Abstract: OBJECTIVE: To summarize the current world position on laparoscopic liver surgery. SUMMARY BACKGROUND DATA: Multiple series have reported on the safety and efficacy of laparoscopic liver surgery. Small and medium sized procedures have become commonplace in many centers, while major laparoscopic liver resections have been performed with efficacy and safety equaling open surgery in highly specialized centers. Although the field has begun to expand rapidly, no consensus meeting has been convened to discuss the evolving field of laparoscopic liver surgery. METHODS: On November 7 to 8, 2008, 45 experts in hepatobiliary surgery were invited to participate in a consensus conference convened in Louisville, KY, US. In addition, over 300 attendees were present from 5 continents. The conference was divided into sessions, with 2 moderators assigned to each, so as to stimulate discussion and highlight controversies. The format of the meeting varied from formal presentation of experiential data to expert opinion debates. Written and video records of the presentations were produced. Specific areas of discussion included indications for surgery, patient selection, surgical techniques, complications, patient safety, and surgeon training. RESULTS: The consensus conference used the terms pure laparoscopy, hand-assisted laparoscopy, and the hybrid technique to define laparoscopic liver procedures. Currently acceptable indications for laparoscopic liver resection are patients with solitary lesions, 5 cm or less, located in liver segments 2 to 6. The laparoscopic approach to left lateral sectionectomy should be considered standard practice. Although all types of liver resection can be performed laparoscopically, major liver resections (eg, right or left hepatectomies) should be reserved for experienced surgeons facile with more advanced laparoscopic hepatic resections. Conversion should be performed for difficult resections requiring extended operating times, and for patient safety, and should be considered prudent surgical practice rather than failure. In emergent situations, efforts should be made to control bleeding before converting to a formal open approach. Utilization of a hand assist or hybrid technique may be faster, safer, and more efficacious. Indications for surgery for benign hepatic lesions should not be widened simply because the surgery can be done laparoscopically. Although data presented on colorectal metastases did not reveal an adverse effect of the laparoscopic approach on oncological outcomes in terms of margins or survival, adequacy of margins and ability to detect occult lesions are concerns. The pure laparoscopic technique of left lateral sectionectomy was used for adult to child donation while the hybrid approach has been the only one reported to date in the case of adult to adult right lobe donation. Laparoscopic liver surgery has not been tested by controlled trials for efficacy or safety. A prospective randomized trial appears to be logistically prohibitive; however, an international registry should be initiated to document the role and safety of laparoscopic liver resection. CONCLUSIONS: Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery. National and international societies, as well as governing boards, should become involved in the goal of establishing training standards and credentialing, to ensure consistent standards and clinical outcomes.
Abstract: BACKGROUND: Primary intrahepatic bile duct dilatation (IHBD) may present as a localized form in which resection of the affected liver can prevent immediate and late complications. Laparoscopy has gained large interest in liver surgery. It also allows a safe and efficient exploration of the common bile duct. METHODS: We performed 10 laparoscopic liver resections for localized IHBD, on 7 women and 3 men (mean age 47 years). Resections were 2 right hepatectomies, 4 left hepatectomies, and 4 left lateral sectionectomies. Three patients had associated common bile duct stones that were treated through intraoperative cholangioscopy. RESULTS: The mean operative time was 303.9 minutes. The mean blood loss was 217 mL. None of these patients required hand assistance or conversion to open surgery. One patient suffered a residual collection that was drained percutaneously. The postoperative course was uneventful in the other patients. The mean hospital stay was 5.3 days. No recurrence of cholangitis was observed during the follow-up period. CONCLUSIONS: The laparoscopic treatment of IHBD is safe and should be performed by teams with expertise in both hepatobiliary surgery and laparoscopy.
Abstract: BACKGROUND: Laparoscopic major resections remain a challenge for liver surgeons. This video illustrates, step by step, our laparoscopic technique for left hepatectomy. METHODS: The control of vascular inflow and outflow as well as the division of the left hepatic duct were carried out extraparenchymally before liver transection. Between 2002 and 2008, 11 left hepatectomies were performed by laparoscopy: 7 for liver tumor and 4 for localized Caroli's disease. RESULTS: Mean duration of surgery was 248 +/- 25 min. Mean operative blood loss was 129 +/- 42 ml. Intraoperative blood transfusion or conversion to laparotomy were never required. One postoperative biliary collection occurred and was drained percutaneously. None of the patients died. Mean hospital stay was 7.6 +/- 2.2 days. CONCLUSIONS: This technique has proved to be safe and easily reproducible.
Abstract: Transplantation of hepatocytes, whether genetically modified or not, has become an alternative to orthotopic liver transplantation for the treatment of patients with metabolic disease. However, more than ten years after the first clinical trial of ex vivo gene therapy to treat patients with Familial Hypercholesterolemia, there are still a number of impediments to these approaches. Numerous animal models are still being developed on the one hand to improve hepatocyte integration within hepatic parenchyma and function, and on the other hand to develop vectors that drive long-term transgene expression in situ. These include large animal models such as non-human primates, which have recently led to significant progress in hepatocyte transplantation. Simultaneous development of lentiviral vectors from different lentivirus species has permitted the transfer of genes into mitotically-quiescent primary cells including differentiated hepatocytes. Particularly third generation vectors derived from HIV-1 lentivirus are the most widely used and have significantly improved the safety and efficiency of these vectors. Given the shortage of organs and problems related to immunosuppression on one hand, and recent progresses in hepatocyte transduction and transplantation on the other hand, ex vivo approach is becoming a real alternative to allogeneic hepatocyte transplantation. We review the present progresses and limits of the ex vivo liver gene therapy approach in different animal models, emphasizing clinically relevant procedures.
