Georges Mantion

Hepatic Resection for Noncolorectal Nonendocrine Liver Metastases: Analysis of 1452 Patients and Development of a Prognostic Model

Objective:To determine the utility of hepatic resection (HR) in the treatment of patients with noncolorectal nonendocrine liver metastases (NCNELM). Summary Background Data:The place of HR in the treatment of NCNELM remains controversial, primarily due to the limitations of previously published reports and the heterogeneity of primary tumor sites and histologies. Methods:A multivariate risk model was developed by analyzing prognostic factors and long-term outcomes in 1452 patients with NCNELM treated with HR at 41 centers from 1983 to 2004. Results:Hepatic metastases were solitary in 56% and unilateral in 71% (mean diameter, 50.5 mm). Extrahepatic metastases were present in 22%. The most common primary sites were breast (32%), gastrointestinal (16%), and urologic (14%). The most common histologies were adenocarcinoma (60%), GIST/sarcoma (13.5%), and melanoma (13%). R0 resection was achieved in 83% of patients with a 60-day mortality rate of 2.3% and a major complication rate of 21.5%. Tumor recurred in 67% of patients (liver, 24%; extrahepatic, 18%; both, 25%). Overall and disease-free survivals at 5 years were 36% and 21% and at 10 years were 23% and 15%, respectively. In multivariate analysis, factors associated with poor prognosis were patient age >60 years, nonbreast origin, melanoma or squamous histology, disease-free interval <12 months, extrahepatic metastases, R2 resection, and major hepatectomy (all P ≤ 0.02). A prognostic model based on these factors effectively stratified patients into low-risk (0–3 points, 46% 5-year survival), mid-risk (4–6 points, 33% 5-year survival), and high-risk (>6 points, <10% 5-year survival) groups (P = 0.0001). Discussion:HR for NCNELM is safe and effective, with outcomes mainly dependent on primary tumor site and histology. For individual patients, a statistical model based on key prognostic factors could validate the indication for hepatic resection by predicting long-term survivals.

Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report.

OBJECTIVE The purpose of this study was to assess the value and timing of orthotopic liver transplantation (OLT) in the treatment of metastatic neuroendocrine tumors (NET). SUMMARY BACKGROUND DATA Liver metastasis from NET seems less invasive than other secondary tumors. This observation suggests that OLT may be indicated when other therapies become ineffective. However, the potential benefit of this highly aggressive procedure is difficult to assess due to the scarcity and heterogeneity of NET. METHODS A retrospective multicentric study was carried out, including all cases of OLT for NET performed in France between 1989 and 1994. There were 15 cases of metastatic carcinoid tumor and 16 cases of islet cell carcinomas. Hormone-related symptoms were present in 16 cases (55%). Only 5 patients (16%) had no previous surgical or medical therapy before OLT. Median delay from diagnosis of liver metastasis and OLT was 19 months (range, 2 to 120). RESULTS The primary tumor was removed at the time of OLT in 11 cases, by upper abdominal exenteration in 7 cases and the Whipple resection in 3. Actuarial survival rate after OLT was 59% at 1 year, 47% at 3 years, and 36% at 5 years. Survival rates were significantly higher for metastatic carcinoid tumors (69% at 5 years) than for noncarcinoid apudomas (8% at 4 years), because of higher tumor- and non-tumor-related mortality rates for the latter. CONCLUSION OLT can achieve control of hormonal symptoms and prolong survival in selected patients with liver metastasis of carcinoid tumors. It does not seem indicated for other NET.

Preoperative radiochemotherapy in rectal cancer:: Long-term results of a phase II trial☆

PURPOSE To assess toxicity and long-term results of preoperative chemoradiotherapy in rectal cancer. METHODS AND MATERIALS Between 1989 and 1997, as a phase II study, 66 patients with T3 M0, rectal cancer received preoperatively a 45 Gy dose pelvic radiotherapy (XRT) combined with two 5-day chemotherapy courses (CT) of 5-Fluorouracil (5-FU) and Leucovorin (LV) delivered the first and fifth week of XRT. For each CT course, LV:20 mg/m2/d1-d5,. While the 5-FU dose was variable from 450 to 350 mg/m2/d first course and 370 to 350 mg/m2/d second course. Surgery was planned 3 weeks later. RESULTS XRT-CT was stopped in 1 patient due to progressive disease. CT was stopped in 1 patient due to toxicity. Grades 2 and 3 diarrhea were observed in 8 and 3 patients, respectively. One patient died from acute diarrhea due to deviation from recommendations; 60 patients went to surgery. Among the 58 patients operated on for cure, 5 had an R1-resection. After a 4.5-year median follow-up, the 5-year pelvic disease-free survival was 92% for the whole group and 96% in the R0-resection group. CONCLUSION Preoperative combined XRT-5-FU-LV is feasible if optimal XRT and patients are carefully managed. The recommended 5-FU daily dose is 350 mg/m2 for both CT courses. This approach is currently tested in a large EORTC phase III trial.

