Outcomes of surgical shunts and transjugular intrahepatic portasystemic stent shunts for complicated portal hypertension.

BACKGROUND: Transjugular intrahepatic portasystemic stent shunt (TIPSS), instead of surgical shunt, has become the standard treatment for patients with complicated portal hypertension. This study compared outcomes in patients who underwent TIPSS or surgical shunting for complicated portal hypertension. METHODS: This was a retrospective study of all consecutive patients who received portasystemic shunts from 1994 to 2014 at a single institution. Patients who underwent surgical shunting were compared with those who had a TIPSS procedure following one-to-one propensity score matching. The primary study endpoints were overall survival and shunt failure, defined as major variceal rebleeding, relapse of refractory ascites, irreversible shunt occlusion, liver failure requiring liver transplantation, or death. RESULTS: A total of 471 patients received either a surgical shunt or TIPSS. Of these, 334 consecutive patients with cirrhosis who underwent elective surgical shunting (34) or TIPSS (300) for repeated variceal bleeding or refractory ascites were evaluated. Propensity score matching yielded 31 pairs of patients. There were no between-group differences in morbidity and 30-day mortality rates. However, shunt failure was less frequent after surgical shunting than TIPSS (6 of 31 versus 16 of 31; P = 0·016). The 5-year shunt failure-free survival (77 versus 15 per cent; P = 0·008) and overall survival (93 versus 42 per cent; P = 0·037) rates were higher for patients with surgical shunts. Multivariable analysis revealed that a Model for End-Stage Liver Disease (MELD) score exceeding14 and TIPSS were independently associated with shunt failure. In patients with MELD scores of 14 or less, the 5-year overall survival rate remained higher after surgical shunting than TIPSS (100 versus 40 per cent; P < 0·001). CONCLUSION: Surgical shunting achieved better results than TIPSS in patients with complicated portal hypertension and low MELD scores.

Nomogram for prediction of prognosis in patients with initially unresectable colorectal liver metastases.

BACKGROUND: Although recent advances in surgery and chemotherapy have increasingly enabled hepatectomy in patients with initially unresectable colorectal liver metastases (CRLM), not all such patients benefit from surgery. The aim of this study was to develop a nomogram to predict survival after hepatectomy for initially unresectable CRLM. METHODS: Patients with initially unresectable CRLM treated with chemotherapy followed by hepatectomy between 1990 and 2012 were included in the study. A nomogram to predict survival was developed based on a multivariable Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan-Meier curve and calibration plots. RESULTS: Of a total of 439 patients, liver and globally completed surgery was achieved in 380 (86·6 per cent) and 335 (76·3 per cent) patients respectively. The 5-year overall and disease-free survival rates were 39·9 and 10·0 per cent respectively. Based on the Cox model, the following five factors were selected for the nomogram and assigned specific scores: node-positive primary, 5; more than six metastases at hepatectomy, 7; carbohydrate antigen 19-9 level at hepatectomy above 37 units/ml, 10; disease progression during first-line chemotherapy, 9; and presence of extrahepatic disease, 4. The model achieved relatively good discrimination and calibration, with a C-statistic of 0·66. The overall survival rate for patients with a score greater than 16 was significantly worse than that for patients with a score of 16 or less (5-year survival rate 4 versus 46·3 per cent respectively; P < 0·001). CONCLUSION: The nomogram facilitates personalized assessment of prognosis for patients with initially unresectable CRLM treated with chemotherapy and with planned resection.

Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor.

Liver transplantation (LT) for cirrhotic/Hepatocellular carcinoma (HCC) is associated with reduced survival in patients with poor histological features. Preoperative levels of alphafetoprotein (AFP) could predict negative biological features. AFP progression could be more relevant than static AFP levels in predicting LT outcomes. A total of 252 cirrhotic/HCC patients transplanted between 1985 and 2005 were reviewed. One hundred fifty-three patients were analyzed, 99 excluded (for nonsecreting tumors and/or salvage transplantation). Using receiver operating characteristics analysis for recurrence after LT, 'progression' of AFP was defined by >15 microg/L per month before LT. A total of 127 (83%) were transplanted under and 26 (16%) over this threshold. After 45 months of follow-up (median), 5-year overall survival (OS) and recurrence free-survival (RFS) were 72% and 69%, respectively. Five-year survival in the progression group was lower than the nonprogression group (OS 54% vs. 77%; RFS 47% vs. 74%). Multivariate analysis showed progression of AFP>15 microg/L per month and preoperative nodules>3 were associated with decreased OS. Progression group and age>60 years were associated with decreased RFS. Male gender, progression of AFP and size of tumor>30 mm were associated with satellite nodules and/or vascular invasion. In conclusion, increasing AFP>15 microg/L/month while waiting for LT is the most relevant preoperative prognostic factor for low OS/DFS. AFP progression could be a pathological preoperative marker of tumor aggressiveness.

