Patrick Pessaux

EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81–claudin-1 co-receptor associations and viral glycoprotein–dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.

Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka.

OBJECTIVE This review aims to assess the impact of implementing dedicated emergency surgical services, in particular acute care surgery, on clinical outcomes. BACKGROUND The optimal model for delivering high-quality emergency surgical care remains unknown. Acute Care Surgery (ACS) is a health care model combining emergency general surgery, trauma, and critical care. It has been adopted across the United States in the management of surgical emergencies. METHOD A systematic review was performed after PRISMA recommendations using the MEDLINE, Embase, and Psych-Info databases. Studies assessing different care models and institutional factors affecting the delivery of emergency general surgery were included. RESULTS Twenty-seven studies comprising 744,238 patients were included in this review. In studies comparing ACS with traditional practice, mortality and morbidity were improved. Moreover, time to senior review, delays to operating theater, and financial expenditure were often reduced. The elements of ACS models varied but included senior clinicians present onsite during office hours and dedicated to emergency care while on-call. Referrals were made to specialist centers with primary surgical assessments taking place on surgical admissions units rather than in the emergency department. Twenty-four-hour access to dedicated emergency operating rooms was also described. CONCLUSIONS ACS models as well as centralized units and hospitals with dedicated emergency operating rooms, access to radiology and intensive care facilities (ITU) are all factors associated with improved clinical and financial outcomes in the delivery of emergency general surgery. There is, however, no consensus on the elements that constitute an ideal ACS model and how it can be implemented into current surgical practice.

External pancreatic duct stent decreases pancreatic fistula rate after pancreaticoduodenectomy: prospective multicenter randomized trial.

Objective: Pancreatic fistula (PF) is a leading cause of morbidity and mortality after pancreaticoduodenectomy (PD). The aim of this multicenter prospective randomized trial was to compare the results of PD with an external drainage stent versus no stent. Methods: Between 2006 and 2009, 158 patients who underwent PD were randomized intraoperatively to either receive an external stent inserted across the anastomosis to drain the pancreatic duct (n = 77) or no stent (n = 81). The criteria of inclusion were soft pancreas and a diameter of wirsung <3 mm. The primary study end point was PF rate defined as amylase-rich fluid (amylase concentration >3 times the upper limit of normal serum amylase level) collected from the peripancreatic drains after postoperative day 3. CT scan was routinely done on day 7. Results: The 2 groups were comparable concerning demographic data, underlying pathologies, presenting symptoms, presence of comorbid illness, and proportion of patients with preoperative biliary drainage. Mortality, morbidity, and PF rates were 3.8%, 51.8%, and 34.2%, respectively. Stented group had a significantly lower overall PF (26% vs. 42%; P = 0.034), morbidity (41.5% vs. 61.7%; P = 0.01), and delayed gastric emptying (7.8% vs. 27.2%; P = 0.001) rates compared with nonstented group. Radiologic or surgical intervention for PF was required in 9 patients in the stented group and 12 patients in the nonstented group. There were no significant differences in mortality rate (3.7% vs. 3.9%; P = 0.37) and in hospital stay (22 days vs. 26 days; P = 0.11). Conclusion: External drainage of pancreatic duct with a stent reduced. PF and overall morbidity rates after PD in high risk patients (soft pancreatic texture and a nondilated pancreatic duct). This study is registered at http://www.clinicaltrials.gov: Clinical trial ID# NCT01068886.

Monoclonal Anti-Claudin 1 Antibodies Prevent Hepatitis C Virus Infection of Primary Human Hepatocytes

BACKGROUND & AIMS Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The tight junction protein claudin-1 (CLDN1) has been shown to be required for entry of HCV into the cell. METHODS Using genetic immunization, we produced 6 monoclonal antibodies against the host entry factor CLDN1. The effects of antibodies on HCV infection were analyzed in human cell lines and primary human hepatocytes. RESULTS Competition and binding studies demonstrated that antibodies interacted with conformational epitopes of the first extracellular loop of CLDN1; binding of these antibodies required the motif W(30)-GLW(51)-C(54)-C(64) and residues in the N-terminal third of CLDN1. The monoclonal antibodies against CLDN1 efficiently inhibited infection by HCV of all major genotypes as well as highly variable HCV quasispecies isolated from individual patients. Furthermore, antibodies efficiently blocked cell entry of highly infectious escape variants of HCV that were resistant to neutralizing antibodies. CONCLUSIONS Monoclonal antibodies against the HCV entry factor CLDN1 might be used to prevent HCV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.

