Abstract: HYPOTHESIS: Laparoscopic pancreatic resection can safely duplicate all of the open pancreatic procedures. DESIGN: A prospective evaluation of laparoscopic pancreatic resection. Surgical procedure, postoperative course, and follow-up data were collected. SETTING: Department of Abdominal Surgery at Haut-Lévêque Hospital, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. PATIENTS: Sixty patients with presumed pancreatic neoplasms. Final diagnoses were benign disease in 57 patients (95%) and malignant pancreatic disease in 3 patients (5%). MAIN OUTCOME MEASURES: Complication and success rates of resections. RESULTS: Twenty percent of procedures were switched to open laparotomy. Laparoscopically successful procedures included 20 distal pancreatectomies with spleen preservation, 5 distal splenopancreatectomies, 16 enucleations, 5 medial pancreatectomies, 1 pancreatoduodenectomy, and 1 total pancreatectomy. Postoperative death occurred in 1 patient (1.6%). The overall postoperative complication rate was 36%, including a 13% rate of clinical fistulae. In successful laparoscopic operations, the mean (SD) postoperative hospital stay was 12.7 (6) days. Multivariate, stepwise analysis identified pancreatic consistency and pancreatic resection that required anastomosis as independent factors of postoperative complication (P = .02 and P = .002, respectively). The 3 patients operated on for pancreatic malignancies were still alive at follow-up (median, 23 months); all patients with benign disease were alive at long-term follow-up. CONCLUSIONS: This series demonstrates that laparoscopic pancreatic resection is not only feasible but also safe. Our study suggests that the best indications for a laparoscopic approach are presumably benign pancreatic tumors not requiring pancreaticoenteric reconstruction.

Abstract: Hepatitis C virus-positive serum (HCVser, genotypes 1a to 3a) or HCV cell culture (JFH1/HCVcc) infection of primary normal human hepatocytes was assessed by measuring intracellular HCV RNA strands. Anti-CD81 antibodies and siRNA-CD81 silencing markedly inhibited (>90%) HCVser infection irrespective of HCV genotype, viral load, or liver donor, while hCD81-large intracellular loop (LEL) had no effect. However, JFH1/HCVcc infection of hepatocytes was modestly inhibited (40 to 60%) by both hCD81-LEL and anti-CD81 antibodies. In conclusion, CD81 is involved in HCVser infection of human hepatocytes, and comparative studies of HCVser versus JFH1/HCVcc infection of human hepatocytes and Huh-7.5 cells revealed that the cell-virion combination is determinant of the entry process.

Abstract: BACKGROUND/AIMS: The direct implication of low-density lipoprotein receptor (LDLR) in hepatitis C virus (HCV) infection of human hepatocyte has not been demonstrated. Normal primary human hepatocytes infected by serum HCV were used to document this point. METHODS: Expression and activity of LDLR were assessed by RT-PCR and LDL entry, in the absence or presence of squalestatin or 25-hydroxycholesterol that up- or down-regulates LDLR expression, respectively. Infection was performed in the absence or presence of LDL, HDL, recombinant soluble LDLR peptides encompassing full-length (r-shLDLR4-292) or truncated (r-shLDLR4-166) LDL-binding domain, monoclonal antibodies against r-shLDLR4-292, squalestatin or 25-hydroxycholesterol. Intracellular amounts of replicative and genomic HCV RNA strands used as end point of infection were assessed by RT-PCR. RESULTS: r-shLDLR4-292, antibodies against r-shLDLR4-292 and LDL inhibited viral RNA accumulation, irrespective of genotype, viral load or liver donor. Inhibition was greatest when r-shLDLR4-292 was present at the time of inoculation and gradually decreased as the delay between inoculation and r-shLDLR4-292 treatment increased. In hepatocytes pre-treated with squalestatin or 25-hydroxycholesterol before infection, viral RNA accumulation increased or decreased in parallel with LDLR mRNA expression and LDL entry. CONCLUSIONS: LDLR is involved at an early stage in infection of normal human hepatocytes by serum-derived HCV virions.

Abstract: Perturbations to the Wnt signaling pathway have been implicated in a large proportion of human hepatocellular carcinomas (HCCs). Activating beta-catenin mutations and loss of function mutations in Axin1 are thought to be functionally equivalent. We examined the Wnt pathway in HCC by comparing the expression of beta-catenin target genes and the level of beta-catenin-dependent transcriptional activation, in 45 HCC tumors and four cell lines. Among these samples, beta-catenin and AXIN1 were mutated in 20 and seven cases, respectively. We found a significant correlation between activated beta-catenin mutations and overexpression of mRNA for the target genes glutamine synthetase (GS), G-protein-coupled receptor (GPR)49 and glutamate transporter (GLT)-1 (P=0.0001), but not for the genes ornithine aminotransferase, LECT2, c-myc and cyclin D1. We also showed that GS is a good immunohistochemical marker of beta-catenin activation in HCC. However, we observed no induction of GS, GPR49 or GLT-1 in the five inactivated Axin1 tumors. Beta-catenin-dependent transcriptional activation in two Axin1-mutated HCC cell lines was much weaker than in beta-catenin-mutated cell lines. Our results strongly suggest that in HCC, contrary to expectation, the loss of function of Axin1 is not equivalent to the gain of function of beta-catenin. Our results also suggest that the tumor suppressor function of Axin1 in HCC may be related to another, non-Wnt pathway.