Comparison of simultaneous or delayed liver surgery for limited synchronous colorectal metastases.

BACKGROUND: The optimal surgical strategy for patients with synchronous colorectal liver metastases (CLMs) is still unclear. The aim of this study was to compare simultaneous colorectal and hepatic resection with a delayed strategy in patients who had a limited hepatectomy (fewer than three segments). METHODS: All patients with synchronous CLMs who underwent limited hepatectomy between 1990 and 2006 were included retrospectively. Short-term outcome, overall and progression-free survival were compared in patients having simultaneous colorectal and hepatic resection and those treated by delayed hepatectomy. RESULTS: Of 228 patients undergoing hepatectomy for synchronous CLMs, 55 (24.1 per cent) had a simultaneous colorectal resection and 173 (75.9 per cent) had delayed hepatectomy. The mortality rate following hepatectomy was similar in the two groups (0 versus 0.6 per cent respectively; P = 0.557), but cumulative morbidity was significantly lower in the simultaneous group (11 per cent versus 25.4 per cent in the delayed group; P = 0.015). Three-year overall and progression-free survival rates were 74 and 8 per cent respectively in the simultaneous group, compared with 70.3 and 26.1 per cent in the delayed group (overall survival: P = 0.871; progression-free survival: P = 0.005). Significantly more recurrences were observed in the simultaneous group at 3 years (85 versus 63.6 per cent; P = 0.002); a simultaneous strategy was an independent predictor of recurrence. CONCLUSION: Combining colorectal resection with a limited hepatectomy is safe in patients with synchronous CLMs and associated with less cumulative morbidity than a delayed procedure. However, the combined strategy has a negative impact on progression-free survival.

Reinfection of liver graft by hepatitis C virus after liver transplantation.

We have investigated hepatitis C virus (HCV) viremia before and after orthotopic liver transplantation (OLT). 38 patients were examined; 16 were anti-HCV positive and 22 anti-HCV negative pre-OLT in a RIBA-2 test (Ortho Diagnostic Systems Inc., Westwood, MA). HCV-RNA was detected using a modified nested polymerase chain reaction in 14/38 and 10/38 patients before and after OLT, respectively. 7 of these 14 subjects who were HCV-RNA positive before OLT were also positive for serum hepatitis B surface antigen. After OLT, six patients became HCV-RNA positive, likely as a result of transfusions, while four developed a probable recurrence of HCV infection. Infection of the liver graft by the same strain of HCV was indeed demonstrated by sequence analysis of a hypervariable domain (in the envelope region) in two cases. This establishes the possibility of HCV recurrence and shows the usefulness of polymerase chain reaction as the only assay currently capable of identifying HCV infection after OLT.

Modifications of 3'-methyl-4-dimethylaminoazobenzene carcinogenesis of rat liver and carcinogen metabolism by portacaval anastomosis.

The effect of portacaval shunt on hepatocarcinogenesis was studied in rats fed 3'-methyl-4-dimethylaminoazobenzene. Portacaval anastomosis resulted in a decrease of hepatocarcinogenesis as reflected by a delay in the early peak of alpha-fetoproteins, an absence of late appearance of alpha-fetoproteins, and a significantly lower incidence of tumors than in nonshunted rats. Reduction of hepatocarcinogenesis in shunted rats was associated with a decrease of the binding of 3'-methy-4-dimethylamioazobenzene metabolites to liver proteins. This effect seemed to be related to modifications of carcinogen-metabolic pathways. While the detoxifying azoreductase activity was not affected by portal diversion, the activating pathway leading to the binding of 4-dimethylaminoazobenzene metabolites to DNA, a major step for cell carcinogenesis that is mediated by microsomal enzymes, was decreased in shunted rats to about 50 percent of control values. The decrease of liver weight that occurred in shunted rats without loss of body weight produced a very significant reduction of the total capacity of liver to activate 4-dimethylaminoazobenzene while the total capacity of detoxification remained unchanged. This could be a direct consequence of portacaval anastomosis, as has been shown for other microsomal enzymes.

