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Gene therapy using herpes simplex type 1 thymidine kinase gene (HSV1-TK) transfer followed by ganciclovir (GCV) treatment has revealed an important intratumoral and regional bystander effect that is at least partly immune-mediated. The aim of this work was to study the modifications of T lymphocyte subpopulations in a model of distant bystander effect occurring between ovary tumors. Bilateral ovarian tumors were generated in 21 WKY rats by injection in the ovarian pouch of either parental or HSV1-TK-expressing DWA-OC-1 ovarian cancer cells. After 14 days, rats were treated for two weeks with GCV (75 mg/kg x 2/d) or saline. All rats were killed at day 29 for pathological examination. The tumor-infiltrating mononuclear cells were analyzed by semi-quantitative immunohistochemistry. As compared to rats receiving saline, GCV-treated animals exhibited a complete disappearance of the HSV1-TK+ tumors with residual fibrotic scars (ovary weights: 0.46 +/- 0.4 g vs 10.11 +/- 1.5 g, P0.001). Interestingly, the contralateral HSV1-TK negative tumor showed a significant regression (12.39 +/- 1.93 g vs 22.24 +/- 237 g, P0.014). Furthermore, a lower incidence of tumoral ascitis was found in the GCV-receiving group (20% vs 90% P0.02). Within both TK- and TK+ tumors, there was a significant increase of CD4+, CD8+ and NK cells in the GCV-treated group compared to the saline-treated group. This study thus indicates that a distant bystander effect not only acts between close tumors within a given organ such as the liver, but also between more distant tumors in the peritoneal cavity. This effect is associated with significant infiltration of the tumor by immune system cells, supporting the notion that the distant bystander effect is immune-mediated.

Delivering retroviruses targeted to hepatocytes in vivo involves the injection of retroviruses directly into the portal vein. The aim of this work was to establish a clinically relevant system for retrovirus-mediated gene transfer in a new model of in vivo, in situ perfused rat liver and to study the transgene expression. At 24 h after partial hepatectomy, the liver was completely excluded from the splanchnic circulation using an extracorporeal shunt. Two independent normothermal, oxygenated perfusion systems were used. First, liver perfusion was carried out with a recirculating system (1 h). Culture supernatant containing retroviruses (1.5 x 10(8) ffu/ml, beta-galactosidase gene) was used as perfusate. Then the liver perfusion was maintained for more 30 min in a single liver passage system using culture medium without retroviruses as perfusate. High hepatocyte transduction rates (up to 34.4%) were obtained. PCR analysis showed no provirus in extrahepatic organs. Viral titrations performed simultaneously (inflow and outflow liver lines) showed that after 1 h of perfusion (up to 30 successive liver passages) retroviruses were still detected in the liver outflow perfusate (up to 2.0 x 10(7) ffu/ml). Washing the liver for 30 min dramatically decreased the leakage of retroviruses in the outflow. In order to be of clinical use, the injection of retroviruses targeted to hepatocytes in vivo should be done while the liver is completely excluded from the splanchnic circulation to avoid any extrahepatic retrovirus diffusion.

Delivering retroviruses targeted to hepatocytes in vivo involves the injection of retroviruses directly into the blood stream of the portal vein. The aim of this work was to delineate the conditions for delivering retroviruses in vivo by perfusing in situ the bile duct of the regenerating rat liver, and to study the hepatocyte transgene expression. At 24 hr after partial hepatectomy, during the S phase of the cell cycle, regenerating livers were perfused for 2.8+/-0.5 hr through the bile duct with 36.2+/-6.8 ml (0.3+/-01 ml/min) of fresh culture supernatant containing amphotropic recombinant retroviruses encoding the beta-galactosidase gene. The virus total titer was 1.5 x 10(8) ffu (group I) or 6.5 x 10(8) ffu (groups II and III). The hepatic artery blood flow was either maintained (groups I and II) or interrupted (group III) during bile duct perfusion. Liver biopsies taken 7 days later showed that 31.4+/-24.2% (group I), 58.7+/-23.6% (group II), and 45.1+/-21.4% (group III) of hepatocytes expressed beta-galactosidase activity, predominantly in the periportal and mediolobular zones. This study demonstrates that hepatocytes of regenerating rat livers that have entered the S phase of the cell cycle as a result of partial hepatectomy can be transduced in vivo by retroviral vectors delivered in situ by bile duct perfusion. Furthermore, the number of transduced hepatocytes closely correlated with the viral total titer and was diminished by hepatic artery blood flow occlusion during perfusion.