Abstract:

Abstract: BACKGROUND: In recent years, advances in laparoscopic techniques have allowed surgeons to treat pancreatic lesions laparoscopically. Insulinoma, the most prevalent pancreatic endocrine tumor, is mostly benign and curable with surgical resection. This study aimed to assess the results from laparoscopic resection (LG) of insulinomas and to compare them with the results from open surgery (OG). METHODS: From September 1999 to December 2005, 56 laparoscopic pancreatic resections were performed for selected patients, including 12 laparoscopic resections of insulinomas. The results were compared with those of patients who underwent open resection of insulinomas selected from the authors' pancreatic database. RESULTS: Three conversions to the open approach were required because of inability to identify the tumor. There were no deaths in either group, and the morbidity rates were 25% (3/12) for LG and 55% (5/9) for OG (nonsignificant difference). The pancreatic fistula rate after laparoscopic enucleation was statistically lower than after open enucleation (14% vs 100%; p = 0.015). The mean postoperative hospital stay was 13 +/- 5.9 days for LG and 17.6 +/- 7.5 days for OG (nonsignificant difference). After exclusion of the patients who underwent conversion to laparotomy, the mean postoperative hospital stay was 11.5 +/- 5.8 days for LG and 17.6 +/- 7.5 days for OG (p = 0.04). CONCLUSION: This study demonstrates the feasibility and safety of laparoscopic resection of insulinomas. The laparoscopic approach was associated with a decrease in hospital stay and pancreatic fistula after enucleation. Preoperative localization tests and laparoscopic ultrasonography seem necessary to prevent conversion.

Abstract: BACKGROUND: Medial pancreatectomy is an alternative technique for benign or low-grade malignant tumors of the neck of the pancreas. We describe our experience of laparoscopic central pancreatectomy. METHODS: We conducted a prospective evaluation of laparoscopic pancreatic resection in the Department of Abdominal Surgery at Haut-Lévêque Hospital, CHU Bordeaux. From January 1999 until February 2006, 397 patients underwent pancreatic resection for pancreatic lesions, of whom 60 (15%) were enrolled for laparoscopic pancreatic resection. Of the 60 patients, 6 underwent laparoscopic central pancreatectomy. Surgical procedure, postoperative course, and follow-up data were collected. RESULTS: Laparoscopic central pancreatectomy was successful in all patients. In 1 case, we had to perform a laparotomy to find the specimen, which had been lost in the cavity during the anastomosis. The median operative time was 225 minutes (range, 180 to 365 minutes). None of the patients required blood transfusion in the perioperative period, and there was no mortality. Symptomatic pancreatic fistula occurred in 2 patients (33%). None of the patients required reoperation or radiologic drainage. Oral feeding was resumed in a median of 11 days (range, 9 to 21 days). The median postoperative hospital stay was 18 days (range, 15 to 25 days). At a median follow-up of 15 months (range, 4 to 34 months), all patients were alive without exocrine or endocrine insufficiency. CONCLUSIONS: Laparoscopic central pancreatectomy is feasible and safe. Laparoscopic central pancreatectomy may become the standard approach for resection of benign or low-grade malignant tumors of the neck of the pancreas if performed by highly skilled surgeons.

Abstract: BACKGROUND: Repeat liver resection because of recurrent colorectal liver metastases can provide survival benefit with a low rate of complications. DESIGN: Retrospective study. PARTICIPANTS: Forty patients who underwent a second hepatectomy because of liver metastases from colorectal cancer. MAIN OUTCOME MEASURES: Short- and long-term results of a second hepatectomy and determination of prognostic factors. RESULTS: The postoperative mortality rate was 2.5%. The postoperative morbidity rate was not significantly different after a second hepatectomy compared with single hepatectomy (42.5% and 27.5%, respectively; P = .10). Transfusion requirement and hospital stay were comparable for both a single and a second hepatectomy. Three- and 5-year overall survival rates were 55% and 31%, respectively. Disease-free survival rates at 3 and 5 years were, respectively, 49% and 27%. The interval between first and second hepatectomies and the presence of extrahepatic disease were independently related to survival (multivariate analysis). CONCLUSIONS: A second liver resection because of recurrent liver metastases from colorectal cancer is safe and provides a survival benefit similar to that with single hepatectomy. Our analysis suggests that the benefit of treatment is limited in patients who undergo a second hepatectomy within 1 year of the first operation and in those with extrahepatic disease.

Abstract: Activation and proliferation of human liver progenitor cells has been observed during acute and chronic liver diseases. Our goal was to investigate the presence of these putative progenitors in the liver of patients who underwent lobectomy for various reasons but did not show any hepatic insufficiency. Hepatic lesions were evaluated by histological analysis. Nonparenchymal epithelial (NPE) cells were isolated from samples of human liver resections located at a distance from the lesion that motivated the operation and were cultured and characterized. These cells exhibited a marked proliferative potential. They did not express the classic set of stem cell/progenitor markers (Oct-4, Rex-1, alpha-fetoprotein, CD90, c-kit, and CD34) and were faintly positive for albumin. When cultured at confluence in the presence of hepatocyte growth factor and either epidermal growth factor or fibroblast growth factor-4, they entered a differentiation process toward hepatocytes. Their phenotype was quantitatively compared with that of mature human hepatocytes in primary culture. Differentiated NPE cells expressed albumin; alpha1-antitrypsin; fibrinogen; hepatobiliary markers such as cytokeratins 7, 19, and 8/18; liver-enriched transcription factors; and genes characterized by either a fetal (cytochrome P4503A7 and glutathione S-transferase pi) or a mature (tyrosine aminotransferase, tryptophan 2,3-dioxygenase, glutathione S-transferase alpha, and cytochrome P4503A4) expression pattern. NPE cells could be isolated from the liver of several patients, irrespective of the absence or presence of lesions, and differentiated toward hepatocyte-like cells with an intermediate hepatobiliary and mature/immature phenotype. These cells are likely to represent a resident progenitor population of the adult human liver, even in the absence of hepatic failure. Disclosure of potential conflicts of interest is found at the end of this article.