Frequent microsatellite instability in post hepatitis B viral cirrhosis.

The molecular basis of cirrhosis, the most frequent underlying liver disease in hepatocellular carcinoma, remains unclear. We investigated microsatellite instability at six different loci on chromosomes 2p, 3p, 5q, 9p, 13q and 17p, in DNA from 38 cirrhotic livers of viral (n=28) and nonviral (n=10) origin. Sixty percent of the patients exhibited microsatellite alterations in at least one chromosome locus. A striking feature was the close association between genomic instability and cirrhosis linked to hepatitis B viral infection (P<0.01). This high instability may be a clue to the etiology of cancer induced by the hepatitis B virus.

Microsatellite instability in European hepatocellular carcinoma.

Genetic instability has been detected in many types of cancers but poorly investigated in hepatocellular carcinoma (HCC). We have studied the incidence of microsatellite instability (MI) at eight highly polymorphic microsatellite markers and the poly A tract BAT26 and tested for mutations at two sites of repetitive sequence (poly-A nucleotides 709-718 and GT repeat-nucleotides 1931-1936) in the Transforming Growth Factor beta (TGFbeta) type II receptor (RII) gene, in a group of 46 European HCCs and the surrounding nontumour tissue. This analysis showed that 63% of HCCs exhibit MI in at least one chromosome locus and 41% in two or more loci. No mutations of the TGFbetaRII gene were found in the MI positive tumours. No correlation was found with clinicopathological characteristics of the tumours such as cirrhosis, etiology, number of nodules, Edmondson's grade and vascular invasion. However, in patients who had a rearranged D16S402 microsatellite in their tumour, the recurrent disease and the number of nodules were significantly higher than in the others (P<0.005 and P<0.02, respectively). We propose to consider D16S402 rearrangement in HCC as a prognostic factor to identify patients presenting a higher risk of recurrence.

Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

Circadian rhythm-modulated chemotherapy with high-dose 5-fluorouracil: a pilot study in patients with pancreatic adenocarcinoma.

From November 1986 to April 1989, 16 patients with advanced measurable pancreatic carcinoma were involved in a pilot phase I-II study. 5-Fluorouracil was given every 3 weeks by 5-day continuous chronomodulated venous infusion (CMVI) with peak 5-FU delivery at 4 a.m. Intrapatient dose escalation started at 1200 mg/m2/day up to 1600 mg/m2/day in the absence of grade III (WHO) toxicity. Mucositis and diarrhoea were dose limiting in the 131 cycles given. Three partial responses (21%) and 5 stable diseases were seen in the 14 patients with measurable disease. Dose intensity after three or after six courses (1800 mg/m2/week) was significantly correlated with time to progression (Pearson r = 0.64; P < 0.004). These results, although modest, support a multicentre phase II trial with 5-FU CMVI.

Effect of portacaval or mesentericocaval anastomosis on cholesterol metabolism in rats.

Portacaval anastomosis (PCA) lowered by 50% the cholesterol concentration in the plasma of rats. The free and esterified cholesterol contents in the lipoproteins were decreased with the very low density lipoproteins most affected (-85%). Cholesterol concentration as total content in the liver was reduced. The major change in the cholesterol metabolism, as studied with an isotopic equilibrium method, was the decrease in the intestinal absorption coefficient of dietary cholesterol (56.0 +/- 2.7% instead of 73.3 +/- 1.9% in controls). The rate of cholesterol transformation into bile acids was decreased (10.5 +/- 0.3 vs 14.5 +/- 0.5 mg/day/rat in controls). The rate of internal secretion of cholesterol was slightly reduced while the rate of fecal external secretion was increased, suggesting that the synthesis of cholesterol by extra-digestive tissues (including liver) was reduced after PCA. The effects of PCA on cholesterol metabolism were similar to those described for glucagon administration. Since this shunt results in hyperglucagonemia, it is suggested that this hormonal perturbation was the main factor involved in the modifications of cholesterol metabolism after PCA. Moreover, mesentericocaval anastomosis, which shunts only the intestinal blood and allows the pancreatic hormones a normal transport through the liver, did not significantly modify cholesterol metabolism. Only cholesterolemia (-28%) and the absorption coefficient of dietary cholesterol (66.0 +/- 2.3%) were slightly reduced.