Because of the current shortage of donor organs, the routine performance of tertiary liver transplantation (LT) may be questioned. In this study, the indications of tertiary LT are discussed, paying particular attention to intraoperative technique. Of 501 LTs performed from 1986 to 1995, eight (1.6%) were tertiary LTs. Three patients underwent an emergent third LT because of associated hepatic artery and portal vein thromboses (n = 2) or hyperacute rejection (n = 1). Five patients had an elective third LT for ischemic cholangitis (n = 4) or chronic rejection (n = 1). The 3 patients who underwent retransplantation emergently died early from multiple-organ failure. Because of previous surgery and subsequent technical difficulties, the third LT in the remaining 5 patients required unroutine surgical procedures including the following: intrapericardial control of the suprahepatic vena cava (n = 1), "en bloc" clamping of both the infrahepatic vena cava and the hepatic pedicle (n = 1), arterial reconstruction onto the aorta via an aortoiliac conduit (n = 5), and aortic resection with aortoaortic prosthetic reconstruction (n = 1). Of these 5 patients, 4 required reoperation because of bowel perforation (n = 5) or intraperitoneal bleeding (n = 1). The 5 patients (62%) who were regrafted electively are alive and well after a median follow-up of 45 months. A third LT can be reasonably offered to selected young recipients if performed electively. Tertiary LT may require unroutine surgical procedures and may lead to severe morbidity. (Liver Transpl Surg 1997 Nov;3(6):624-7)

Background The prevalence of chronic pancreatitis in patients with alcoholic cirrhosis ranges from 7% to 11% and is not considered a contraindication for liver transplantation. Methods Among 59 liver transplant recipients grafted for alcoholic cirrhosis, we report two observations of common bile duct stenosis due to chronic pancreatitis. Results In both cases, pretransplant work-up disclosed no clinical or radiological evidence of chronic pancreatitis. The diagnosis of common bile duct stricture was made 6 and 60 months after liver transplantation. One patient was reoperated upon, and his choledochocholedochostomy was converted into a Rouxen-Y choledochojejunostomy. The second patient experienced metastatic laryngeal carcinoma and died before reoperation. Conclusions These observations suggest that common bile duct stricture caused by chronic pancreatitis may occur after liver transplantation for alcoholic cirrhosis, even after a long-standing history of abstinence.

A 42-year-old man with a history of repeated abdominal surgery and lymph node tuberculosis underwent orthotopic liver transplantation for primary sclerosing cholangitis. Two years after transplantation, this patient developed a severe protein-losing enteropathy with no evidence of cardiac disease or lymphoproliferative disorder. Imaging work-up revealed hemodynamically significant stenosis of the supra-hepatic caval anastomosis, which was treated by percutaneous balloon angioplasty. All clinical and biochemical disorders resolved within 1 month after percutaneous dilatation, but relapsed simultaneously with recurrent anastomotic stenosis 15 months later. Repeat caval angioplasty resulted in rapid recovery, which strongly suggests that hepatic venous outflow obstruction was responsible for the protein-losing enteropathy in this patient.