Abstract: Hepatocellular adenomas (HCA) with activated beta-catenin present a high risk of malignant transformation. To permit robust routine diagnosis to allow for HCA subtype classification, we searched new useful markers. We analyzed the expression of candidate genes by quantitative reverse transcription polymerase chain reaction QRT-PCR followed by immunohistochemistry to validate their specificity and sensitivity according to hepatocyte nuclear factor 1 alpha (HNF1alpha) and beta-catenin mutations as well as inflammatory phenotype. Quantitative RT-PCR showed that FABP1 (liver fatty acid binding protein) and UGT2B7 were downregulated in HNF1alpha-inactivated HCA (P <or= 0.0002); GLUL (glutamine synthetase) and GPR49 overexpression were associated with beta-catenin-activating mutations (P <or= 0.0005), and SAA2 (serum amyloid A2) and CRP (C-reactive protein) were upregulated in inflammatory HCA (P = 0.0001). Immunohistochemistry validation confirmed that the absence of liver-fatty acid binding protein (L-FABP) expression rightly indicated HNF1alpha mutation (100% sensitivity and specificity), the combination of glutamine synthetase overexpression and nuclear beta-catenin staining were excellent predictors of beta-catenin-activating mutation (85% sensitivity, 100% specificity), and SAA hepatocytic staining was ideal to classify inflammatory HCA (91% sensitivity and specificity). Finally, a series of 93 HCA was unambiguously classified using our 4 validated immunohistochemical markers. Importantly, new associations were revealed for inflammatory HCA defined by SAA staining with frequent hemorrhages (P = 0.003), telangiectatic phenotype (P < 0.001), high body mass index, and alcohol intake (P <or= 0.04). Previously described associations were confirmed and in particular the significant association between beta-catenin-activated HCA and hepatocellular carcinomas (HCC) at diagnosis or during follow-up (P < 10(-5)). CONCLUSION: We refined HCA classification and its phenotypic correlations, providing a routine test to classify hepatocellular adenomas using simple and robust immunohistochemistry.

Abstract: Cross-talk between nuclear receptors involved in the control of drug metabolism is being increasingly recognised as a source of drug side effects. Omeprazole is a well known activator of the aryl hydrocarbon receptor (AhR). We investigated the regulation of AhR by omeprazole-sulphide, a degradation metabolite of omeprazole, using CYP1A mRNA induction, reporter gene assay, receptor DNA binding, ligand binding, nuclear translocation, trypsin digests, and drug metabolism analysis in mouse Hepa-1c1c7, human HepG2 cells and primary human hepatocytes. Omeprazole-sulphide is a pure antagonist of AhR in Hepa-1c1c7 and HepG2 hepatoma cell lines. In Hepa-1c1c7 cells, omeprazole-sulphide is a ligand of AhR, inhibits AhR activation to a DNA-binding form, induces a specific pattern of AhR trypsin digestion and inhibits AhR nuclear translocation and subsequent degradation in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, in highly differentiated primary human hepatocytes treated with rifampicin an agonist of the pregnane X receptor (PXR), omeprazole-sulphide behaves as an agonist of AhR. Inhibition of drug metabolizing enzymes by ketoconazole restores the antagonist effect of omeprazole-sulphide. Metabolic LC/MS analysis reveals that omeprazole-sulphide (AhR antagonist) is efficiently converted to omeprazole (AhR activator) by cytochrome P450 CYP3A4, a target gene of PXR, in primary human hepatocytes but not in hepatoma cells in which PXR is not expressed. This report provides the first evidence for a cross-talk between PXR/CYP3A4 and AhR. In addition, it clearly shows that conclusions drawn from experiments carried out in cell lines may lead to erroneous in vivo predictions in man.

Abstract: OBJECTIVES: The aim of this study was to evaluate the possibility of subsequent resection of locally advanced pancreatic adenocarcinoma after chemotherapy and external-beam radiotherapy. PATIENTS AND METHODS: Between January 1996 and January 2001, 33 consecutive patients (18 males and 15 women, mean age 63 years) with locally advanced PA were treated with chemotherapy and concurrent external-beam radiotherapy. Radiotherapy delivered 45-50.4 Gy, in a classical manner (N=27) or on a split-course (N=6). Chemotherapy was made of 5FU by continuous infusion for all patients during 5 weeks and cisplatin at the 1st and 5th weeks (N=22). Tumor resectability was reassessed at the end of the chemoradiotherapy; surgical resection of tumour was attempted in patients whose tumor demonstrated reduction in size, and supplementary radiotherapy of 10 to 15 Gy was delivered to the others. RESULTS: Thirty-nine percent of patients experienced grade 3 acute toxicity. WHO criteria response to chemoradiotherapy four weeks after the end of treatment were: 4 partial responders (12%), 6 minor responders (18%), 14 stable disease (42%), 9 progression (28%). Ten patients underwent exploratory laparotomy, in one case vascular encasement did not allow for tumor resection, and in another patient, there was peritoneal carcinomatosis. In the 8 remaining patients, surgical (R0) resection was possible. In one patient histological examination showed fibrosis with no residual tumour. After a median follow-up period of 40 months, median survival was 16 months (66% and 37% of survival at 1 and 2 years respectively). In operated and non-operated patients, survival rates at 24 months were 73% and 12.5% respectively. At 1 year, 80% of the patients treated with radiochemotherapy developed recurrence, metastatic recurrence in 88%. Initial laparotomy, split course radiotherapy were poor outcome factors whereas chemotherapy appears to be a favorable outcome factor. CONCLUSION: Subsequent resection of locally advanced pancreatic adenocarcinoma is possible after chemoradiotherapy allowing for a prolonged survival in some patients.