Abstract: BACKGROUND: The safety of laparoscopic major liver resections is still uncertain. The aim of this study was to compare our results for laparoscopic right hepatectomy (LRH) with those for open right hepatectomy (ORH). METHODS: Patients undergoing LRH were compared with retrospectively selected patients from our ORH database. The 2 groups were well matched for sex, age, American Society of Anesthesiologists score, body mass index, liver disease, and tumor size. Surgical and postsurgical outcomes were compared. RESULTS: Seventy-two patients were analyzed: 22 in the LRH group and 50 in the ORH group. Operating time was similar. Blood loss was significantly less in laparoscopic resections (P = .038). Specific morbidity rates were not different, general morbidity was lower after laparoscopy (P = .04), and the severity of postsurgical complications was not different. Mean hospital stay was significantly shorter after laparoscopy (P = .009). COMMENTS: Laparoscopy improved surgical and postsurgical outcomes for ORH in selected patients. This is the first comparative study to demonstrate an advantage of laparoscopy for a major liver resection. Prospective randomized studies with a greater number of cases are needed to confirm the role of laparoscopy in major liver resections.
Abstract: The feasibility of ex vivo gene therapy as an alternative to liver transplantation for the treatment of liver metabolic diseases needs to be analyzed in large animal models. This approach requires appropriate gene transfer vectors and effective hepatocyte engraftment. Lentiviral vectors have the ability to transduce nondividing differentiated cells, such as hepatocytes, and portal vein occlusion increases hepatocyte engraftment. We investigated whether reversible portal vein embolization combined with ex vivo lentivirus-mediated gene transfer is an effective approach for successful hepatocyte engraftment in nonhuman primates and whether the transgene remains expressed in the long term in transplanted hepatocytes in situ. Simian hepatocytes were isolated after left lobe resection, and the left and right anterior portal branches of animals were embolized with absorbable material. Isolated hepatocytes were labeled with Hoechst dye or transduced in suspension with lentiviruses expressing green fluorescent protein under the control of the human apolipoprotein A-II promoter and transplanted via the inferior mesenteric vein. The whole procedure was well tolerated. The embolized liver was revascularized within 2 weeks. The volume of nonembolized liver increased from 38.7% +/- 0.8% before embolization to 55.9% +/- 1% after embolization and hepatocytes significantly proliferated (10.5% +/- 0.4% on day 3 after embolization). Liver repopulation after transplantation with Hoechst-labeled hepatocytes was 7.4% +/- 1.2%. Liver repopulation was 2.1% +/- 0.2% with transduced hepatocytes, a proportion similar to that obtained with Hoechst-labeled cells, given that the mean transduction efficacy of simian hepatocyte population was 34%. Transgene expression persisted at 16 weeks after transplantation. Conclusion: We have developed a new approach to improve hepatocyte engraftment and to express a transgene in the long term in nonhuman primates. This strategy could be suitable for clinical applications.
Abstract: More than 30 years after the first hepatocyte transplant to treat the Gunn rat, the animal model for Crigler-Najjar syndrome, there are still a number of impediments to hepatocyte transplantation. Numerous animal models are still used in work aimed at improving hepatocyte engraftment and/or long-term function. Although other cell sources, particularly hepatic and extrahepatic stem cells, are being explored, adult hepatocytes remain the cells of choice for the treatment of liver diseases by cell therapy. In recent years, diverse approaches have been developed in various animal models to enhance hepatocyte transduction and amplification in vitro and cell engraftment and functionality in vivo. They have led to significant progress in hepatocyte transplantation for the treatment of patients with metabolic diseases and for bridging patients with acute injury until their own livers regenerate. This review presents and considers the results of this work with a special emphasis on procedures that might be clinically applicable.
Abstract: No detailed description of nonhuman primate liver anatomy has been reported and little is known about the similarity between such livers and human liver. The cynomolgus monkey (Macaca fascicularis) was used to establish a preclinical model of genetically modified hepatocytes auto transplantation. Here, we report information gleaned from careful observation and notes obtained from 59 female cynomolgus monkeys undergoing 44 anatomical hepatic resections, 12 main portal vein division dissections and selective branch ligations, and 46 portographies. Additionally, three anatomical liver dissections after total resection at autopsy were performed and served to confirm peroperative observations and for photography to provide illustrations. Our results indicate that the cynomolgus monkey liver has four lobes: the median (the largest), the right and left lateral, and the caudate lobes. In 60% (N=20) of individuals the portal bifurcates into right and left portal veins, in the remaining 40% (N=14) the portal vein trifurcates into right anterior, right posterior, and left portal veins. The anatomy and branching pattern of the hepatic artery and bile ducts closely follow those of the portal branches. Functionally, the cynomolgus monkey liver can be divided into eight independent segments. Thus, we report the first detailed description of the hepatic and portal surgical anatomy of the cynomolgus monkey. The cynomolgus monkey liver is more similar to the human liver than are livers of any small or large nonprimate mammals that have been described.