Liver cells can produce nitric oxide from L-arginine through either constitutive NO synthase or inducible NO synthase (NOS) detected after in vivo or in vitro treatment with cytokines and/or lipopolysaccharide (LPS). The effects of NO on liver cells are associated with protein synthesis and mitochondrial electron transfer inhibition. L-Arginine is also the precursor of L-ornithine and polyamines. The latter are considered to be protective in the liver in several experimental models. The aim of the present work was to test the effects of polyamines on LPS-inducible NOS activity in rat liver cytosol using the test of radioactive L-citrulline synthesis from L-[guanido-14C]arginine. The three polyamines inhibited inducible NO synthase activity with the following hierarchy: spermine > spermidine approximately equal to putrescine. The 0.5 mM spermine was found to inhibit 50% of inducible NO synthase activity. The present data suggest an inhibitory interrelationship in the liver between two metabolites derived from the common precursor L-arginine.

We reviewed our experience with 34 patients with metastatic endocrine tumors (METs) who were treated by different modalities. Eight patients were treated by chemotherapy or chemoembolization because of stable disease or surgical contraindications. Seventeen patients underwent curative or cytoreductive surgical resection. Nine patients received grafts based on the following criteria: no extrahepatic spread on imaging workup and nonresectable symptomatic metastatic disease. Of the eight medically treated patients, the five patients with initial stable clinical condition are alive 32 to 56 months after referral. Of the 17 patients treated by liver resection, 13 are alive 6 to 108 months after surgery, and 7 are disease-free. After curative resection, the 5-year actuarial survival and disease-free survival rates were 62% and 52%, respectively. Of the nine grafted patients, three patients grafted for carcinoid tumor are alive at 15, 24, and 62 months, one of whom has a late recurrence. Our results indicate that therapeutic indications for METs should be based on age, clinical symptoms, histologic type, and tumor extension: Patients with stable MET may benefit from surgical restraint; liver resection in patients with aggressive MET may provide good long-term palliation and possibly cure one-third of the patients; liver transplantation should be restricted to young patients with nonresectable carcinoid MET but remains a high-risk operation because of previous surgery and chemoembolization.

Multiple-organ failure (MOF), defined as the failure of initially uninvolved organs, is the final step of definitive and massive liver necrosis. Emergency liver transplantation (ELT) has radically modified the outcome of acute liver failure and early primary graft failure, but the results of ELT in cases of MOF are unknown. From May 1988 to June 1993, 243 patients underwent a liver transplantation (LT). Thirty-seven patients (15.2%) who had an acute liver necrosis complicated by a MOF underwent an ELT. Twenty-one patients were children. An emergency retransplantation was performed in 16 patients. Three or 4 organ-system failures (OSF) were present in 13 patients. Before ELT, the mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 26.3 ± 5.1. Six-month and 1-year survival rates were 37.8% and 25.9%, respectively, after ELT complicated by MOF, and 78% and 73.5%, respectively, in other cases of LT. Twenty-six patients had surgical complications (70%), whereas thirty-one patients had medical complications (84%). Twentytwo patients died during the postoperative period (60%). Before ELT, infection (P < .05), cardiovascular failure (P < .03), and more than two OSF (P < .05) were more frequent in patients who died after intervention. The APACHE II score (P < .05) and the length of stay in the intensive care unit before ELT (P < .05) were lower among survivors. In the context of liver allograft shortage, our results suggest that an ELT should not be performed in patients with cardiac failure, more than two OSF, or an APACHE II score higher than 30. Copyright © 1996 by the American Association for the Study of Liver Diseases.