Abstract: AIM: This retrospective study aims at analyzing the functional results obtained in patients operated by laparoscopy for a para-esophageal hernia. PATIENTS AND METHODS: From 1994 to 2004, 38 patients underwent a laparoscopic procedure for a symptomatic para-esophageal hiatal hernia of at least 3/4 of the proximal stomach: 27 females and 11 males, mean age 65 years (extreme: 22-84). There was no case on emergency, 4 patients had have at least one episode of intrathoracic volvulus. The operation consisted in gastric reduction into the abdominal cavity, excision of the sac, suture of the crura reinforced with a mesh in 6 patients and the construction of a gastric wrap. A postoperative barium swallow was performed on POD 3 in order to confirm the anatomical result. RESULTS: Mean operating time was 157 minutes (75-480), no case was converted into laparotomy. Four postoperative complications were observed (morbidity 10.8%): one gastric perforation diagnosed on POD 1, 2 severe dysphagias linked to the wrap, and one atelectasia. There was no death in this series. Functional results were evaluated by the mean of a questionnaire in 33 patients who had a follow up more than 6 months. Thirty-three questionnaires have been sent, 3 patients were lost and one was dead. Among the 29 patients analyzed, 14 were very satisfied, 11 were satisfied and 3 were deceived by the operation. Best results are obtained in patients with GERD, dysphagia or postprandial cardiothoracic symptoms. CONCLUSION: These results compared to the published data allow us to discuss about indications of surgery, the necessity to removal the hernia sac, and the advantages to reinforce the crura by the mean of a non absorbable mesh.

Abstract: BACKGROUND & AIMS: Telangiectatic focal nodular hyperplasia (TFNH) of the liver is generally believed to belong to the focal nodular hyperplasia (FNH) family. The aim of this study was to use molecular markers, in addition to morphologic features, to better characterize TFNH. METHODS: Thirteen patients with TFNH were compared with 28 patients with FNH and 17 patients with hepatocellular adenoma. Full clinical and morphologic data were analyzed. Molecular markers included determination of clonality by examining the active X chromosome, genome-wide allelotyping, a search for hepatocyte nuclear factor 1alpha (HNF1alpha) mutations, and determination of ANGPT1/ANGPT2 transcript levels. RESULTS: No clinical differences were evident between patients with TFNH and adenoma; in particular, bleeding was observed in 77% and 53% of the cases, respectively. Patients with TFNH were more likely to experience nodule recurrence and the presence of multiple nodules than those with either FNH or adenoma. All TFNH and adenoma samples that were available for analysis were monoclonal, in contrast to 40% of the FNH samples. Chromosome losses confirmed monoclonality and were significantly less frequent in TFNH and FNH (22% and 26%) than in adenoma (53%). HNF1alpha mutations were found exclusively in half of the adenomas. ANGPT2 was overexpressed in TFNH and down-regulated in adenoma (P < .01) and FNH (P < .0005). CONCLUSIONS: TFNHs are monoclonal lesions frequently subject to bleeding that are similar to adenomas not carrying HNF1alpha mutations and require a similar type of treatment. However, morphologic and molecular data support the hypothesis that TFNH is a separate entity.

Abstract: BACKGROUND: The aim of this study was to evaluate pancreatic exocrine and endocrine function after pancreaticoduodenectomy. STUDY DESIGN: Pancreatic exocrine function was evaluated by a questionnaire and medical examination of stools after discontinuing pancreatic enzyme supplements for at least 10 days. Severe steatorrhea was defined as frequent, nauseating, yellow, and pasty stools, fecal output >200 g/d for more than 3 days. Endocrine function was evaluated by blood glucose level. Association between severe steatorrhea and age, indication, histologic obstructive pancreatitis, pancreaticojejunal anastomosis (PJA), pancreaticogastric anastomosis (PGA), and morbidity was studied. RESULTS: Fifty-two patients underwent pancreaticoduodenectomy, complication rate was 33%. PJA was performed in 41 patients (79%) and PGA in 11 patients (21%). At a median followup of 75 months (24 to 156 months), 65% of the patients received pancreatic enzyme supplements. Severe steatorrhea was observed in 22 patients (42%). Incidence of postoperative diabetes was 14.6%. Patient age (more than 60 years), postoperative complication, and obstructive pancreatitis were not associated with postoperative severe steatorrhea. In cases of nonhistologic obstructive pancreatitis, PGA was more frequently associated with severe steatorrhea than PJA (70% versus 21.7%, p < 0.025). No factor significantly influenced incidence of postoperative diabetes. CONCLUSIONS: After pancreaticoduodenectomy, 42% of patients presented with severe steatorrhea. PJA allows better pancreatic exocrine function preservation than PGA and should be recommended.