Reduction of nonresectable liver metastasis from colorectal cancer after oxaliplatin chemotherapy.

Until recently, approximately 30% of patients with resectable hepatic metastases from colorectal cancer survived 5 years after surgery. Additionally, many patients present with unresectable metastases and can look forward only to palliative care. Whereas therapeutic approaches such as cryosurgery appear to improve resectability, a key to resecting hepatic metastases is the ability to shrink the metastatic sites to make them more amenable to surgery. The administration of traditional chemotherapeutic modalities by conventional means or via intra-arterial or portal vein infusion has not provided significant improvements. The recent introduction of the combination oxaliplatin-5-fluorouracil/folinic acid administered as a chronomodulated regimen, however, has provided better response rates with minimal toxicity. Recent results show that the resection of previously unresectable metastases became possible in up to 16% of patients after chemotherapy with a chronomodulated regimen of oxaliplatin plus 5-fluorouracil/folinic acid. Of the patients who had successful resections, 54% and 40% were alive at 3 years and 5 years after surgery, respectively. The results of these studies demonstrate that this new approach can significantly prolong survival for patients with a previously bleak outlook. As a result, new treatment algorithms are evolving, integrating chemotherapeutic and surgical strategies for the treatment of patients with metastatic colorectal cancer.

Sclerosing cholangitis following human orthotopic liver transplantation.

Sclerosing cholangitis defined by cholangiographic criteria may occur after orthotopic liver transplantation. In this retrospective study, we analyzed failed grafts and antecedent serial biopsies of 24 patients who developed this type of nonanastomotic biliary strictures. Sclerosing cholangitis was histologically diagnosed if there was a combination of periductal fibrosis and features of large bile duct obstruction. The condition was observed in all but one available failed allografts. This later showed ischemic-type lesions without periductal fibrosis. Liver biopsy specimens were nondiagnostic relative to sclerosing cholangitis, although 85% of the patients had evidence of large bile duct obstruction. Numerous associated factors may explain the pathogenesis of secondary sclerosing cholangitis: an immunologically related etiologic factor (10 recipients of ABO-incompatible allografts) and compromised arterial blood flow that likely resulted from hepatic artery thrombosis (12 patients), focal arterial fibrointimal hyperplasia (three patients), chronic ductopenic arteriopathic rejection (three patients) and/or preservation-related ischemia (four patients). Sclerosing cholangitis may be a significant cause of graft failure that often has misleading biopsy manifestations. From a practical standpoint, cholestasis with evidence of large bile duct obstruction warrants cholangiographic assessment of the biliary tree.

Development of anti-tissue antibodies in the rat liver transplant model.

BACKGROUND: The aim of this study was to analyze the humoral immune response associated with orthotopic liver transplantation in the rat liver transplant model, and in particular to test the presence of anti-tissue antibodies. METHODS: Rearterialized liver transplantations were performed in the Dark Agouti (DA)-to-Lewis (LEW) and the LEW-to-DA rat strain combinations. Sera of recipients were analyzed by immunofluorescence (on DA and LEW organ sections) and by western blotting (with DA and LEW liver proteins). RESULTS: We have shown that liver (but not heart or skin) recipients develop a humoral response against non-MHC tissue antigens as evidenced (1) by a pattern of staining comparable to that described in human patients harboring anti-smooth muscle antibodies and (2) by the presence of donor liver peptides recognized in the sera of the recipient by Western blotting. CONCLUSIONS: These experiments indicate that orthotopic transplantation of a nonacutely rejected liver allograft is associated with the development of a previously undescribed anti-tissue antibody response that seems to be neither organ nor MHC restricted.

Anti-donor antibody class switching after liver transplantation.

