Antoinette Lemoine

Resection of nonresectable liver metastases from colorectal cancer after percutaneous portal vein embolization.

OBJECTIVE To assess the influence of preoperative portal vein embolization (PVE) on the long-term outcome of liver resection for colorectal metastases. SUMMARY BACKGROUND DATA Preoperative PVE of the liver induces hypertrophy of the remnant liver and increases the safety of hepatectomy. METHODS Thirty patients underwent preoperative PVE and 88 patients did not before resection of four or more liver segments. PVE was performed when the estimated rate of remnant functional liver parenchyma (ERRFLP) assessed by CT scan volumetry was less than 40%. RESULTS PVE was feasible in all patients. There were no deaths. The complication rate was 3%. The post-PVE ERRFLP was significantly increased compared with the pre-PVE value. Liver resection was performed after PVE in 19 patients (63%), with surgical death and complication rates of 4% and 7% respectively. PVE increased the number of resections of more than four segments by 19% (17/88). Actuarial survival rates after hepatectomy with or without previous PVE were comparable: 81%, 67%, and 40% versus 88%, 61%, and 38% at 1, 3, and 5 years respectively. CONCLUSIONS PVE allows more patients with previously unresectable liver tumors to benefit from resection. Long-term survival is comparable to that after resection without PVE.

Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver.

ObjectiveTo assess the influence of preoperative portal vein embolization (PVE) on the long-term outcome of liver resection for hepatocellular carcinoma (HCC) in injured liver. Summary Background DataOn an healthy liver, PVE of the liver to be resected induces hypertrophy of the remnant liver and increases the safety of hepatectomy. On injured liver, this effect is still debated. MethodsDuring the study period, 10 patients underwent preoperative PVE and 19 patients did not before resection of three or more liver segments for HCC in injured liver (cirrhosis or fibrosis). PVE was performed when the estimated rate of remnant functional liver parenchyma (ERRFLP) assessed by computed tomographic scan volumetry was less than 40%. ResultsIn all patients, PVE was feasible. There were no deaths or complications. The ERRFLP after PVE was significantly increased compared with the pre-PVE value. Liver resection was performed after PVE in 9 of 10 patients, with surgical death and complication rates of 0% and 45%, respectively. PVE increased the number of resections of three or more segments by 47% (9/19). Overall actuarial survival rates with or without previous PVE (89%, 67%, and 44% vs. 80%, 53%, and 53% at 1, 3 and 5 years, respectively) and disease-free actuarial survival rates (86%, 64%, and 21% vs. 55%, 17%, and 17% at 1, 3, and 5 years respectively) after hepatectomy were comparable. ConclusionWith the use of PVE, more patients with previously unresectable HCC in injured liver can benefit from resection. Long-term survival rates are comparable to those after resection without PVE.

Stage II Colon Cancer Prognosis Prediction by Tumor Gene Expression Profiling

PURPOSE This study mainly aimed to identify and assess the performance of a microarray-based prognosis predictor (PP) for stage II colon cancer. A previously suggested 23-gene prognosis signature (PS) was also evaluated. PATIENTS AND METHODS Tumor mRNA samples from 50 patients were profiled using oligonucleotide microarrays. PPs were built and assessed by random divisions of patients into training and validation sets (TSs and VSs, respectively). For each TS/VS split, a 30-gene PP, identified on the TS by selecting the 30 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Two schemes were considered: single-split validation, based on a single random split of patients into two groups of equal size (group 1 and group 2), and Monte Carlo cross validation (MCCV), whereby patients were repeatedly and randomly divided into TS and VS of various sizes. RESULTS The 30-gene PP, identified from group 1 patients, yielded an 80% prognosis prediction accuracy on group 2 patients. MCCV yielded the following average prognosis prediction performance measures: 76.3% accuracy, 85.1% sensitivity, and 67.5% specificity. Improvements in prognosis prediction were observed with increasing TS size. The 30-gene PS were found to be highly-variable across TS/VS splits. Assessed on the same random splits of patients, the previously suggested 23-gene PS yielded a 67.7% mean prognosis prediction accuracy. CONCLUSION Microarray gene expression profiling is able to predict the prognosis of stage II colon cancer patients. The present study also illustrates the usefulness of resampling techniques for honest performance assessment of microarray-based PPs.