Buts du travail Avec environ 34 000 nouveaux cas par an, le cancer colorectal (CCR) est le cancer digestif le plus frequent dans la population francaise. Le risque de survenue de metastase est eleve avec au premier rang les metastases hepatiques. La chimiotherapie systemique neo-adjuvante represente un des traitements les plus prometteurs pour augmenter le succes de la chirurgie des metastases hepatiques des CCR. Si cliniquement, l’efficacite de nouveaux cytotoxiques comme l’oxaliplatine ou l’irinotecan dans le traitement des metastases hepatiques de CCR a ete demontree, une eventuelle toxicite de ces derniers n’a pas ete analyse au niveau du foie non tumoral. Methodes Nous avons etudie retrospectivement l’aspect morphologique du foie non tumoral de 153 resections de metastases hepatiques de CCR effectuees entre Janvier 1994 et Decembre 2002 a l’hopital Cochin et a l’hopital de Geneve. Quatre vingt sept malades avaient ete prealablement traites par chimiotherapie avant la resection chirurgicale. Differents criteres ont ete evalues comme l’architecture hepatique, la steatose et la presence de lesions vasculaires. Une etude en microscopie electronique du foie non tumoral a egalement ete effectuee dans 3 cas. Resultats Des dilatations sinusoidales centro-lobulaires, d’intensite parfois marquee, etaient observees chez 44 des 83 malades (51 %) traites prealablement par chimiotherapie. Ces anomalies etaient associees dans 50 % des cas a une fibrose sinusoidale et des veines centro-lobulaires. Dans 7 cas, des lesions d’hyperplasie nodulaire regenerative etaient observees. L’etude en microscopie electronique confirmait l’existence d’une atteinte de la barriere sinusoidale. Ces lesions etaient significativement correlees a l’utilisation de l’oxaliplatine avec 34 des 43 malades (78 %) presentant cette atteinte vasculaire (p Conclusion La chimiotherapie systemique pre-operatoire des metastases de CCR induit de frequentes alterations vasculaires hepatiques similaires a celles observees au cours de la maladie veino-occlusive ou Syndrome d’Obstruction des Sinusoides (SOS). Ces lesions devraient etre incluses dans la liste des effets secondaires de la chimiotherapie, en particulier en relation avec l’utilisation de l’oxaliplatine. Les consequences cliniques de ces alterations vasculaires sont a evaluer d’autant que certains preconisent l’utilisation de l’oxaliplatine en chimiotherapie adjuvante des CCR au stade 3.

Patients with cystic fibrosis who have end-stage respiratory failure and associated liver cirrhosis have been considered poor candidates for lung transplantation because of high morbidity and mortality resulting from hepatic insufficiency after the operation. Since April 1989, our policy has been to combine heart-lung or lung and liver transplantation in this group of patients. Between June 1990 and March 1995, among 25 patients accepted in the program for combined transplantation, nine died awaiting transplantation and 10 underwent one of the following procedures: heart-lung-liver transplantation ( n = 5), en bloc double lung–liver transplantation ( n = 1), sequential double lung–liver transplantation ( n = 3), and bilateral lobar lung transplantation from a split left lung and reduced liver transplantation ( n = 1). There were 5 male and 5 female patients. The ages of the recipients ranged from 10 to 24 years. Mean forced expiratory volume in 1 second was 29% and mean forced vital capacity was 35% of predicted values. All patients were infected with resistant Pseudomonas, three with Pseudomonas cepaceia, and two patients had Aspergillus species in addition. All patients had severe cirrhosis with portal hypertension. Four patients had a history of esophageal variceal bleeding and two had had previous portosystemic shunts. The operation was performed as a two-stage procedure, the intrathoracic operation being completed before the abdominal stage was begun. Cardiopulmonary bypass was used in all patients because of poor clinical condition. Immunosuppression consisted of azathioprine, cyclosporine, and prednisone, as for isolated lung transplantation. There were two perioperative deaths, one caused by primary liver failure and the second by early lung dysfunction. For the first 3 months after transplantation pulmonary infection was the most common cause of morbidity. Other complications included tracheal stenosis ( n = 1), bronchial stenosis ( n = 1), biliary stricture ( n = 2), and severe ascites ( n = 3). All were successfully treated. Obliterative bronchiolitis developed in three patients. This was stabilized with FK 506 in two patients; the other patient underwent retransplantation at 38 months but eventually died of bleeding. Actuarial survival was 70% at 1 year and remained unchanged at 3 years. Significant functional improvement was observed in all survivors. For patients who have chronic respiratory failure with advanced cirrhosis, lung transplantation combined with liver transplantation can be performed with a satisfactory outcome. (J THORAC CARDIOVASC SURG 1995;110:1415-23)