Abstract: AIM OF THE STUDY: To report the results of transduodenal excision (TDE) for tumors of the ampulla of Vater. PATIENTS AND METHODS: From 1998 to 2003, 10 patients underwent a transduodenal excision for presumed benign tumors of the ampulla of Vater. After resection, frozen sections were performed to ensure negative margins. RESULTS: There was no operative mortality. A postoperative pancreatitis occurred in one patient. For nine patients the postoperative course was uneventful. The mean duration of hospital stay was 18 +/-11 days. The final pathology showed adenoma in 8 patients, an adenocarcinoma in one patient and inflammatory lesions in other one. With a mean follow-up of 20 months, endoscopy did not show any recurrence in patients with benign lesion. Patient with an invasive cancer developed recurrence. CONCLUSION: Transduodenal excision is safe and effective treatment for benign ampullary tumors. TDE should be the operation of choice for patients with histologically-proven benign ampulloma, staged as uT1 by endoscopic ultrasound. This approach could reduce the rate of pancreaticaduodenoctomy performed for benign ampullomas.

Abstract: BACKGROUND: The presence of a hypervascular nodule in a patient with cirrhosis is highly suggestive of a hepatocellular carcinoma. CASE PRESENTATION: A 55 year old man with idiopathic refractory anaemia was addressed for the cure of a recently appeared 3.3 cm hypervascular liver nodule. The nodule was not visible on the resected fresh specimen, but a paler zone was seen after formalin fixation. The surrounding liver was fibrotic (METAVIR score F3) and overloaded with iron. However, the paler zone, thought to be the nodule, had in fact a normal architecture, was less fibrotic, and contained some "portal tract-like structures" (but with arteries only); moreover, this paler area was devoid of iron, contained less glycogen and was characterized by foci of clear hepatocytes. CONCLUSION: In spite of the absence of architectural distortion, and a normal proliferative index, the possibility of premalignancy or malignancy should be considered in this type of hypervascular and hyposiderotic nodule, occurring in the context of an iron overloaded liver.

Abstract:

Abstract: BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in cirrhotic and noncirrhotic liver is increasing in the world, probably because of the high prevalence of infections by hepatitis B and C viruses. Despite numerous publications on hepatic resection, prognostic factors for intrahepatic recurrence and survival are not well known for patients with HCC without cirrhosis. STUDY DESIGN: One hundred eight consecutive patients with HCC in noncirrhotic liver have been treated by hepatic resection in the past 18 years in our center. Clinical, biologic, and histopathologic parameters of these patients were collected. Risk factors for intrahepatic recurrence and prognostic factors for survival were evaluated by univariate and multivariate analyses. RESULTS: Postoperative morbidity and mortality rates were 23% and 6.5%, respectively. The 3- and 5-year disease-free and overall survival rates were 55% and 43%, and 43% and 29%, respectively. Blood transfusion, absence of tumor capsule, and daughter nodules were independently associated with overall survival. But the only risk factors for recurrence were blood transfusion, absence of tumor capsule, daughter nodules, and margin resection < 10 mm. CONCLUSIONS: In the treatment of HCC without cirrhosis, hepatectomy remains a safe and legitimate treatment, but longterm results are impaired by a high rate of early recurrence likely related to metastatic dissemination. Only histopathologic factors related to the tumor are predictive of recurrence and overall survival.

Abstract: INTRODUCTION: Management of obstructed colonic carcinomas is a surgical challenge because it happens more often in elderly patients. The aim of our study is to assess mortality and morbidity rates of procedures performed in emergency for this pathology. PATIENTS AND METHOD: Between January 1st, 1998 and December 31st 2003, 22 patients underwent an emergency procedure for obstructive colonic obstruction due to an adenocarcinoma. Obstruction was defined as an emesis, distension on examination, no gas or stool since 24 hours and confirmatory plain radiograph film. RESULTS: Twenty patients (91%) underwent surgical procedure and two others received a colonic stent. Eleven patients (50%) underwent left colonic resection and intraoperative colonic cleansing was undertaken in 3 of these patients. One patient underwent a lateral colostomy, three patients (14%) underwent a right colectomy. A Hartmann's procedure was performed in six cases (27%). Morbidity occurred in 23% (50% were from anastomotic complication). Mortality rate was 27% (44% if aged more than 75 years old) (one superior mesenteric ischemia, and five heart and respiratory failures). Two-year survival rate was 61% and five year survival rate was 47%. Median survival was 24 months. CONCLUSION: Our study confirms that obstructed colonic cancer has a bad prognosis because it happens in elderly and not healthy patients. Priority must be given to the restoration of colonic permeability.

Abstract: BACKGROUND: The use of chemoradiotherapy for pancreatic cancer has been advocated for its potential ability to downstage locally advanced tumors. This article reports our experience with chemoradiotherapy for patients with unresectable, locally advanced pancreatic cancer (superior mesenteric artery or celiac axis encasement). STUDY DESIGN: Since 1998, 61 patients with radiographically unresectable, pathologically confirmed pancreatic adenocarcinoma have received standard fractionation radiation therapy (total dose, 45 Gy at 1.8 Gy, 5 d/wk) with chemotherapy, which included a continuous infusion of fluorouracil (5-FU: 650 mg/m(2)/D1-D5 and D21-D25) and cisplatin (80 mg/m(2)/bolus D2 and D22). Patients with tumor response at restaging CT scan underwent surgical exploration to determine whether the tumor was resectable. RESULTS: Thirty-eight of 61 (62%) restaged patients demonstrated a disease progression. Twenty-three patients (38%) had an objective response, with, in all cases, persistence of arterial encasement. Twenty-three patients underwent exploratory operations after chemoradiotherapy, and 13 underwent standard Whipple resection. So 13 of 23 (56%) patients who had exploratory operation, or 23 of 61 (21%) patients, underwent surgical resection. With a median followup of 27 months, median survival for the resected patients was 28 months. Median survival was 11 months in the nonresponder group (n = 38) and 20 months in the group who received a palliative procedure (n = 10). CONCLUSIONS: Locally advanced, unresectable pancreatic adenocarcinoma may be downstaged by chemoradiotherapy to allow for surgical resection. Patients whose cancer becomes resectable have a median survival at least comparable with survival after resection for initially resectable pancreatic adenocarcinoma.

