-term results. 4. Reduced-size liver grafts have been used successfully to reduce pretransplant mortality and posttransplant morbidity and mortality by shortening the wait for our pediatric patients. 5. Split-liver transplantation has increased the number of transplantable livers by 28%. 6. Split-liver transplantation for 2 adults. Using optimal livers we have transplanted 34 adults with grafts prepared by ex-vivo or in-situ splitting with good survival rates. 7. Adult-to-adult living-related donor liver transplantation. In 2000, 7 adult-to-adult living donor transplants were performed with no complications from the donor surgeries. One recipient was retransplanted for arterial thrombosis, but all 7 recipients are alive at home. The Paul Brousse Hospital is committed to exploring new technologies to improve the outcome of and expand the indications for liver transplantation. We have taken a surgical approach to the organ shortage, finding new ways to serve the most patients with the limited number of livers available.

We report the digestive, hepatic, intestinal and nutritional history of the first combined liver-small bowel transplantation performed in France in an adult recipient. Currently, the clinical course has been favorable at 30 months.In May 1997, a 21-year-old man underwent a double liver-small bowel transplantation for irreversible chronic bowel failure with severe chronic liver disease subsequent to post-surgical short-bowel syndrome. After 28 laparotomies, there were 15 cm of small bowel left for the gastric anastomosis. The patient had a terminal jejunostomy and a left colostomy, excluding a short segment of the transverse colon and the rectum. Total parenteral nutrition including lipids and been initiated in December 1992 (3500 kcal/d) and had led to severe complications. Intestinal absorption before and after the graft were studied with the balance method (input-output) and used bomb calorimetry and measurements of the steatorhhea and creatorrhea. Functional enterocyte mass was assessed from serum citrullin.The postoperative period after the liver-bowel graft (220 cm small bowel with terminal ileostomy and jejunostomy) was uneventful. The immunosuppression protocol included tacrolimus, corticosteroids and azathioprin. One mild episode of acute rejection occurred at day 26 and was controlled with a corticosteroid bolus. No episode of liver rejection occurred. Moderate renal failure regressed partially after reestablishing the fluid-electrolyte balance and adapting tacrolimus dosage. Total parenteral nutrition which had sustained the patient for 4 and a half years was definitely discontinued three months after transplantation. Oral nutrition was initially associated with enteral nutrition (from day 20 to day 90) and became exclusive three months after the transplantation. Intestinal absorption coefficients measured before tranplantation, at 3 months (2200 kcal/d, ileostomy flow 1600 g/d), and at 18 months (2400 kcal/d, ileostomy flow 1300 g/d) post transplantation were, respectively, 22%, 90% and 88% for overall calorie absorption, 25%, 65% and 73% for fat absorption, and 47%, 83% and 67% for nitrogen absorption. At 18 months post-graft, there was a spectacular improvement in the patient's neurological status and his liver function was normal. Endoscopy, radiography, histology, and immunohistochemistry explorations were normal. Ileo-rectal anastomosis was re-established at 23 months post-transplantation. At 30 months the patient is living in his home and on 100% oral nutrition.Clinical, nutritional and functional outcome at 30 months in this first French case of liver-small bowel transplantation in an adult recipient has been excellent.

Liver-graft shortages justify the development of adult living-related liver transplantation. The preliminary experience with this technique at Paul-Brousse Hospital is reported. PATIENTS ET METHODES: From January to July 2000, 7 adult to adult living-related liver transplantations were performed. Donors were 5 females and 2 males aged 20 to 53 years old (median: 41). A right liver graft was harvested in all cases. Recipients were 5 males and 2 females aged from 17 to 58 years old (median: 50) transplanted for viral cirrhosis (4 cases including 2 with hepatocellular carcinoma), subfulminant hepatitis (1 case), hepatocellular carcinoma on a healthy liver (1 case), and epithelioid hemangioendothelioma (1 case). Follow-up ranged from 41 to 157 days (median: 117 days).One donor had a biliary fistula that healed spontaneously. One donor had asterixis for 24 hours. The 7 donors are alive at home without any late complications. One recipient was retransplanted for hepatic artery thrombosis and 2 recipients had a biliary fistula that healed spontaneously. The 7 recipients are alive at home with normal liver function.Our experience and other reports suggest that adult to adult living-related liver transplantation is feasible with rare mortality and low morbidity in donors. Results in recipients are comparable to those obtained with cadaveric grafts. For a given patient the possibility of living related donation might extend the indications for transplantation without penalizing patients waiting for a cadaveric graft.