Somatostatin is used to treat variceal hemorrhage in patients with cirrhosis and portal hypertension. Its systemic hemodynamic effects, however, are not yet well defined. Since cardiomyopathy or pulmonary artery hypertension may occur in patients with cirrhosis, definition of the systemic hemodynamic effects of somatostatin or its analogue octreotide is of clinical importance. The aim of this study was to evaluate the effects of somatostatin, at different doses and under different conditions of administration, on the systemic hemodynamics in 17 patients with cirrhosis. Two sets of experiments were performed. In the first, eight patients received two different bolus doses (100 and 250 micrograms) of somatostatin. The second set of experiments was designed to study the hemodynamic effects of the combination of a bolus and an infusion of somatostatin. Nine other patients received one bolus of 250 micrograms of somatostatin, followed by a 250 micrograms/h infusion for 65 min. A second bolus of 250 micrograms of somatostatin was injected in these patients after 35 min of infusion. Before and for 30 min after each bolus, systemic hemodynamics were measured. Following a bolus of somatostatin, a dose-dependent decrease in heart rate (from 77 +/- 3 to 73 +/- 5 beats/min with 100 micrograms, and from 78 +/- 4 to 68 +/- 5 beats/min with 250 micrograms, p < 0.05) and increases in systemic and pulmonary artery pressures were observed. The combination of an infusion and a bolus of somatostatin significantly reduced the increases in systemic and pulmonary artery pressures.(ABSTRACT TRUNCATED AT 250 WORDS)

Background/Aims Proteolysis may persist in the liver aliograft during cold storage. The aim of this study was to determine the significance of proteolysis within liver allografts stored at 4°C in University of Wisconsin preservation fluid. Methods Thirty recipients of 32 liver allografts were studied prospectively. Amino acid content of the preservation fluid was analyzed at the end of cold storage and was correlated to graft and patient outcome after transplantation. Results Analysis of the preservation fluid showed the presence of free amino acids, the profile of which was different from that of stored liver parenchyma. Concentrations of amino acids (alanine, cysteine, leucine, isoleucine, methionine, lysine, ornithine, and threonine) and transaminases (alanine aminotransferase and aspartate aminotransferase) in the preservation fluid correlated with the duration of cold ischemia. Indexes of graft dysfunction (serum alanine aminotransferase and aspartate aminotransferase peaks and prothrombin rate) correlated with concentrations of cysteine, alanine, isoleucine, leucine, methionine, lysine, ornithine, and threonine, whereas enzyme concentrations in the fluid were not predictive of graft dysfunction. Conclusions These data suggest that liver proteolysis occurs during cold storage and may have a detrimental effect on the outcome after transplantation. The measurement of the amino acids in the preservation fluid at the end of the cold storage period could help to identify the most severely damaged organs.

Alpha-1-antitrypsin deficiency is an inborn metabolism error which can cause emphysema and liver disease. As regards the pathophysiology of liver disease, this deficiency is poorly understood, and it is also not known why only a small proportion of Pi ZZ individuals progress towards cirrhosis and liver failure. Since there is no specific therapy for end-stage liver disease associated with alpha-1-antitrypsin deficiency, patients are considered candidates for liver transplantation. In this paper, the natural history of 16 children who underwent liver transplantation is reviewed. Fourteen patients had neonatal cholestasis as a first symptom of the disease and hepatosplenomegaly was present in all children by the age of 12 months. In 11 children, jaundice recurred, always with liver function deterioration. Two patients had a histological paucity of interlobular bile ducts and required early transplantation due to rapid progression of liver failure. At the time of pretransplant assessment, all the patients in this study had portal hypertension and seven of them had experienced at least one episode of gastrointestinal bleeding. One child had moderate intrapulmonary shunts with hypoxemia, but the others had normal spirometry and blood gases. There was no other extrahepatic complication of alpha-1-antitrypsin deficiency. Eighteen orthotopic liver transplantations were performed in 16 patients. One patient died 8 days after retransplantation due to graft necrosis. Fifteen patients (94%) were alive after a median follow-up of 22 months with an excellent quality of life, normal serum alpha-1-antitrypsin levels and without evidence of liver disease recurrence or pulmonary complications. Liver disease related to alpha-1-antitrypsin deficiency should be diagnosed early; infants with jaundice persisting after the age of 6 months and older patients, as well as patients who have experienced recurrent jaundice, prolonged prothrombin time and/or development of portal hypertension, should be referred to a transplant center for assessment. In most cases, liver disease evolves slowly, but liver transplantation should be performed before the onset of possible extrahepatic complications.