Abstract: OBJECTIVE: To analyze the results of 6 international surgical centers performing laparoscopic major liver resections. SUMMARY BACKGROUND DATA: The safety and feasibility of laparoscopy for minor liver resections has been previously demonstrated. Major anatomic liver resections, initially considered to be unsuitable for laparoscopy, are increasingly reported by several centers worldwide. METHODS: Prospective databases of 3 European, 2 U.S., and 1 Australian centers were combined. Between 1997 and 2008, 210 major liver resections were performed: 136 right and 74 left hepatectomies. Results and differences in surgical techniques between the 6 centers are outlined. RESULTS: Surgical duration was 250 minutes (range: 90-655 minutes). Operative blood loss was 300 mL (range: 20-2500 mL). Thirty patients (14.3%) received blood transfusion. Conversion to open surgery was required in 26 patients (12.4%). Portal triad clamping was performed in 24 patients (11.4%). Median tumor size was 5.4 cm (range: 1-25 cm) and surgical margin was 10.5 mm (range: 0-70 mm). Two patients died during the postoperative period from pulmonary embolism and urosepsis. Liver-specific and general complications occurred in 17 (8.1%) and 29 patients (13.8%), respectively. Hospital length of stay was 6 days (range: 1-34 days). A further analysis of early (n = 90) and late (n = 120) experience showed improved surgical and postoperative results in the latter group. CONCLUSIONS: This multicenter study demonstrates that laparoscopic major liver resections are feasible in selected patients and results improve with experience. However, proficiency in both open liver surgery and advanced laparoscopy is compulsory and surgeons must begin with minor laparoscopic resections.
Abstract: Major liver resections remain a challenge for liver surgeons. This video illustrates, step by step, a totally laparoscopic technique for left hepatectomy with intraoperative exploration of the remaining biliary tree in a patient with unilateral hepatolithiasis.
Abstract: INTRODUCTION: Laparoscopic right hepatectomy remains a challenge for liver surgeons. This video illustrates, step by step, a standardized technique for laparoscopic right hepatectomy with selective vascular exclusion. METHODS: The main steps of this totally laparoscopic technique are: extraparenchymal control of vascular inflow, extraparenchymal division of the right hepatic duct, complete mobilization of the right liver, control and division of the right hepatic vein, and parenchymal transection. RESULTS: The duration of surgery was 280 min, and the blood loss was 100 ml. The postoperative period was uneventful, and the length of stay was 7 days. CONCLUSION: This technique has been proven to be safe and easily reproducible in hands of surgeons with expertise in both liver and laparoscopic surgery.
Abstract: BACKGROUND: Only a few series have demonstrated the safety of laparoscopic resection for hepatocellular carcinoma (HCC) and the benefits of this approach. Moreover, these studies reported mostly minor and nonanatomic hepatic resections. This report describes the results of a pair-matched comparative study between open and laparoscopic liver resections for HCC in a series of essentially anatomic resections. METHODS: Patients were retrospectively matched in pairs for the following criteria: sex, age, American Society of Anesthesiology (ASA) score, severity of liver disease, tumor size, and type of resection. A total of 42 patients undergoing laparoscopy were compared with patients undergoing laparotomy during the same period. Surgeons from the authors' department not trained in laparoscopy performed open resections. Operative, postoperative, and oncologic outcomes were compared. RESULTS: The mean duration of surgery was similar in the two groups. Significantly less bleeding was observed in the laparoscopic group (364.3 vs. 723.7 ml; p < 0.0001). Transfusion was required for four patients (9.5%) in the laparoscopic group and seven patients (16.7%) in the open surgery group (p = 0.51). Postoperative ascites was less frequent after laparoscopic resections (7.1 vs. 26.1%; p = 0.03). General morbidity was similar in the two groups (9.5 vs. 11.9%; p = 1.00). The mean hospital stay was significantly shorter for the patients undergoing laparoscopy (6.7 vs. 9.6 days; p < 0.0001). The surgical margin and local recurrence adjacent to the liver stump were not affected by laparoscopy. The overall postoperative survival rates in the laparoscopic group were 93.1% at 1 year, 74.4% at 3 years, and 59.5% at 5 years and, respectively, 81.8, 73, and 47.4% in the open surgery group (p = 0.25). The postoperative disease-free survival rates in the laparoscopic group were at 81.6% at 1 year, 60.9% at 3 years, and 45.6% at 5 years, respectively, 70.2, 54.3, and 37.2% in the open surgery group (p = 0.29). CONCLUSIONS: Laparoscopic resection of HCC for selected patients gave a better postoperative outcome without oncologic consequences. Prospective trials are required to confirm these results.
Abstract: OBJECTIVE: To evaluate a multicenter, international series on minimally invasive liver resection for colorectal carcinoma (CRC) metastasis. SUMMARY BACKGROUND DATA: Multiple single series have been reported on laparoscopic liver resection for CRC metastasis. We report the first collaborative multicenter, international series to evaluate the safety, feasibility, and oncologic integrity of laparoscopic liver resection for CRC metastasis. METHODS: We retrospectively reviewed all patients who underwent minimally invasive liver resection for CRC metastasis from February 2000 to September 2008 from multiple medical centers from the United States and Europe. The multicenter series of patients were accumulated into a single database. Patient demographics, preoperative, operative, and postoperative characteristics were analyzed. Actuarial overall survival was calculated with Kaplan-Meier analysis. RESULTS: A total of 109 patients underwent minimally invasive liver resection for CRC metastasis. The median age was 63 years (range, 32-88 years) with 51% females. The most common sites of primary colon cancer were sigmoid/rectum (51%), right colon (25%), and left colon (13%). Synchronous liver lesions were present in 11% of patients. For those with metachronous lesions liver lesions, the median time interval from primary colon cancer surgery to liver metastasectomy was 12 months. Preoperative chemotherapy was administered in 68% of cases prior to liver resection. The majority of patients underwent prior abdominal operations (95%). Minimally invasive approaches included totally laparoscopic (56%) and hand-assisted laparoscopic (41%), the latter of which was employed more frequently in the US medical centers (85%) compared with European centers (13%) (P = 0.001). There were 4 conversions to open surgery (3.7%), all due to bleeding. Extents of resection include wedge/segmentectomy (34%), left lateral sectionectomy (27%), right hepatectomy (28%), left hepatectomy (9%), extended right hepatectomy (0.9%), and caudate lobectomy (0.9%). Major liver resections (> or =3 segments) were performed in 45% of patients. Median OR time was 234 minutes (range, 60-555 minutes) and blood loss was 200 mL (range, 20-2500 mL) with 10% receiving a blood transfusion. There were no reported perioperative deaths and a 12% complication rate. Median length of hospital stay for the entire series was 4 days (range, 1-22 days) with a shorter stay in medical centers in the United States (3 days) versus that seen in Europe (6 days) (P = 0.001). Negative margins were achieved in 94.4% of patients. Actuarial overall survivals at 1-, 3-, and 5-year for the entire series were 88%, 69%, and 50%, respectively. Disease-free survivals at 1-, 3-, and 5-year were 65%, 43%, and 43%, respectively. CONCLUSIONS: Minimally invasive liver resection for colorectal metastasis is safe, feasible, and oncologically comparable to open liver resection for both minor and major liver resections, even with prior intra-abdominal operations, in selected patients and when performed by experienced surgeons.