Abstract: BACKGROUND: Laparoscopic gastric banding is the most common operation in Europe for morbid obesity. Many devices from different companies are now available. The aim of this study was to compare the results over a 2-year period of 2 types of band: the Lap-Band and the Minimizer band. METHODS: In a non-randomized study, 2 consecutive groups were prospectively analyzed. Group A consisted of 120 patients who received the Lap-Band, and group B consisted of 68 patients who received the Minimizer band which contains eyelets. All the bands were placed above the lesser sac by the perigastric approach. RESULTS: 4 early complications were observed in group A (1 phlebitis, 1 pneumopathy and 2 early displacements of the band); and 1 in group B (1 retention of urine). After a follow-up of 2 years, the displacement rate of the band was 10.8% in group A and 0% in group B. One gastric erosion was observed in group B, but not in group A. After 2 years, the average loss of excess weight was 50% in both groups. CONCLUSION: With the Minimizer band, we did not observe any slipping, and the efficacy with respect to weight loss was equivalent to the Lap-Band.

Abstract:

Abstract: BACKGROUND: Macroscopic hepatic lymph node involvement is usually a contraindication to hepatic resection. Only a few studies have investigated the impact of hepatic lymph node involvement on survival. The aim of this retrospective study was to assess microscopic hepatic lymph node involvement in resectable colorectal liver metastasis and outcomes in patients with such involvement. STUDY DESIGN: From January 1985 to December 2000, 156 patients underwent curative liver resection in association with systematic hepatic lymph node dissection for colorectal liver metastasis. A first analysis was performed to assess the association between hepatic lymph node metastasis and patients' characteristics. A second analysis assessed survival after resection of liver colorectal metastasis by using the Kaplan-Meier method. RESULTS: Twenty-three of the 156 patients (15%) had microscopically involved hepatic lymph nodes. No predictive factor of lymph node metastasis was identified. Multivariate analysis showed that lymph node metastasis, preoperative carcinoembryonic antigen level, number of metastases, and morbidity were factors influencing survival. The 3- and 5-year survival rates of patients with lymph node metastasis were 27% and 5%, respectively, compared with 56% and 43% without lymph node metastasis (p = 0.0001). CONCLUSIONS: During resection of liver colorectal metastasis, microscopic lymph node involvement occurred in 15% of the patients and was associated with a poor 5-year survival. Hepatic lymph node dissection should be performed systematically to select high-risk patients.

Abstract: BACKGROUND/AIMS: Combined hepatocellular-cholangiocarcinoma (HCC-CC) show dual hepatocellular and biliary epithelial differentiation. To better understand the relations between cholangiocarcinoma (CC), HCC-CC and hepatocellular carcinoma (HCC), we screened for genetic alterations. METHODS: A series of nine CC, 15 HCC-CC and three separated HCC and CC lesions ('collision tumors') were screened for loss of heterozygosity (LOH) using 400 microsatellite markers and for p53 and beta-catenin mutations. A comparison with a previously characterized series of 137 HCC was performed. RESULTS: In six cases of CC and HCC-CC, we identified TP53 gene mutations. A CTNNB1/beta-catenin was identified in two patients presenting collision tumors, but no mutations were found in CC or in HCC-CC. A high level of chromosome instability in both CC and HCC-CC was found. Recurrent specific LOH were identified at 3p and 14q in more than 50% of the CC and the HCC-CC cases, whereas these chromosomal regions were deleted in less than 10% of the HCC cases (P<10(-5)). Minimal common regions of deletion (MCRD) were defined at 3p24-p14 and 14q24-q32, respectively. CONCLUSIONS: These results suggest that combined HCC-CC are genetically closer to CC than HCC and common carcinogenesis pathways may be altered in HCC-CC and CC.

Abstract:

Abstract:

Abstract:

Abstract: BACKGROUND: Survival after resection of colorectal liver metastases may be influenced by the patient, the primary tumour and the liver metastases. Postoperative morbidity is associated with poor survival in several cancers. The aim of this retrospective study was to evaluate prognostic factors of survival after resection of colorectal liver metastases, including postoperative morbidity. METHODS: From 1985 to 2000, 311 consecutive patients with liver metastases from colorectal cancer underwent resection with curative intent. Univariate and multivariate analyses were performed to assess the influence of age, sex, site and stage of the colorectal tumour, disease-free interval, number, size and distribution of metastases, type of hepatectomy, pedicular clamping, resection margin, blood transfusion, postoperative morbidity and adjuvant chemotherapy on overall and disease-free survival. RESULTS: The postoperative mortality and morbidity rates were 3 and 30 per cent respectively. The 3- and 5-year overall survival rates were 53 and 36 per cent respectively. Both overall and disease-free survival rates were independently associated with nodal status of the colorectal tumour, number of metastases and postoperative morbidity. Patients with postoperative morbidity had an overall and disease-free 5-year survival rate half that of patients with no morbidity: 21 versus 42 per cent for overall survival (P < 0.001) and 12 versus 28 per cent for disease-free survival (P = 0.001) respectively. CONCLUSION: Long-term survival can be altered by postoperative morbidity after resection of colorectal liver metastases by increasing the risk of tumour recurrence. This justifies optimizing the surgical treatment of colorectal liver metastases to decrease postoperative morbidity and the use of efficient adjuvant treatments in patients with postoperative morbidity.