A technique of controlled liver splitting for transplantation in two recipients is proposed, based on a full anatomical assessment of the graft including arteriography and cholangiography on the back-table. Using eight livers, 16 patients received a graft: right liver (eight patients), left lobe (four) or left liver (four). Twelve patients required urgent or very urgent transplantation. Anatomical assessment of the graft demonstrated a portal bifurcation in all cases, a common trunk of the left and middle hepatic veins in five, a right biliary duplication in three and duplication of the left branch of the middle hepatic artery in one. After revascularization of the graft, bleeding was greater in patients with a right graft, particularly if the middle hepatic vein had been ligated. The main postoperative complications were hepatic artery thrombosis (four cases), biliary complications (four), portal vein thrombosis (two), haematoma (two) and abscess (two). No primary non-function of the graft was observed. The postoperative survival rate was 75 per cent. The four patients in whom transplantation was not considered urgent are still alive. The immediate survival rate of the grafts was 69 per cent. These results compare favourably with those in the literature. In spite of the technical, logistical and ethical problems raised by this technique, the results suggest that controlled liver splitting for transplantation in two recipients may in the future significantly improve the feasibility of liver transplantation.

In patients with cirrhosis the renal response to amino acid infusion is controversial. In addition, the renal and systemic metabolic effects of amino acids are unknown. Therefore, the present study examined the effects of amino acids on renal hemodynamics, renal and systemic oxygen (O2) consumption, and hormones in patients with cirrhosis. Twelve patients received an 8% amino acid solution for 30 minutes at a rate providing 250 mg of amino acids/kg body wt. Renal blood flow increased by 45% (P less than 0.05) and the glomerular filtration rate by only 9% (P greater than 0.05). Renal vascular resistance decreased by 23% (P less than 0.05), and renal perfusion pressure did not change significantly. Renal and systemic O2 consumption and pulmonary artery plasma glucagon level significantly increased. There were no significant changes in plasma osmolality, plasma volume, and plasma atrial natriuretic peptide concentrations. In conclusion, the results show that amino acid-induced renal vasodilation caused hyperperfusion but not renal hyperfiltration in patients with cirrhosis. In addition, renal hyperemia was associated with renal and systemic hypermetabolism.

We studied the relationships in 29 patients with cirrhosis between pulmonary arterial atrial natriuretic peptide concentrations and the following: systemic and splanchnic hemodynamics, the hematocrit, arterial oxyhemoglobin saturation, oxygen tension and the severity of cirrhosis. Plasma atrial natriuretic peptide concentrations ranged from 21 to 208 pg/ml and averaged 78 ± 8 pg/ml (mean ± S.E.M.). Simple regression analysis showed significant correlations between plasma atrial natriuretic peptide concentration and the following: hematocrit, mean pulmonary arterial pressure, wedged hepatic venous pressure, free hepatic venous pressure, pulmonary wedged pressure and serum bilirubin concentrations. No significant correlations were found between plasma atrial natriuretic peptide concentrations and all other hemodynamic values, arterial oxyhemoglobin saturation and oxygen tension. Multiple stepwise regression analysis showed that the hematocrit, mean pulmonary arterial pressure and wedged hepatic venous pressure were significant and independent predictors of pulmonary artery plasma atrial natriuretic peptide concentrations (R2 = 0.69). Partial regression coefficients were −0.74 (p