Predictors of Long-Term Survival After Liver Transplantation for Metastatic Endocrine Tumors: An 85-Case French Multicentric Report

Liver transplantation (LTx) for metastatic endocrine tumors (MET) remains controversial due to the lack of clear selection criteria. From 1989 to 2005, 85 patients underwent LTx for MET. The primary tumor was located in the pancreas or duodenum in 40 cases, digestive tract in 26 and bronchial tree in five. In the remaining 14 cases, primary location was undetermined at the time of LTx. Hepatomegaly (explanted liver ≥120% of estimated standard liver volume) was observed in 53 patients (62%). Extrahepatic resection was performed concomitantly with LTx in 34 patients (40%), including upper abdominal exenteration (UAE) in seven.

A twenty-year history of alveolar echinococcosis: analysis of a series of 117 patients from eastern France.

Objectives Alveolar echinococcosis of the liver is a very rare and severe parasitic disease due to the growth of the larva of Echinococcus multilocularis. The aim of this paper was to describe a 20‐year study of the epidemiological, clinical and therapeutic aspects of alveolar echinococcosis in eastern France. Design One hundred and seventeen consecutive cases, diagnosed and followed in our liver unit, were studied from 1972 to 1993. Methods Data from 85 patients followed since 1983 (period B) were compared to data from a first series of 32 patients (period A) collected from 1972 to 1982; 1983 was chosen as the cut‐off year because of the numerous changes that occurred in the diagnosis, follow‐up and treatment of the disease at this time, in particular the introduction of parasitostatic benzimidazoles. Results The results of patient follow‐up were evaluated in December 1997. The cumulative prevalence was 2.5 per 100 000 persons in period A whereas it reached 6.6 per 100 000 in period B. The annual incidence in period B was 7.3 on average, compared with 2.7 in period A. Twenty‐nine per cent of patients from period B were asymptomatic at the time of diagnosis compared with 10% in period A. This change was correlated with less advanced liver lesions, and was related to the extensive use of abdominal ultrasound, and from 1987, serological screening. Curative resections were performed in 24% of the cases in period B versus only 3% in period A. From 1986, liver transplantations were performed in eight patients from period A and 13 patients from period B. In period B, palliative surgery was frequently replaced by radiological non‐operative procedures to treat abscesses and jaundice. From 1982, 73 patients received benzimidazoles for a period of time ranging from 4 to 138 months. Stabilization of the lesions was observed in two‐thirds of the patients. Episodes of jaundice or digestive haemorrhage due to portal hypertension were 31.5 and 11 times less frequent respectively in patients from period B compared with period A. Actuarial survival at 5 years improved from 67% in period A to 88% in period B in patients of similar age. Conclusions Radical changes in the diagnosis and the management of alveolar echinococcosis have occurred during the last decade. Together they have contributed to an improvement in the status of the patients affected by this very severe parasitic disease. Eur J Gastroenterol Hepatol 12:327‐336

Gene expression in human hepatocytes in suspension after isolation is similar to the liver of origin, is not affected by hepatocyte cold storage and cryopreservation, but is strongly changed after hepatocyte plating

Isolated primary human hepatocytes are a well accepted system for evaluating pharmacological and toxicological effects in humans. However, questions remain regarding how culturing affects the liver-specific functions of the hepatocytes. In addition, cryopreservation could also potentially affect the differentiation state of the hepatocytes. The first aim of the present study was to compare gene expression in freshly isolated primary hepatocytes to that of the liver of origin and to evaluate the expression changes occurring after cryopreservation/thawing, both when maintained in suspension and after plating. The second aim of the present study was to evaluate gene expression in hepatocytes after cold storage of suspensions up to 24 h compared with freshly isolated hepatocytes in suspension. Our results show that the gene expression in freshly isolated human hepatocytes in suspension after isolation is similar to that of the liver of origin. Furthermore, gene expression in primary human hepatocytes in suspension is not affected by hepatocyte cold storage and cryopreservation. However, the gene expression is profoundly affected in monolayer cultures after plating. Specifically, gene expression changes were observed in cultured relative to suspensions of human hepatocytes that are involved in cellular processes such as phase I/II metabolism, basolateral and canalicular transport systems, fatty acid and lipid metabolism, apoptosis, and proteasomal protein recycling. An oxidative stress response may be partially involved in these changes in gene expression. Taken together, these results may aid in the interpretation of data collected from human hepatocyte experiments and suggest additional utility for cold storage and cryopreservation of hepatocytes.