Functions of autophagy in normal and diseased liver

Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases.

Epidermal Growth Factor Gene Functional Polymorphism and the Risk of Hepatocellular Carcinoma in Patients With Cirrhosis

CONTEXT Overexpression of epidermal growth factor (EGF) in the liver induces transformation to hepatocellular carcinoma in animal models. Polymorphisms in the EGF gene modulate EGF levels. OBJECTIVE To assess the relationship among human EGF gene single-nucleotide polymorphism, EGF expression, and risk of hepatocellular carcinoma. DESIGN, SETTING, AND PARTICIPANTS Molecular mechanisms linking the 61*G allele polymorphism to EGF expression were examined in human hepatocellular carcinoma cell lines and human liver tissue. A case-control study involving 207 patients with cirrhosis was conducted at the Massachusetts General Hospital (1999-2006) and a validation case-control study involving 121 patients with cirrhosis was conducted at Hôpital Paul Brousse (1993-2006). Restriction fragment-length polymorphism was used to determine the EGF gene polymorphism genotype. Logistic regression analysis was used to assess the association between the EGF polymorphism and hepatocellular carcinoma risk. MAIN OUTCOME MEASURES Mechanisms by which the EGF gene polymorphism modulates EGF levels and associations among EGF gene polymorphism, EGF levels, and hepatocellular carcinoma. RESULTS Transcripts from the EGF 61*G allele exhibited more than a 2-fold longer half-life than those from the 61*A allele, and EGF secretion was 2.3-fold higher in G/G hepatocellular carcinoma cell lines than A/A cell lines. Serum EGF levels were 1.8-fold higher in G/G patients than A/A patients, and liver EGF levels were 2.4-fold higher in G/G patients than A/A patients. Among the 207 patients with cirrhosis in the Massachusetts study population, 59 also had hepatocellular carcinoma. Analysis of the distribution of allelic frequencies revealed that there was a 4-fold odds of hepatocellular carcinoma in G/G patients compared with A/A patients in the Massachusetts study population (odds ratio, 4.0; 95% confidence interval [CI], 1.6-9.6; P = .002). Logistic regression analysis demonstrated that the number of copies of G was significantly associated with hepatocellular carcinoma after adjusting for age, sex, race, etiology, and severity of cirrhosis (G/G or A/G vs A/A; hazard ratio, 3.49; 95% CI, 1.29-9.44; P = .01). The significant association was validated in the French patients with alcoholic cirrhosis and hepatocellular carcinoma. CONCLUSION The EGF gene polymorphism genotype is associated with risk for development of hepatocellular carcinoma in liver cirrhosis through modulation of EGF levels.

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 μg/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 μg/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 μg/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.

Decision for Retransplantation of the Liver: An Experience- and Cost-Based Analysis