We investigated the effects of early coronic administration of propranolol on systemic and splanchnic hemodynamic changes, and the development of portal-systemic shunts in conscious, unrestrained, portal vein stenosed rats. Compared to rats receiving placebo, early chronic propranolol (75 mg kg −1 day −1 ) administration to rats begun 3 days before portal vein stenosis and then continued for 10 consecutive days, resulted in a significant decrease in both portal pressure (11.8 ± 1.5 mmHg) and portal-systemic shunts (48 ± 18%) which were measured 2 to 3 h after the final dose of propranolol (15.2 ± 1.5 mmHg and 84 ± 5%, respectively). These beneficial effects were also observed 18 to 24 h after the final dose of chronic propranolol. In rats given propranolol continuously for 5 days starting 5 days after portal vein stenosis, portal pressure (11.8 ± 1.2 mmHg) was significantly lower than in the placebo group but portal-systemic shunts (76 ± 14%) were not significantly different. In rats receiving a single dose of propranolol (75 mg/kg) 10 days after portal vein stenosis and measured 2 to 3 h after propranolol administration, portal pressure (12.8 ±1.0 mmHg) was significantly lower than in the placebo group. Portal-systemic shunts (72 ± 17%), however, showed no significant difference from the placebo group. Similar values in portal pressure (13.3 ± 1.2 mmHg) and portal-systemic shunts (83 ± 21%) were also observed in rats 18 to 24 h after a single dose of propranolol. In addition, although propranolol administration did not alter hepatic artery blood flow, the fraction of cardiac output reaching the liver increased significantly after chronic propranolol administration. We also demonstrated that chronic propranolol administration started before portal vein stenosis limited the initial rise in portal pressure which follows portal vein stenosis. We concluded that early chronic propranolol administration reduces the severity of portal hypertension and portal-systemic shunts in portal vein stenosed rats. These beneficial effects are probably a result of a limited initial increase in portal pressure immediately following portal vein stenosis.

Byler disease is a rare form of familial intrahepatic cholestasis that is fatal before puberty. This retrospective study reviewed the results of orthotopic liver transplantation in 14 children with Byler disease using 12 whole-liver grafts and 2 reduced-size grafts. One post-operative death occurred after retransplantation for arterial thrombosis. In the other patients, infectious problems and rejection episodes were the most frequent complications during the postoperative period. In the 13 patients alive, graft function, growth, and quality of life were good after an average follow-up of 17 months without any sign of disease recurrence.

14119 Background: The addition of bevacizumab (BV), an anti-VEGF monoclonal antibody with antiangiogenic activity, to cytotoxic chemotherapy (CH) improves survival in metastatic colorectal cancer patients (pts). Reversal of VEGF inhibition is associated with rapid vascular regrowth in tumors in vivo (M.R. Mancuso et al, J Clin Invest; 116(10): 2610–2621, 2006). In the clinical setting, the consequences of BV interruption are poorly documented, especially in interactions with the surgical resection of liver metastases. Methods: We describe the kinetics of tumor growth prior to, during, and after interruption of BV and under BV reintroduction, in consecutive colorectal cancer pts experiencing objective response under CH+BV, followed by surgical resection of metastases. We measured either clinically, of using CT-scan, the diameter of target lesions according to RECIST criteria, and the doubling time. Results: 7 pts (3 F, 4M), with median age of 54 years (41–70), were treated with 5-FU based CH (+oxaliplatin: 5; + irinotecan: 1 pt) and BV for metastatic colo- (6 pts) rectal (1 pt) cancer received a median number of 6 (4–18) cycles. Median time between BV interruption and surgery: 8 weeks (3–12). Under BV, all pts experienced objective response, with a median tumor reduction of 13%/month (extr: 6–15%). After BV interruption, under CH alone, 2/7 pts experienced disease progression, with a tumor growth of the residual disease of +7% and +200%/month, respectively. In pts who underwent surgery, during the off therapy period, tumor growth occurred in all 7 pts with a kinetics of +17 to +400%/month. Tumor growth doubling time after BV interruption ranged between 2 and 5 weeks. Reintroduction of BV re-induced a tumor response in 5/7 pts with a median time to response of 8 weeks (6–12) and a reduction of 10%/month. Conclusions: We show reproducible evidence of tumor growth acceleration following BV interruption. Surgery might transiently modify the balance between angiogenic and anti-angiogenic factors. We suggest to reduce the duration of BV interruption and to restart BV as soon as possible after surgery. These observations justify a large prospective analysis of the variations of tumor growth in this setting. No significant financial relationships to disclose.