Liver Transplantation for Neuroendocrine Tumors in Europe—Results and Trends in Patient Selection A 213-Case European Liver Transplant Registry Study

Objective:The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. Background:LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. Methods:This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1–149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. Results:Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. Conclusions:LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

The AFC Score: Validation of a 4-Item Predicting Score of Postoperative Mortality After Colorectal Resection for Cancer or Diverticulitis: Results of a Prospective Multicenter Study in 1049 Patients

Objective:The aim of the present prospective study was to validate externally a 4-item predictive score of mortality after colorectal surgery (the AFC score) by testing its generalizability on a new population. Summary Background Data:We have recently reported, in a French prospective multicenter study, that age older than 70 years, neurologic comorbidity, underweight (body weight loss >10% in <6 months), and emergency surgery significantly increased postoperative mortality after resection for cancer or diverticulitis. Patients and Methods:From June to September 2004, 1049 consecutive patients (548 men and 499 women) with a mean age of 67 ± 14 years, undergoing open or laparoscopic colorectal resection, were prospectively included. The AFC score was validated in this population. We assessed also the predictive value of other scores, such as the “Glasgow” score and the ASA score. To express and compare the predictive value of the different scores, a receiver operating characteristic curve was calculated. Results:Postoperative mortality rate was 4.6%. Variables already identified as predictors of mortality and used in the AFC score were also found to be associated with a high odds ratio in this study: emergency surgery, body weight loss >10%, neurologic comorbidity, and age older than 70 years in a multivariate logistic model. The validity of the AFC score in this population was found very high based both on the Hosmer-Lemeshow goodness of fit test (P = 0.37) and on the area under the ROC curve (0.89). We also found that discriminatory capacity was higher than other currently used risk scoring systems such as the Glasgow or ASA score. Conclusion:The present prospective study validated the AFC score as a pertinent predictive score of postoperative mortality after colorectal surgery. Because it is based on only 4 risk factors, the AFC score can be used in daily practice.

Evaluation of efficacy of liver transplantation in alcoholic cirrhosis by a case-control study and simulated controls.

To assess the efficacy of liver transplantation in patients with alcoholic cirrhosis, we compared 2-year survival of 169 liver transplantation patients in 12 French centres with survival of two control groups treated conservatively. The matched group was 169 patients of similar age, cirrhosis severity, and bleeding history; the simulated group was 169 patients whose theoretical survival was determined in a cohort of 797 patients with alcoholic cirrhosis. The probability of survival to 2 years in transplanted patients was 73 (95% confidence interval 67-79%) versus 67% (59-75) in the matched and 67% (63-71) in simulated controls. When prognostic factors were taken into account, transplantation was associated with survival (r = 0.527; p = 0.069). Patients with severe liver disease (high-risk group) benefited most for 2-year survival: 64% (42-86) vs 41% (23-59) in the matched and 23% (19-27) in the simulated control groups (p < 0.01). There was no difference for patients at low and at medium risk. Liver transplantation increases the 2-year survival of patients with severe alcoholic cirrhosis. In patients with less severe disease, further studies should be done by non-randomised controlled studies with longer follow-up or by randomised trials.

Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes

The mRNA expression profile in control and clofibric acid (CLO)-treated mouse, rat, and human hepatocytes was analyzed using species-specific oligonucleotide DNA microarrays (Affymetrix). A statistical empirical Bayes procedure was applied in order to select the significantly differentially expressed genes. Treatment with the peroxisome proliferator CLO induced up-regulation of genes involved in peroxisome proliferation and in cell proliferation as well as down-regulation of genes involved in apoptosis in hepatocytes of rodent but not of human origin. CLO treatment induced up-regulation of microsomal cytochrome P450 4a genes in rodent hepatocytes and in two of six human hepatocyte cultures. In addition, genes encoding phenobarbital-inducible cytochrome P450s were also up-regulated by CLO in rodent and human hepatocyte cultures. Up-regulation of phenobarbital-inducible UDP-glucuronosyl-transferase genes by CLO was observed in both rat and human but not in mouse hepatocytes. CLO treatment induced up-regulation of L-fatty acid binding protein (L-FABP) gene in hepatocytes of both rodent and human origin. However, while genes of the cytosolic, microsomal, and mitochondrial pathways involved in fatty acid transport and metabolism were up-regulated by CLO in both rodent and human hepatocyte cultures, genes of the peroxisomal pathway of lipid metabolism were up-regulated in rodents only. An up-regulation of hepatocyte nuclear factor 1alpha (HNF1alpha) by CLO was observed only in human hepatocyte cultures, suggesting that this trans-activating factor may play a key role in the regulation of fatty acid metabolism in human liver as well as in the nonresponsiveness of human liver to CLO-induced regulation of cell proliferation and apoptosis.