Stapled hemorrhoidopexy versus milligan-morgan hemorrhoidectomy : A prospective, randomized, multicenter trial with 2-year postoperative follow up

Purpose:The purpose of this study was to compare the outcome of stapled hemorrhoidopexy (SH group) performed using a circular stapler with that of the Milligan-Morgan technique (MM group). The goals of the study were to evaluate the efficacy and reproducibility of stapled hemorrhoidopexy and define its place among conventional techniques. Methods:A series of 134 patients were included at 7 hospital centers. They were randomized according to a single-masked design and stratified by center (with balancing every 4 patients). Patients were clinically evaluated preoperatively and at 6 weeks, 1 year, and a minimum of 2 years after treatment. Patients completed a questionnaire before and 1 year after surgery to evaluate symptoms, function, and overall satisfaction. Results:The mean follow-up period was 2.21 years ± 0.26 (1.89–3.07). Nine patients (7%) could not be monitored at 1 or 2 years, but 4 of these 9 nevertheless filled in the 1-year questionnaire. The patients in the SH group experienced less postoperative pain/discomfort as scored by pain during bowel movement (P < 0.001), total analgesic requirement over the first 3 days (according to the World Health Organization [WHO] class II analgesics [P = 0.002]; class III [P = 0.066]), and per-patient consumption frequency of class III analgesics (P = 0.089). A clear difference in morphine requirement became evident after 24 hours (P = 0.010). Hospital stay was significantly shorter in the SH group (SH 2.2 ± 1.2 [0; 5.0] versus MM 3.1 ± 1.7 [1; 8.0] P < 0.001). At 1 year, no differences in the resolution of symptoms were observed between the 2 groups, and over 2 years, the overall incidence of complications was the same, specifically fecaloma (P = 0.003) in the MM group and external hemorrhoidal thrombosis (P = 0.006) in the SH group. Impaired sphincter function was observed at 1 year with no significant difference between the groups for urgency (12%), continence problems (10%), or tenesmus (3%). No patient needed a second procedure for recurrence within 2 years, although partial residual prolapse was detected in 4 SH patients (7.5%) versus 1 MM patient (1.8%) (P = 0.194). Conclusion:Stapled hemorrhoidopexy causes significantly less postoperative pain. The technique is reproducible and can achieve comparable outcomes as those of the MM technique as long as the well-described steps of the technique are followed. Like with conventional surgery, anorectal dysfunction can occur after stapled hemorrhoidopexy in some patients. Its effectiveness in relieving symptoms is equivalent to conventional surgery, and the number of hemorrhoidal prolapse recurrences at 2 years is not significantly different. Hemorroidopexy is applicable for treating reducible hemorrhoidal prolapse.

PANCREATIC METASTASIS OF RENAL CELL CARCINOMA: PRESENTATION, TREATMENT AND SURVIVAL

PURPOSE The pancreas is an uncommon site of metastasis from renal cell carcinoma, comprising 2% of pancreatic tumors removed in sizable series of operations. To our knowledge the role of operative resection in the setting of metastatic malignancy to the periampullary region has not yet been defined. We reviewed the records of 6 women and 2 men who underwent pancreatic resection due to malignancy and analyzed various prognostic factors. MATERIALS AND METHODS Between 1985 and 1995, 269 patients underwent pancreatic resection for malignancy at our hospitals, including 150 (56%) for pancreatic duct cancer, 65 (24%) for carcinoma of the ampulla, 27 (10%) for distal bile duct cancer, 19 (7%) for duodenal carcinoma and 8 (3%) for renal cell carcinoma metastasis. We reviewed the records of these latter 8 cases, and analyzed demographics, primary tumor type, disease-free interval, resection type, concomitant other organ resection, histological examination of the specimen, morbidity, adjuvant therapy and survival. RESULTS Pancreatic metastasis of renal cell carcinoma was managed by duodenopancreatectomy in 5 patients and total pancreatectomy in 3. There were no perioperative deaths. Mean tumor size in cases of a solitary pancreatic metastasis was 4 cm. (range 1.5 to 8). In the 3 patients treated with total pancreatectomy there were 2, 5 and 3 pancreatic metastases, respectively. Pathological examination revealed negative lymph nodes in all cases. Mean survival was 48 months. At study end 6 patients were alive at 24, 26, 30, 46, 84 and 88 months, while 2 died at 13 and 70 months, respectively. CONCLUSIONS We advocate aggressive surgical resection when possible. Surgical removal of metastatic lesions prolongs survival but radical lymph node dissection is not mandatory. We also recommend careful long-term followup of patients with a history of renal cell carcinoma.

Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation

End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.