The effects of administration of endotoxin to donors or recipients on the mortality rate, evolution of endotoxin levels, and tumor necrosis factor alpha (TNF-alpha) release were investigated in a syngenic orthotopic liver transplantation model in Lewis rats with portal reperfusion only. No significant recipient endotoxemia, TNF-alpha release, or mortality occurred in control recipients following transplantation from normal donors. The doses of endotoxin needed to kill 50% and 100% of animals after hepatic artery ligation were, respectively, 4 mg/kg and 10 mg/kg. Transplantation of animals' livers with no preservation phase from donors who were administered a lethal dose of endotoxin for this combination (10 mg/kg) produced significant recipient endotoxemia at 10 min (6.9 +/- 2.5 x 10(3) endotoxin unit/ml (EU/ml), P0.01), 45 min (8.8 +/- 1.1 x 10(3) EU/ml, P0.001) and 8 hr (18.5 +/- 3.5 x 10(3) EU/ml, P0.001) after graft reperfusion. Significant levels of TNF-alpha were also detected in these animals at 45 min (280 +/- 70 pg/ml, P0.007) and 8 hr (80 +/- 40 pg/ml, P0.05) when compared with the controls. Mortalities in recipients of OLT from donor animals that had received endotoxin (2 mg/kg or 4 mg/kg) immediately prior to the harvesting procedure was 0% and 20%, respectively, compared with no death in the control group. When recipient animals were administered endotoxin immediately after graft reperfusion the resistance to endotoxin administration was significantly reduced compared with animals that had not received OLT (LD502 mg/kg versus 4 mg/kg; LD100 4 mg/kg versus 10 mg/kg, respectively). These results show that endotoxin and its effects can be transferred from the liver graft donor to the recipient and that OLT per se reduces the recipient resistance to endotoxin with subsequent increase in mortality.

Objectives: A laparoscopic approach improves short-term outcomes and maintains long-term outcomes compared to an open approach. In turn, the recent development of robotic surgery raises the question whether it performs as well as laparoscopic surgery. The aim of this study was to compare the short- and long-term outcomes of laparoscopic liver resection (LLR) and robotic liver resection (RLR) for malignancies. Method: From 2011 to 2017, the study population included 111 patients in the LLR group and 61 in the RLR group. Short- and long-term outcomes were compared before and after propensity score matching (PSM). Results: Operative mortality rate was nil. The intraoperative blood transfusion rate was higher during RLR (15% vs. 2%, p = 0.0009). Major morbidity and hospital stay were not different between the two groups. The resection margin width (LLR 7mm vs. RLR 10mm, p = 0.13) and R1 resection rates (resection margin width < 1mm; LLR 15% vs. RLR 11%, p = 0.49) were similar. After PSM (55 patients in each group), the blood transfusion, major morbidity, hospital stay and R1 resection were similar between the two groups. When considering the largest subset of patients with hepatocellular carcinoma including 114 patients (66%), the 3-year overall survival rate was 80% in the LLR group and 97% in the RLR group (p = 0.10) and remained similar after PSM (p = 0.27). The 3-year recurrence-free survival rate was 50% in the LLR group and 64% in the RLR group (p = 0.30) and remained similar after PSM (p = 0.26). Conclusions: No differences were found in blood transfusion, incidence of positive resection margins and long-term outcomes between the two techniques. RLR does not compromise short-term and oncologic outcomes in patients with liver cancers.

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.