ObjectiveTo determine the patient factors affecting patient outcome of first liver retransplantation at a single center to help in the decision process for retransplantation. Summary Background DataGiven the critical organ shortage, one of the most controversial questions is whether hepatic retransplantation, the only chance of survival for patients with a failing first organ, should be offered liberally despite its greater cost, worse survival, and the inevitable denial of access to primary transplantation to other patients due to the depletion of an already-limited organ supply. The authors’ experience of 139 consecutive retransplantations was reviewed to evaluate the results of retransplantation and to identify the factors that could improve the results. MethodsFrom 1986 to 2000, 1,038 patients underwent only one liver transplant and 139 patients underwent a first retransplant at the authors’ center (first retransplantation rate = 12%). Multivariate analysis was performed to identify variables, excluding intraoperative and donor variables, associated with graft and patient long-term survival following first retransplantation. Lengths of hospital and intensive care unit stay and hospital charges incurred during the transplantation admissions were compared for retransplanted patients and primary-transplant patients. ResultsOne-year, 5-year, and 10-year graft and patient survival rates following retransplantation were 54.0%, 42.5%, 36.8% and 61.2%, 53.7%, and 50.1%, respectively. These percentages were significantly less than those following a single hepatic transplantation at the authors’ center during the same period (82.3%, 72.1%, and 66.9%, respectively). On multivariate analysis, three patient variables were significantly associated with a poorer patient outcome: urgency of retransplantation (excluding primary nonfunction), age, and creatinine. Primary nonfunction as an indication for retransplantation, total bilirubin, and factor II level were associated with a better prognosis. The final model was highly predictive of survival: according to the combination of the factors affecting outcome, 5-year patient survival rates varied from 15% to 83%. Retransplant patients had significantly longer hospital and intensive care unit stays and accumulated significantly higher total hospital charges than those receiving only one transplant. ConclusionsThese data confirm the utility of retransplantation in the elective situation. In the emergency setting, retransplantation should be used with discretion, and it should be avoided in subgroups of patients with little chance of success.

In Situ Hypothermic Perfusion of the Liver Versus Standard Total Vascular Exclusion for Complex Liver Resection

Summary Background Data:We compare the results of liver resection performed under in situ hypothermic perfusion versus standard total vascular exclusion (TVE) of the liver <60 minutes and ≥60 minutes in terms of liver tolerance, liver and renal functions, postoperative morbidity, and mortality. The safe duration of TVE is still debated. Promising results have been reported following TVE associated with hypothermic perfusion of the liver with durations of up to several hours. The 2 techniques have not been compared so far. Methods:The study population includes 69 consecutive liver resections under TVE <60 minutes (group TVE<60′, 33 patients), ≥60 minutes (group TVE≥60′, 16 patients), and in situ hypothermic perfusion (group TVEHYOPOTH, 20 patients). Liver tolerance (peaks of transaminases), liver and kidney function (peak of bilirubin, minimum prothrombin time, and peak of creatinine), morbidity, and in-hospital mortality were compared within the 3 groups. Results:The postoperative peaks of aspartate aminotransferase (IU/L) and alanine aminotransferase (IU/L) were significantly lower (P[r] < 0.05) in group TVE HYPOTH (450 ± 298 IU/L and 390 ± 391 IU/L) compared with the groups TVE<60′ (1000 ± 808; 853 ± 743) and TVE≥60′ (1519 ± 962; 1033 ± 861). In the group TVEHYPOTH, the peaks of bilirubin (μmol/L) (84 ± 31), creatinine (μmol/L) (75 ± 22), and the number of complications per patient (1.2 ± 0.9) were comparable to those of the group TVE<60′ (80 ± 111; 109 ± 77; and 0.8 ± 1.1 respectively) and significantly lower to those of the group TVE≥60′ (196 ± 173; 176 ± 176, and 2.6 ± 1.8). In-hospital mortality rates were 1 in 33, 2 in 16, and 0 in 20 for the groups TVE<60′, TVE≥60′, and TVEHYOPOTH, respectively, and were comparable. On multivariate analysis, the size of the tumor, portal vein embolization, and a planned vascular reconstruction were significantly predictive of TVE ≥60 minutes. Conclusions:Compared with standard TVE of any duration, hypothermic perfusion of the liver is associated with a better tolerance to ischemia. In addition, compared with TVE ≥60 minutes, it is associated with better postoperative liver and renal functions and a lower morbidity. Predictive factors for TVE ≥60 minutes may help to indicate hypothermic perfusion of the liver.