Abstract: OBJECTIVE: To evaluate results of laparoscopic pancreatectomy for benign lesions of the pancreas. Peri-operative data, surgical outcomes and techniques are presented. PATIENTS AND METHODS: Eighteen women and four men underwent laparoscopic pancreatectomy and were collected retrospectively from 1999 to 2003. RESULTS: Laparoscopic pancreatectomy was attempted in 22 patients and completed successfully in 18: 10 enucleations, three distal pancreatectomies, four left pancreatectomies and one total pancreatectomy for endocrine and cystic tumors. Left and distal pancreatectomies were performed with preservation of the spleen. Four patients were converted (one enucleation, one whipple procedure and two left pancreatectomy). There was no mortality; the post-operative morbidity included two pancreatic leaks and one case of half splenic infarction. The median length of hospital stay was 12 days. CONCLUSION: Patients appear to benefit from laparoscopic pancreatectomy for pancreatic benign tumors.

Abstract: SHP (small heterodimer partner, NR1I0) is an atypical orphan member of the nuclear receptor subfamily in that it lacks a DNA-binding domain. It is mostly expressed in the liver, where it binds to and inhibits the function of nuclear receptors. SHP is up-regulated by primary bile acids, through the activation of their receptor farnesoid X receptor, leading to the repression of cholesterol 7alpha-hydroxylase (CYP7alpha) expression, the rate-limiting enzyme in bile acid production from cholesterol. PXR (pregnane X receptor, NR1I2) is a broad-specificity sensor that recognizes a wide variety of synthetic drugs as well as endogenous compounds such as bile acid precursors. Upon activation, PXR induces CYP3A and inhibits CYP7alpha, suggesting that PXR can act on both bile acid synthesis and elimination. Indeed, CYP7alpha and CYP3A are involved in biochemical pathways leading to cholesterol conversion into primary bile acids, whereas CYP3A is also involved in the detoxification of toxic secondary bile acid derivatives. Here, we show that PXR is a target for SHP. Using pull-down assays, we show that SHP interacts with both murine and human PXR in a ligand-dependent manner. From transient transfection assays, SHP is shown to be a potent repressor of PXR transactivation. Furthermore, we report that chenodeoxycholic acid and cholic acid, two farnesoid X receptor ligands, induce up-regulation of SHP and provoke a repression of PXR-mediated CYP3A induction in human hepatocytes as well as in vivo in mice. These results reveal an elaborate regulatory cascade, tightly controlled by SHP, for both the maintenance of bile acid production and detoxification in the liver.

Abstract: BACKGROUND: The feasibility of laparoscopic rectal resection in patients with mid or low rectal cancer was studied prospectively with regard to quality of mesorectal excision, autonomic pelvic nerve preservation and anal sphincter preservation. METHODS: Laparoscopic rectal excision was performed in 32 patients (21 men) with rectal carcinoma located 5 cm from the anal verge. Most patients had T3 disease and received preoperative radiotherapy. The surgical procedure was performed 6 weeks after radiotherapy and included total mesorectal excision, intersphincteric resection, transanal coloanal anastomosis with coloplasty and loop ileostomy. RESULTS: Three patients needed conversion to a laparotomy. Postoperative morbidity occurred in ten patients, related mainly to coloplasty. Macroscopic evaluation showed an intact mesorectal excision in 29 of 32 excised specimens; microscopically, 30 of the 32 resections were R0. Sphincter preservation was achieved in 31 patients. The hypogastric nerves and pelvic plexuses were identified and preserved in 24 of the 32 patients. Sexual function was preserved in ten of 18 evaluable men. CONCLUSION: A laparoscopic approach can be considered in most patients with mid or low rectal cancer.

Abstract:

Abstract: BACKGROUND/AIMS: The antitumor efficiency of thymidine kinase (tk) in Herpes Simplex virus-tk-based gene therapy of rat hepatocellular carcinoma (HCC) was examined by specific transcriptional targeting of tk to tumor cells by the alpha-fetoprotein (AFP) gene promoter and by multiple infusions of recombinant adenovirus Ad.AFPtk.METHODS: We developed a surgical procedure that allows efficient, non-invasive delivery (during 2 months) of recombinant Ad via the intra-hepatic artery (IHA) route.RESULTS: Treatment of tumor-bearing rats with either three or five doses of 5x10(9)pfu Ad.AFPtk, administered every 3 days, and followed by intra-peritoneal treatment with ganciclovir (GCV), resulted in tumor growth inhibition and apoptosis, when compared to untreated tumor-bearing rats or animals treated with Ad.AFPlacZ or buffered saline. No treatment-related toxicity was noted. Antitumor efficacy, based on tumor size and number of tumors, was demonstrated in more than 50% of Ad.AFPtk+GCV-treated rats, as compared to control rats (P<0.0005).CONCLUSIONS: Our results demonstrate the safety and potential of multiple Ad.AFPtk administrations by the IHA route to inhibit HCC tumor growth, and support further clinical investigation of Ad.AFPtk gene therapy for treatment of multifocal tumor lesions in most primary liver cancers.