Abstract: The poor hepatocyte engraftment efficiency and the low level of their expansion in the host liver are a major limitation to cell therapy for the treatment of life-threatening liver diseases. Many rodent models have shown that liver repopulation via transplanted hepatocytes occurs only when liver growth capacity is impaired for an extended period of time. However, these models are not transposable to the clinics and to date there is no safe method to achieve this result in a clinical setting.Therefore, it is necessary to define on large animal models strategies that provide to transplanted hepatocytes sufficient proliferation stimuli to induce their division and that could permit a direct extrapolation to humans. Such procedures should be transposable to patients. We have defined a protocol of liver partial portal branch embolisation and shown that it induces the proliferation of transplanted hepatocytes in non-human primates (Macaca mulatta). This animal model is also appropriate to evaluate the lentiviral-mediated ex vivo gene therapy approach, since simian hepatocytes are efficiently transduced by HIV-1-derived lentivirus vectors.
Abstract: BACKGROUND & AIMS: Hepatic lipid retention (steatosis) predisposes hepatitis. We investigated the mechanisms of lymphocyte homing to fatty liver and the role of lipopolysaccharide (LPS) in the onset of inflammation in ob/ob mice. METHODS: We decreased intestinal bacterial compounds by oral antibiotic treatment to test the role of endogenous LPS in liver inflammation. Adoptive transfer of lymphocytes was used to study the respective contributions of steatosis and lymphocytes to liver inflammation. We tested lymphocyte response to chemokines by in vitro chemotaxis assays in ob/ob, their lean controls, and "non-obese ob/ob" mice, generated by controlling caloric intake to distinguish between the effects of obesity and leptin deficiency. RESULTS: Antibiotic treatment decreased liver infiltration with CD4(+) T, CD8(+) T, natural killer (NK)T, B, and NK cells. Adoptive transfer of lymphocytes from ob/ob or control mice showed that (1) steatosis increased lymphocyte recruitment to the liver; (2) CD4(+) T, CD8(+) T, and B cells from ob/ob mice had a greater propensity to migrate specifically to the liver. This migration was enhanced by LPS. These results were also observed in a model of high-fat diet-induced obesity. CD4(+) T and B cells were hyperresponsive to CXCL12 and CXCL13, respectively. Weight normalization in "non-obese ob/ob" mice decreased liver inflammation, lymphocyte response to chemokines, and homing to the liver. CONCLUSIONS: Our study provides the first evidence that liver inflammation in mice with genetic or diet-induced obesity results from both steatosis and lymphocyte hyperresponsiveness to chemokines expressed in the liver. These abnormalities are reversible with weight normalization.
Abstract: BACKGROUND: Single, small hepatocarcinomas (HCC) are still an indication for partial liver resection in patients ineligible for transplantation. Anatomical resections are recommended for oncological reasons. The mini-invasive approach of laparoscopy should minimize hepatic and parietal injury, thereby decreasing the risk of liver failure and ascites. However, the oncological results of this approach and its presumed benefits remain undemonstrated. We evaluated the short- and midterm results of laparoscopic liver resections for HCC. METHODS: Between 1999 and 2006, we performed 32 laparoscopic liver resections for HCC. Mean tumor size was 3.8 +/- 2 cm and the mean age of the patients was 65 +/- 11 years. Twenty-two patients had cirrhosis (21 Child A and one Child C). Operative and postoperative results were analyzed, together with recurrence and survival rates. RESULTS: We carried out 13 unisegmentectomies, nine bisegmentectomies, one trisegmentectomy, two right hepatectomies, one left hepatectomy, and six atypical resections. The duration of the operation was 231 +/- 101 minutes. Conversion to laparotomy was required in three patients (9%), none in emergency situations. Mean blood loss was 461 ml, with five patients (15.6%) requiring blood transfusion. The mean surgical margin was 10.4 mm. One cirrhotic patient (Child C) underwent surgery for a partially ruptured tumor and died of liver failure. Two patients had ascites and no transient liver failure occurred in the other 19 cirrhotic patients. Mean hospital stay was 7.1 days. During a mean follow-up of 26 months, 10 patients (31%) presented recurrence within the liver. None of the patients had peritoneal carcinomatosis or trocar site recurrence. Three-year overall and disease-free survival rates were 71.9% and 54.5%, respectively. CONCLUSIONS: Laparoscopic liver resection for HCC is feasible and well tolerated. Midterm survival and recurrence rates are similar to those after laparotomy.