The decreasing incidence of chronic rejection after liver transplantation emphasizes the need for an alternative end-point to assess the long-term consequences of acute rejection. The purpose of this study was to determine the effects of resolved episodes of acute rejection on late liver allograft function.Parameters of hepatic function (liver biochemistry, indocyanine green and sulfobromophthalein clearances, histology) were analyzed in 170 consecutive adult recipients, who were followed prospectively on the basis of repeat annual work-up. Mean follow-up was 3.7+/-0.2 years.The rates of acute and chronic rejection were 51% and 4.1%, respectively. At the last follow-up, there was no significant difference in graft function between patients with a single episode of acute rejection (n=56) and those without rejection (n=84). Among patients treated for a single episode of acute rejection, late hepatic function was not influenced by the severity of acute rejection and the response to corticosteroids. In contrast, patients with recurrent acute rejection (n=30) had significant impairment of liver function tests (aspartate aminotransferase, p0.05; alanine aminotransferase, p0.01; alkaline phosphatase, p0.01; gamma-glutamyl transpeptidase, p0.001), lower dye clearances (indocyanine green, p0.01; sulfobromophthalein, p0.01) and more severe histologic damage (p0.001).Single episodes of acute rejection do not impair the long-term hepatic function, whereas recurrent episodes leave sequellar damage to the liver allograft. These results provide a rationale for converting patients with rejection to a heavier immunosuppressive regimen, while leaving nearly half the recipients on a lifelong light immunosuppressive regimen.

BackgroundA pancreatic fistula (PF) is the most common complication after pancreaticoduodenectomy (PD), and its reported incidence varies from 2% to 28%. The aim of the present study was to analyse the treatment of a complicated PF comparing the surgical approach with conservative techniques.MethodsFrom January 2000 through to August 2006, 121 patients were submitted for PD. The study consisted of 70 men and 47 women, with a median age of 60 years (SD ± 12). The main indications for PD were pancreatic duct carcinoma in 52 patients (44.5%), ampullary carcinoma or adenoma in 18 (15.4%) and islet cell tumour in 11 (9.4%). Reconstruction by pancreatogastrostomy was performed in 65 patients (55.6%), and pancreatojejunostomy in 52 patients (44%).ResultsThirty-five patients (30%) developed a PF. Amongst these, 20 were managed conservatively and 14 were reoperated. These two groups of patients were compared with patients without a PF for analysis. There was no significant difference in the mean age, the gender ratio, American Society of Anesthesiologists (ASA) classification, surgical time and blood replacement, number of associated procedures, vascular resection and type of reconstruction between the three groups. There were five post-operative deaths (4.2%), three patients (21.4%) in the surgical treatment group (P < 0.01). Mean total number of complications (P= 0.02) and mean length of hospital stay (P < 0.001) were greater in the surgical group. The medium delay between the pancreatic resection and reoperation was 10 days (range, 3–32 days). Completion splenopancreatectomy was required in five patients whereas conservative treatment including debridement and drainage was applied in nine patients.ConclusionThe surgical approach for a PF is associated with a higher mortality and morbidity. There is no advantage in performing completion pancreatectomy (CP) instead of extensive drainage as a result of the same mortality and morbidity rates and the risk of endocrine insufficiency. In cases of complicated PF, radiological or surgical conservative treatment is recommended.

Like other previous treatments and approaches, sorafenib, an antiangiogenic drug, failed to show any benefit in the adjuvant setting for hepatocellular carcinoma in a large clinical trial. We discuss reasons and implications of these negative results and the implications for clinical practice and future research. ClinicalTrials.gov: NCT00692770 . Registered 5 June 2008. This study has been completed.

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. 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. 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. Clinicaltrial.gov: NCT02041871 .