Abstract: The aim of this study was to assess the effect of vascular occlusion on radio-frequency (RF) lesion size and on potential associated biliary and portal lesions. Radio-frequency lesions using a 1-cm exposed-tip cooled electrode were created in pig liver. Liver perfusion was modified by arterial embolization (n=2), left portal clamping (n=2), and both (n=2). Two pigs were used as controls. Two weeks after, control portography was performed, animals were killed, and ex-vivo cholangiography was carried out. Pathological studies evaluated the lesion surface and associated portal and biliary damages. A mathematical regression model showed that portal occlusion increased by 43 mm2 (+40%) the surface of RF lesions, arterial occlusion by 135 mm2 (+126%), and associated occlusion by 466 mm2 (+435%). Biliary stenoses were found in 4 cases (two arterial occlusions, one portal occlusion, and one associated occlusion). One case of partial portal vein thrombosis was found in one case of portal occlusion and resolved at 2 weeks. Ischemic damages adjacent to RF lesions were found in cases of combined occlusions. The reduction of liver perfusion increases significantly the size of RF lesions but is associated with a risk of biliary, portal, or parenchymal complications.

Abstract: Liver metastasis represents the major cause of death of patients who have been treated for colorectal adenocarcinoma. Spontaneous survival rarely exceeds two years. Surgery can offer long-term survival and resection should be considered when liver metastases can be totally resected with clear margins and when there is no non-resectable extra-hepatic disease. The choice between anatomical or wedge resection depends on the number and the location of the metastases but does not influence survival. Clamping methods limit blood loss. Operative mortality is generally less than 5%. The five-year survival rate after surgical resection varies from 20% to 45% according to several prognostic factors. The longer survival is observed in patients with fewer than four lesions, with lesions smaller than 4 cm, without extra-hepatic disease, with lesions that appeared more than two years after the resection of a stage I or II colorectal cancer and whose CEA level is normal. After resection, follow-up can detect hepatic recurrence that can be treated with repeat hepatectomy. The efficacy of systemic chemotherapy using new agents can increase the number of patients amenable to surgery. Regional therapies with cryotherapy or radiofrequency ablation can help to treat unresectable or non-totally resectable lesions and may improve survival. The effects on survival of adjuvant treatments, including pre- or postoperative systemic or postoperative intra-arterial chemotherapy, are currently under evaluation.

Abstract: STUDY AIM: In the treatment of adenocarcinoma of the cardia and lower oesophagus, the choice of the approach (with or without thoracotomy) to perform a proximal oesogastrectomy (POG) is still debated. The aim of this retrospective study was to compare mortality, morbidity and long-term survival in a series of patients operated on with or without thoracotomy. PATIENTS AND METHOD: From January 1991 to June 1997, 59 patients (mean ages: 65 +/- 10 years, range: 30-83) underwent POG through a transthoracic (n = 31) or a transhiatal approach (n = 28). All patients underwent both coeliac and left gastric lymphadenectomy. A mediastinal subaortic lymphadenectomy was only performed in patients who had a transthoracic approach. Both groups were comparable concerning age, weight and height, and tumoral staging according to preoperative imaging and pathologic examination. The transhiatal group included more high-risk patients (respiratory insufficiency, ASA score = 3) (NS). RESULTS: Resection was palliative in four patients in the transthoracic group and two patients in the transhiatal group. Operative mortality was 9% in the transthoracic group and 0% in the transhiatal group (NS). Pulmonary complications were as frequent with and without thoracotomy (35% versus 32% respectively). Global (curative and palliative resections) 3-year actuarial survival was similar in both groups (transthoracic: 39% versus transhiatal: 46%, NS), as well as survival after curative resection (44% versus 49% respectively, NS). The operative approach did not influence survival in patients N+ (22% versus 17% respectively, NS) and in patients N- (86% versus 77% respectively, NS). CONCLUSION: These results suggest that, for adenocarcinoma of the cardia and lower oesophagus, the theoretical carcinologic benefit of mediastinal lymphadenectomy can be balanced with an higher operative risk related to the transthoracic approach.

Abstract: Transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene followed by the administration of ganciclovir (GCV) into hepatocellular carcinoma (HCC)-derived cell lines either in vitro or transplanted into nude mice has been shown to provide a potential strategy for HSV-tk-based gene therapy of HCC. We report herein an analysis of the antitumoral efficacy of two recombinant adenoviruses (Ads), Ad.CMVtk and Ad.AFPtk, in a relevant model of multifocal hepatic lesions induced in rats by a potent alkylating chemical carcinogen, diethylnitrosamine. Two routes of administration of the Ad were studied: intratumoral and intrahepatic artery injections. Both recombinant Ads, Ad.CMVtk and Ad.AFPtk, express the HSV-tk gene under the control of the early enhancer/promoter cytomegalovirus and alpha-fetoprotein regulatory gene sequences, respectively. The antitumor response was assessed by magnetic resonance imaging and by autopsy and histological analysis following postmortem. Tumor growth cessation was demonstrated by magnetic resonance imaging in large tumor nodules of size 5-8 mm treated by intratumoral administration of 2x10(9) pfu Ad.CMVtk plus i.p. treatment with GCV. We also show an antitumor efficacy in small tumor nodules of size <3 mm treated with 2x10(9) pfu Ad.CMVtk plus GCV by the intrahepatic artery route, albeit associated with an adverse toxicity. In vivo targeting of the HSV-tk gene to diethylnitrosamine-induced HCC cells with the recombinant Ad.AFPtk suppresses the hepatic toxicity in the nontumoral liver. The lower antitumor response would argue for the use of multiple injections of such adenoviral constructs. These observations may lead to potential approaches for designing gene therapy destined for early treatment of dysplastic nodules or advanced HCC in cirrhosis.