Abstract: The feasibility of in vitro mature mouse hepatocyte labeling with a novel iron oxide particle was assessed and the ability of 1.5-T magnetic resonance imaging (MRI) to track labeled mouse hepatocytes in syngenic recipient livers following intraportal cell transplantation was tested. Mouse hepatocytes were incubated with anionic iron oxide nanoparticles at various iron concentrations. Cell viability was assessed and iron oxide particle uptake quantified. Labeled hepatocytes were intraportally injected into 20 mice, while unlabeled hepatocytes were injected into two mice. Liver T2 values, spleen-to-muscle relative signal intensity (RI( spleen/muscle )), and liver-to-muscle relative signal intensity (RI( liver/muscle )) on gradient-echo T2-weighted imaging after injection of either labeled or unlabeled hepatocytes were compared with an ANOVA test followed by Fisher's a posteriori PLSD test. Livers, spleens and lungs were collected for histological analysis. Iron oxide particle uptake was saturable with a maximum iron content of 20 pg per cell and without viability alteration after 3 days of culture. Following labeled-cell transplantation, recipient livers showed well-defined nodular foci of low signal intensity on MRI--consistent with clusters of labeled hepatocytes on pathological analysis--combined with a significant decrease in both liver T2 values and liver-to-muscle RI( liver/muscle ) (P = 0.01) with minimal T2 values demonstrated 8 days after transplantation. Conventional MRI can demonstrate the presence of transplanted iron-labeled mature hepatocytes in mouse liver.
Abstract: BACKGROUND/AIMS: Permanent portal vein embolization (PVE) is a widely practised technique. The use of an absorbable material would be safer in clinical situations in which the embolized liver is not resected. We evaluated the efficiency of reversible PVE in terms of liver regeneration and analyzed the precise time course of portal recanalization. METHODS: Nine monkeys underwent PVE of the left and right anterior portal branches using powdered absorbable material. Repeated portograms were carried out until complete revascularization of the embolized liver. Hepatocyte proliferation rates were assessed by BrdU incorporation. Liver segment volumes were determined by CT scans performed before embolization, then 1 month and 1 year after embolization. RESULTS: Reversible PVE induced significant hepatocyte proliferation in the non-embolized segments (13.5+/-1.0%, 10.5+/-0.8% and 9.1+/-2.0% of cells on days 3, 5 and 7, respectively). One month after the embolization, the non-embolized liver volume had increased from 38.4+/-1.3% to 54.8+/-0.5% of total liver volume. Proximal and complete revascularization occurred 6-8 and 12-16 days, respectively. CONCLUSIONS: Reversible PVE efficiently induces liver regeneration. The use of absorbable material avoids long-term liver scarring. Such material may be suitable for several clinical indications, including cell transplantation.
Abstract: OBJECTIVES: The purpose of this work was to evaluate the feasibility and outcome of elective laparoscopic cholecystectomy as a day-case procedure in a French university hospital. METHODS: Since the creation of a surgical day-care centre in 1999, patients without severe chronic disease and anticoagulant therapy were selected for elective laparoscopic cholecystectomy. They were admitted and operated on in the morning hours and discharged after a double check by the surgeon and an anaesthetist 4 to 6 hours later. They were contacted by telephone the day subsequent to surgery and were seen in the outpatient unit 8 to 10 days after. RESULTS: Two hundred eleven laparoscopic cholecystectomies were performed in day-care surgery from January 1999 to December 2005. The proportion of day-case management increased during the six-year period from 32% to 53%. Eighteen percent of patients had an overnight admission. The overall complication rate was 1.8%. None of the patients had an emergency readmission. Incapacity duration went from 1 to 15 days. CONCLUSION: These results suggest that laparoscopic cholecystectomy can be routinely performed as a day-case procedure.
Abstract: BACKGROUND/AIMS: Certain prognostic factors affect the postoperative mortality and long-term survival of patients following hepatic resection for hepatocellular carcinoma (HCC) and may change the surgical strategy. METHODOLOGY: 209 consecutive patients underwent hepatic resection for HCC in our hospital. Seventy-three patients underwent major resection and 136 underwent minor resections. We looked for correlations between clinical, biological, surgical and pathological factors and postoperative mortality, disease-free survival and overall survival. RESULTS: The postoperative mortality rate was 7.7% (it fell to 0% in the last two years). The cumulative overall five-year survival rate was 27% and the overall disease-free survival rate was 7.3%. Multivariate analysis identified: (1) two independent prognostic factors for postoperative mortality: age and tumor size; (2) one risk factor for tumor recurrence: intraoperative blood transfusion, and (3) three independent prognostic factors for overall survival: infiltrative tumor type, surgical margin <10 mm and intraoperative blood transfusion. CONCLUSIONS: In addition to routine staging of the tumor, the preoperative evaluation of HCC patients should include tests to determine whether the tumor is infiltrative or expansive and whether it will be possible to obtain a surgical margin (>10 mm). This procedure should make it possible to propose an appropriate neoadjuvant treatment only to these patients. The prevention of intraoperative bleeding or blood transfusion should improve the disease-free and overall survival rates in HCC patients.