Effects of 10 Minutes of Ischemic Preconditioning of the Cadaveric Liver on the Graft's Preservation and Function: The Ying and the Yang

Summary Background Data:Although extensively studied in animal models, ischemic preconditioning has not yet been studied in clinical transplantation. Objective:To compare the results of cadaveric liver transplantation with and without ischemic liver preconditioning in the donor. Patients and Methods:Alternate patients were transplanted with liver grafts that had (n = 46, GroupPrecond) or had not (n = 45, GroupControl) been subjected to ischemic preconditioning. Liver ischemia-reperfusion injury, liver and kidney function, morbidity, and in-hospital mortality rates were compared in the 2 groups. Initial poor function was defined as a minimal prothrombin time within 10 days of transplantation <30% of normal and/or bilirubin >200 &mgr;mol/L. Results:The postoperative peaks of ASAT (IU/L) and ALAT (IU/L) were significantly lower in GroupPrecond (556 ± 968 and 461±495, respectively) than in the GroupControl (1073 ± 1112 and 997±1071, respectively). The rate of technical morbidity and the incidence of acute rejection were similar in both groups. Initial poor function was significantly more frequent in the GroupPrecond (10 of 46 cases) than in the GroupControl (3 of 45 cases). Hospital mortality rates were similar in the 2 groups. In multivariate analysis, body mass index of the donor, graft steatosis, and ischemic preconditioning were significantly predictive of the posttransplant peak of ASAT. In univariate analysis, only preconditioning was significantly associated with initial poor function. Conclusions:Compared with standard orthotopic liver transplant, ischemic preconditioning of the liver graft in the donor is associated with better tolerance to ischemia. However, this is at the price of decreased early function. Until further studies are available, the clinical value of preconditioning liver grafts remains uncertain.

Combined Liver Resection and Reconstruction of the Supra-Renal Vena Cava: The Paul Brousse Experience

Background:Liver tumors with inferior vena cava (IVC) involvement may require combined resection of the liver and IVC. This approach, with its high surgical risks and poor long-term prognosis, was precluded until the development of neoadjuvant chemotherapy, portal vein embolization, reinforced vascular prostheses, and technical advances in liver transplantation. Methods:We reviewed 22 cases of hepatectomy with retrohepatic IVC resection and reconstruction. The patients had a median age of 51.5 years (range, 32.8–75.3 years). Indications for resection were: liver metastases (n = 9), cholangiocarcinoma (n = 8), hepatocellular carcinoma (n = 2), other cancers (n = 3). The liver resections carried out included 18 first, 3 second, and one third hepatectomy. Segment 1 (caudate lobe) was included in the specimen in 19 cases (86%). Resection concerned 1 to 6 liver segments (median = 5.0). Vascular control was achieved by vascular exclusion of the liver preserving the caval flow (n = 1), standard vascular exclusion of the liver (n = 12), in situ cold perfusion of the liver (n = 9). Ex situ surgery was not necessary in any case. Venovenous bypass was used in 12 cases. The IVC was reconstructed with a ringed Gore-Tex tube graft (n = 10), primarily (n = 8), or by caval plasty (n = 4). A main hepatic vein was reimplanted in 6 cases: into the native IVC (n = 4) or into a Gore-Tex tube graft (n = 2). Results:One patient died (4.5%) due to catheter infection, 7 days after in situ cold perfusion with replacement of the vena cava. Eight patients (36%) had no complications and 14 patients (64%) had 23 complications. In all but 1 case, the complications were transient and successfully controlled. The patients stayed in intensive care for 3.3 ± 2.0 days and in the hospital for 17.7 ± 7.8 days. All vascular reconstructions were patent at last follow-up. With median follow-up of 19 months, 10 patients died of tumor recurrence and eleven were alive with (n = 5) or without (n = 6) disease. Actuarial 1-, 3-, and 5-year survival rates were 81.8%, 38.3%, and 38.3%, respectively. Conclusions:IVC resection and reconstruction combined with liver resection can be safely performed in selected patients. The lack of alternative treatments and the spontaneous poor prognosis justify this approach, provided that surgery is carried out at a center specialized in both liver surgery and liver transplantation. The development of adjuvant chemotherapy regimens is required to improve the long-term results of this salvage surgery.