Laparoscopic cholecystectomy in acute cholecystitis

AbstractBackground: The aim of this prospective study was to compare the outcome of laparoscopic cholecystectomy (LC) in patients with acute cholecystitis versus those with chronic cholecystitis and to determine the optimal timing for LC in patients with acute cholecystitis. Methods: From January 1991 to July 1998, 796 patients (542 women and 254 men) underwent LC. In 132 patients (67 women and 65 men), acute cholecystitis was confirmed via histopathological examination. These patients were divided into two groups. Group 1 (n= 85) had an LC prior to 3 days after the onset of the symptoms of acute cholecystitis, and group 2 (n= 47) had an LC after 3 days. Results: There were no mortalities. The conversion rates were 38.6% in acute cholecystitis and 9.6% in chronic cholecystitis (p < 10−8). Length of surgery (150.3 min vs 107.8 min; p < 10−9), postoperative morbidity (15% vs 6.6%; p= 0.001), and postoperative length of stay (7.9 days vs 5 days; p < 10−9) were significantly different between LC for acute cholecystitis and elective LC. For acute cholecystitis, we found a statistical difference between the successful group and the conversion group in terms of length of surgery and postoperative stay. The conversion rates in patients operated on before and after 3 days following the onset of symptoms were 27% and 59.5%, respectively (p= 0.0002). There was no statistical difference between early and delayed surgery in terms of operative time and postoperative complications. However, total hospital stay was significantly shorter for group 1. Conclusions: LC for acute cholecystitis is a safe procedure with a shorter postoperative stay, lower morbidity, and less mortality than open surgery. LC should be carried out as soon as the diagnosis of acute cholecystitis is established and preferably before 3 days following the onset of symptoms. Early laparoscopic cholecystectomy can reduce both the conversion rate and the total hospital stay as medical and economic benefits.

Laparoscopic vs open colectomy for sigmoid diverticulitis: a prospective comparative study in the elderly.

AbstractBackground: The aim of this prospective comparative study was to assess the outcome of laparoscopic and open colectomy for sigmoid diverticulitis in patients aged ≥75 years. Methods: From January 1993 to December 1998, all patients 75 years of age and older undergoing an elective colectomy for sigmoid diverticulitis were included in the study. The patients were divided into the following two groups: group 1 (n= 22) consisted of patients who underwent a laparoscopic procedure; group 2 (n= 24) consisted of patients who underwent an open procedure. Results: In group 1, there were 12 women and 10 men with a mean age of 77.2 years (range, 75–82); in group 2, there were 14 women and 10 men with a mean age of 78 years (range, 76–84) (p= 0.37). There was no difference between the groups in ASA classification. The operative time was shorter in group 2 (136 vs 234 mins). The postoperative period during which parenteral analgesics were required (5.4 vs 8.2 days, p= 0.001), postoperative morbidity (18% vs 50%, p= 0.02), postoperative length of hospital stay (13.1 vs 20.2 days, p= 0.003), and the inpatient rehabilitation (6 vs 15 patients, p= 0.01) were significantly shorter for group 1 than for group 2. There were no perioperative deaths. The conversion rate was 9% in group 1. Conclusion: The data from the present study suggest that laparoscopic colectomy for sigmoid diverticulitis can be applied safely to older patients with fewer complication, less pain, shorter hospital stay, and a more rapid return to preoperative activity levels than that seen with open colorectal resection.

Utility of staging laparoscopy in subsets of biliary cancers Laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma

BackgroundThe aim of this study was to evaluate the utility of staging laparoscopy in patients with biliary cancers in the era of modern diagnostic imaging.MethodsFrom September 2002 through August 2004, 39 consecutive patients with potentially resectable cholangiocarcinoma underwent preoperative staging laparoscopy before laparotomy. Preoperative imaging included ultrasonography and triphasic computed tomography for all patients and magnetic resonance cholangiography in 35 patients (90%). Final pathological diagnosis included 20 hilar cholangiocarcinomas (HC), 11 intrahepatic cholangiocarcinomas (IHC), and eight gallbladder carcinomas (GBC).ResultsDuring laparoscopy, unresectable disease was found in 14/39 patients (36%). The main causes of unresectability were peritoneal carcinomatosis (11/14) and liver metastases (5/14). At laparotomy, nine patients (37%) were found to have advanced disease precluding resection. Vascular invasion and nodal metastases were the main causes of unresectability during laparotomy (eight out of nine). In detecting peritoneal metastases and liver metastases, laparoscopy had an accuracy of 92 and 71%, respectively. All patients with vascular or nodal involvement were missed by laparoscopy. For prediction of unresectability disease, the yield and accuracy of laparoscopy were highest for GBC (62% yield and 83% accuracy), followed by IHC (36% yield and 67% accuracy) and HC (25% yield and 45% accuracy)ConclusionStaging laparoscopy ensured that unnecessary laparotomy was not performed in 36% of patients with potentially resectable biliary carcinoma after extensive preoperative imaging. In patients with biliary carcinoma that appears resectable, staging laparoscopy allows detection of peritoneal and liver metastasis in one third of patients. Both vascular and lymph nodes invasions were not diagonsed by this procedure. Due to these limitations, laparoscopy is more useful in ruling out dissemination in GBC and IHC than in HC.