Abstract: BACKGROUND: Laparoscopy is slowly becoming an established technique for liver resection. This procedure still is limited to centers with experience in both hepatic and laparoscopic surgery. Preliminary reports include mainly minor resections for benign liver conditions and show some advantage in terms of postoperative recovery. The authors report their experience with laparoscopic liver resection, the evolution of the technique, and the results. METHODS: From 1999 to 2006, 70 laparoscopic liver resections were performed using a procedure similar to resection by laparotomy. RESULTS: There were 38 malignant tumors (54%) and 32 benign lesions (46%). The malignant tumors were mainly hepatocellular carcinomas (19 of 24 patients had cirrhosis). The tumor mean size was 3.8 +/- 1.9 cm (range, 2.2-8 cm). There were 19 major hepatectomies, 34 uni- or bisegmentomies, and 17 atypical resections. The operative time was 227 +/- 109 min. Conversion to laparotomy was required for seven patients (10%), mainly for continuous bleeding during transection. Nine patients (13%) required blood transfusion. One patient had both brisk bleeding and gas embolism from a tear in the section line of the right hepatic vein requiring laparoscopic suture. Blood loss and transfusion requirements were significantly lower in recent than in early cases and in resections with prior vascular control than in those without such control. Postoperative complications were experienced by 11 patients (16%), including one bleed from the hepatic stump requiring hemostasis and two subphrenic collections requiring percutaneous drainage. One cirrhotic patient died of liver failure after resection of a partially ruptured tumor. No ascites was observed in other cirrhotic patients. The mean hospital stay was 5.9 days. CONCLUSION: The study results confirm that laparoscopic liver resection, including major hepatectomies, can be safely performed by laparoscopy.
Abstract: OBJECTIVE: To evaluate the long-term results of aggressive treatment of HCC recurrence. METHODS: Two hundred and nine consecutive patients underwent hepatic resection for HCC in our hospital. Tumour recurrence was diagnosed in 97 (51%) of the 190 patients with curative resection. Sixteen underwent hepatic resection: two right hepatectomies, one three-segmentectomy, one left hepatectomy, five two-segmentectomies, six segmental resections and one subsegmentectomy. Two patients with metastasis in the spine were submitted to a vertebral body resection. Twenty-five patients were treated with percutaneous ethanol injection or intra-arterial chemoembolization. Fifty-four patients with a poor performance status and liver function or multiple extra hepatic recurrences did not receive any treatment. RESULTS: There were no operative deaths. The postoperative mortality rate was 5.5% (one patient). The cumulative overall survival after the second resection was respectively 89%, 46% and 31% at 1, 3 and 5 years. There was a significant difference in survival between patients treated with repeat resection and those submitted to a non-surgical or conservative treatment (p<0.0001). There were no differences in operative deaths, postoperative mortality and morbidity between the first and second hepatic resection. CONCLUSIONS: Aggressive management with combined resection or loco regional therapy for intrahepatic recurrence and resection of isolated extra-hepatic recurrence may offer long-term survival in selected patients. Second liver resection for recurrence of HCC can be safely performed.
Abstract: BACKGROUND/AIMS: Lentivirus-mediated ex vivo gene therapy is becoming a promising approach for the treatment of liver metabolic disorders. However, the feasibility of this approach needs to be studied in large animal models. The purpose of this study was to evaluate the efficacy of ex vivo gene transfer into Macaca hepatocytes with two different HIV-1 derived lentiviral vectors. METHODS: A self-inactivating lentivector was constructed to express GFP under the control of the hepatic apolipoprotein A-II promoter. Freshly isolated and thawed hepatocytes were transduced in suspension with lentiviral vectors expressing the GFP gene under the control of a ubiquitous promoter (EF1-alpha) and the apolipoprotein A-II promoter. Transduced thawed hepatocytes were transplanted into the spleen of newborn mice, and livers analyzed 4 and 12 weeks after transplantation. RESULTS: We show that lentivectors are efficient in transducing hepatocytes in suspension either freshly isolated or cryopreserved. We also show that thawed and transduced hepatocytes engrafted and participated in liver growth after transplantation into newborn mice and that the apolipoprotein A-II promoter is functional. CONCLUSIONS: Our data show that transplantation of transduced hepatocytes into monkeys should allow to evaluate the fate of transplanted cells and transgene expression in a pre-clinical model of ex vivo gene therapy.
Abstract: The authors report a case of choledocal cyst extended to left and right hepatic ducts. An heterogeneous intracystic fluid, partial calcification of cystic wall, a slight positivity of echinoccosis serology in a patient from a highly endemic country erroneously led to diagnosis of hydatid cyst invading the left hepatic duct. The diagnosis of choledocal cyst was done on the resection specimen after left hepatectomy. A small patch of cyst wall with terminations of both right sectorial hepatic ducts was used for cysto-jejunal Roux-en-Y loop anastomosis. Peculiarities of this type of choledocal cyst are discussed.
Abstract: BACKGROUND: Hepatocyte transplantation could be an alternative to whole liver transplantation for the treatment of metabolic liver diseases. However, the results of clinical investigations suggest that the number of engrafted hepatocytes was insufficient to correct metabolic disorders. This may partly result from a lack of proliferation of transplanted hepatocytes. In rodents, portal ligation enhances hepatocyte engraftment after transplantation. We investigated the effects of partial portal ligation and embolization on engraftment and proliferation of transplanted hepatocytes in primates. METHODS: Hepatocyte autotransplantation was performed in Macaca monkeys. The left lateral lobe was resected for hepatocyte isolation. The first group of monkeys underwent surgical ligation of the left and right anterior portal branches; in the second group, the same portal territories were obstructed by embolization with biological glue. To evaluate the proportion of cell engraftment hepatocytes were Hoechst-labeled and transplanted via the portal vein. Cell proliferation was measured by BrdU incorporation. RESULTS: Hepatocyte proliferation was induced by both procedures but it was significantly higher after partial portal embolization (23.5% and 11.2% of dividing hepatocytes on days 3 and 7) than after ligation (3% and 0.8%). Hepatocytes engrafted more efficiently after embolization than after ligation. They proliferated and participated to liver regeneration representing 10% of the liver mass on day seven and their number remained constant on day 15. CONCLUSIONS: These data suggest that partial portal embolization of the recipient liver improves engraftment of transplanted hepatocytes in a primate preclinical model providing a new strategy for hepatocyte transplantation.