The humoral immune response directed against donor antigens was monitored by flow cytometry in 17 liver transplant patients using donor leukocytes as targets. Overall, donor-specific antibodies developed in 15 patients; these included all 9 patients who had experienced a biopsy-proven episode of acute rejection and 6 out of 8 patients who had not had an acute episode of rejection. The isotypes of the donor-specific antibodies in the 9 patients who had experienced an early episode of acute rejection were IgG in 8 patients, IgE in 8 patients, and IgA in 6 patients; all 9 patients had IgE and/or IgA antibodies. In the 6 patients who showed no evidence of acute clinical rejection but nevertheless developed donor-specific antibodies, the isotype was IgM associated in 5 of them, with an immunoglobulin class switching to the IgG isotype; none of these patients had antibodies of the IgA or IgE isotype. These results indicate that the lack of rejection of a liver allograft does not necessarily result from a lack of immune response against donor antigens. Rather, the distinct pattern of (cytokine dependent) immunoglobulin class switching suggests that the lack of liver graft rejection may be the result of an immune activation pathway distinct from that resulting in graft rejection.

High incidence of antitissue antibodies in patients experiencing chronic liver allograft rejection.

BACKGROUND: The precise immunologic mechanisms responsible for chronic rejection of liver allografts are unknown. We have recently shown in a rodent model that recipients of liver allografts developed non-major histocompatibility complex antitissue antibodies. The aim of the present study was to test this hypothesis in the clinical setting. METHODS: Posttransplant sera of 14 patients undergoing chronic rejection and of 48 control patients (12 liver transplant patients with chronic active hepatitis or liver cirrhosis related to hepatitis C virus [HCV] infection and without chronic rejection, 10 with sclerosing cholangitis, and 26 with normal liver function tests and liver biopsy) were tested for the presence of antitissue antibodies by indirect immunofluorescence. Pretransplant sera of all these patients lacked antitissue antibodies. RESULTS: Antitissue antibodies were detected in 71% of patients who developed chronic rejection (before or at the time of chronic rejection). This incidence was significantly greater than that observed in patients not undergoing rejection (HCV-related chronic active hepatitis, 16%; sclerosing cholangitis, 0%; normal liver biopsy, 7%). All these autoantibodies were directed against the smooth muscle and/or the nucleus. In two patients, anti-smooth muscle antibodies had an antiactin or antivimentin specificity. CONCLUSIONS: These results show a strong association between chronic allograft rejection and the development of antitissue antibodies and suggest that these antibodies could be used to identify patients at high risk of developing chronic rejection after liver transplantation.

The value of early transjugular liver biopsy after liver transplantation.

Conventional percutaneous liver biopsy in the early postoperative period, within 30 days, following liver transplantation may be impossible due to coagulopathy and/or ascites. The use of transjugular liver graft biopsy (TJLB) in this setting is an attractive alternative in that a tissue diagnosis can be obtained despite the relative contraindications for percutaneous biopsy during this period. During the early posttransplant period, 124 TJLBs were performed in 105 liver patients, the majority (89%) of whom had standard liver transplantation without preservation of the native inferior vena cava; the others (11%) had the native inferior vena cava intact. The technical success rate was 87%, with adequate specimen for definitive diagnosis in most instances (86%), which included both rejection (61%) and nonrejection (39%) diagnoses on final histopathology. The biopsy diagnosis influenced clinical management in the majority of cases (65%), with decisions made to perform retransplantation (3%), to influence initiation of antirejection therapy (59%), and to institute antiviral therapy (3%). There was no morbidity or mortality associated with TJLB and it is feasible, safe, and effective in the early period after liver transplantation.

Xenotransplantation: baboons as potential liver donors? Scientific and ethical issues.

The dramatic development of liver transplantation compared to a relative shortage of donors has brought a renewed interest to xenotransplantation. Because of anatomical and immunological compatibilities, nonhuman primates are the most appropriate donors. The aim of this work was to analyze the different problems of a baboon-to-man liver xenotransplantation. Thirty baboons bred in a French Primatology Center were studied. The analysis of anatomical, microbiological, and immunological data showed that only 8 baboons out of 30 were suitable as donors for xenotransplantation. Considering these data and the ethical issues, the actual feasibility of xenotransplantation programs is discussed.