Abstract: The role of surgery in cystic diseases of the liver and biliary tract depends upon the kind of cysts. When they are symptomatic, solitary cysts of the liver may require laparoscopic unroofing. Mucinous cystadenoma should be resected since there is a risk of cystadenocarcinoma. Polycystic liver disease may require surgery when massive hepatomegaly results in pain or a worsening of the patient's general condition. Laparoscopic fenestration and partial hepatectomy are only indicated in a small number of selected patients with large or localized cysts. Orthotopic liver transplantation may be recommended in symptomatic cases with massive hepatomegaly even if there is no renal failure and no need for renal transplantation. Caroli's syndrome localized in one lobe or one segment should be resected since it leads to cholangiocarcinoma in more than 10% of cases. When cystic dilatations are diffuse, liver transplantation may be required. Choledochal cysts should be completely resected since cancer may arise in non resected parts. Complete resection may be associated with major hepatectomy.
Abstract: AIMS: To assess the results of laparoscopic liver resection for hepatocellular carcinoma. PATIENTS AND METHODS: From 1998 to 2003, 12 laparoscopic liver resections for hepatocellular carcinoma were performed. RESULTS: There were no operative complications and no deaths. Conversion to laparotomy was required in one patient (8%) and transfusion in three patients (25%). One patient died of liver failure. Postoperative complications occurred in three patients (25%): trocar site bleeding, cardiac failure and biliary collection. The mean hospital stay was 5 days. No ascites and no transient liver failure occurred. During the mean follow up of 15 months the recurrence rate was 45.5%. No port site or peritoneal metastases were observed. Treatment of recurrence was second resection in two patients and microwave coagulation therapy in two other patients. Mean survival was 24 months. CONCLUSION: Laparoscopic liver resection is feasible in hepatocellular carcinoma if the tumor is unique, smaller than 5 centimeters and located in the left lateral segments or in the anterior or inferior segments of the right liver. Postoperative morbidity is low and long-term results seem to be similar to laparotomy.
Abstract: PURPOSE: Despite the growing clinical use of active robotic camera holders there is still a lack of clinical feasibility studies. PATIENTS AND METHODS: We compared the use of a voice controlled robotic camera holder (AESOP 3000, Computer Motion, Goleta, California) to a human camera holder in a series of laparoscopic cholecystectomies and colectomies. Compliance with AESOP, abnormal operative events or complications, operative time, and the duration of hospitalization were prospectively recorded and compared to data recorded before the introduction of the robotic system. RESULTS: Compliance with AESOP was good. There were no abnormal operative events, no differences in operative time, complications, or the mean duration of hospitalization between the patients operated with a robotic or a human camera holder. CONCLUSION: The use of a robotic camera holder does not alter the length of the operative procedure, the duration of hospitalization, or postoperative morbidity. It is a safe and feasible approach to laparoscopic cholecystectomy or colectomy.
Abstract: Engineered retroviruses are widely used vectors for cancer gene therapy approaches. However, the ability to target cells of therapeutic interest while controlling the expression of the transferred genes would improve both the efficiency and the safety of viral vectors. In this study, we investigated the ability of a retroviral amphotropic envelope displaying single-chain variable-fragment (scFv) directed against the c-Met receptor, to target the entry of recombinant retroviruses to human hepatocarcinoma cells. Four single-chain antibody fragments directed against the c-Met receptor were generated and inserted into the viral envelope protein as an N-terminal fusion. The modified envelopes were incorporated into virus particles and one of the chimeric viruses, 3D6-Env, transduced preferentially human hepatoma cells rather than proliferating human hepatocytes. In another construct, the urokinase cleavage site was inserted between the scFv moiety and the envelope. Chimeric scFv-urokinase-Env viruses transduced hepatoma cells with a similar efficiency to that of the control virus and their infectivity in human hepatocytes remained low. These results indicate that amphotropic retroviruses with engineered envelopes to display scFv directed against the c-Met receptor can efficiently and selectively deliver genes into hepatoma cells.
Abstract: OBJECTIVE: To report the case of a 42-year-old patient referred for exploration of a tumor of the right flank and evidence of inflammation. MATERIAL: and methods. Ultrasonography and computed tomography showed a liver mass associated with a heterogeneous adnexal mass. Serum CA-125 was elevated and ovarian cancer with liver metastasis was suspected. An alternative diagnosis was salpingitis complicated by Fitz-Hugh-Curtis syndrome in this patient wearing an intra-uterine contraceptive device. RESULTS: Exploratory laparoscopy was performed and confirmed the diagnosis of salpingitis complicated by an ovarian abscess and Fitz-Hugh-Curtis syndrome with rare abscess formation. Outcome was favorable after adapted antibiotic treatment. CONCLUSION: Fitz-Hugh-Curtis syndrome can take on an atypical aspect and should be entertained as a possible diagnosis in young women presenting pain of the right flank and fever.
Abstract: BACKGROUND: Hospital managers are continually trying to decrease the cost of patient care. The aim of this prospective study was to propose changes that would decrease the operating room costs of laparoscopic cholecystectomy without affecting clinical results. METHODS: The study included 112 consecutive patients who underwent an elective cholecystectomy between January 1997 and December 2000. The procedure was changed in eight ways: the American position, open laparoscopy, reusable trocars, reusable instruments, bipolar coagulation of the cystic artery, intracorporeal ligature of the cystic duct, no use of suction lavage apparatus, and use of a surgical glove as a bag to extract the gallbladder. Complete compliance with the procedure, whether any abnormal operative events or complications occurred, the duration of hospitalization, and the material and labour costs of the procedure were recorded. RESULTS: There were no abnormal operative events. Only two patients suffered from postoperative complications. The mean duration of hospitalization was 55.8 h. Fifteen patients (13.4 per cent) were not hospitalized overnight. The operating costs fell from 560 euros before the study to 330 euros in 2000. CONCLUSION: By applying simple measures, it is possible to decrease the operating room cost of laparoscopic cholecystectomy whilst maintaining good results. Such measures should be applied to other laparoscopic procedures.
Abstract: Liver regeneration after partial hepatectomy results primarily from the simple division of mature hepatocytes. However, during embryonic and fetal development or in circumstances under which postnatal hepatocytes are injured, organ regeneration is believed to occur from a compartment of epithelial liver stem or progenitor cells with biliary and hepatocytic bipotentiality. The ability to identify, isolate, and transplant epithelial liver stem cells from fetal liver would greatly facilitate the treatment of hepatic diseases currently requiring orthotopic liver transplantation. Here we report the identification and immortalization by retrovirus-mediated transfer of the simian virus 40 large T antigen gene of primate fetal epithelial liver cells with a dual hepatocytic biliary phenotype. These cells grow indefinitely in vitro and express the liver epithelial cell markers cytokeratins 8/18, the hepatocyte-specific markers albumin and alpha-fetoprotein, and the biliary-specific markers cytokeratins 7 and 19. Bipotentiality of gene expression was confirmed by clonal analysis initiated from single cells. Endogenous telomerase also is expressed constitutively. After orthotopic transplantation via the portal vein, approximately 50% of the injected cells integrated into the liver parenchyma of athymic mice without tumorigenicity. Three weeks after transplantation, cells having seeded in the liver parenchyma expressed both albumin and alpha-fetoprotein but had lost expression of cytokeratin 19. These results provide strong evidence for the existence of a bipotent epithelial liver stem cell in nonhuman primates. This unlimited source of donor cells also should enable the establishment of a model of allogenic liver cell transplantation in a large animal closely related to humans and shed light on important questions related to liver organogenesis and differentiation.
Abstract: BACKGROUND & AIMS: Involvement of an abnormal von Willebrand factor in the bleeding expression of gastrointestinal angiodysplasias has been suggested but not assessed by prospective studies. METHODS: To address this issue, 27 patients with either nonbleeding (group A, n = 9) or bleeding (group B, n = 9) digestive angiodysplasias or telangiectasias or diverticular hemorrhage (group C, n = 9) were enrolled. In all patients, an analysis of von Willebrand factor and a screening for the most common disorders associated with an acquired von Willebrand disease were performed. RESULTS: In all patients from groups A and C, von Willebrand factor was normal, and no underlying disease could be found. In contrast, all but 1 patient from group B had a variable selective loss of the largest multimeric forms of von Willebrand factor, associated in 7 cases with a stenosis of the aortic valve. CONCLUSIONS: This study indicates that most patients with bleeding angiodysplasia or telangiectasia have a deficiency of the largest multimers of von Willebrand factor induced by a latent acquired von Willebrand disease. Because these multimers are the most effective in promoting primary hemostasis at the very high shear conditions related to these vascular malformations, we suggest that their deficiency is likely to contribute to the bleeding diathesis.
Abstract: BACKGROUND: The transplantation of isolated hepatocytes in large animals, including nonhuman primates, must be evaluated before clinical trials are performed. However, in the absence of large transgenic animals and large-animal (as opposed to small-animal) models of genetic deficiencies, it is difficult to evaluate the fate of transplanted hepatocytes, their localization, survival, and function within the parenchyma of the host liver. In this work, we aimed to develop a technique for delivering hepatocytes to the liver of a nonhuman primate and to evaluate their localization and functionality in the short term. METHODS: A 20% hepatectomy was performed in 34 cynomolgus monkeys (Macaca fascicularis) and hepatocytes were isolated. Hepatocytes were labeled in vitro with a recombinant retrovirus expressing the beta-galactosidase gene and returned to the liver by infusion through a portal catheter left in place. Liver biopsies were performed 4 and 7 d after transplantation. RESULTS: Twenty-four monkeys underwent surgery to define the necessary technical adjustments and to optimize conditions. Six monkeys died. The whole protocol, including the transplantation of genetically marked hepatocytes and procurement of liver biopsies, was performed in the remaining 10 monkeys. In eight monkeys, transplanted hepatocytes expressing the beta-galactosidase gene were widely distributed in the portal tracts, sinusoids, and hepatocyte plates of the host liver 4 and 7 d after transplantation. CONCLUSIONS: We have developed an experimental nonhuman primate model for the evaluation of hepatocyte transplantation. We demonstrated the engraftment and functioning of transplanted hepatocytes in the host liver 4 and 7 d after transplantation.
Abstract: We are developing cell therapy approaches on non-human primates as a preclinical model for the treatment of hepatic metabolic diseases. In foetuses, the tissues, including liver, are in expansion, which should facilitate hepatocytes engraftment, and the immune system becomes fully mature only after birth. We have set out conditions for isolation of fetal hepatocytes from macaca mulatta at the end of the 2nd trimester of gestation (90-100 days), their cryopreservation and retroviral transduction. Two different routes of administration of hepatocytes were evaluated: the umbilical vein which was deleterious for the foetuses, and the intraparenchymatous injection which was well tolerated by the animals. Administration of hepatocytes into the hepatic parenchyma resulted in microchimerism and allogenic cells were visualized 9 days after transplantation. Another approach has been to immortalize simian foetal hepatocytes using a retroviral vector expressing SV40 Large T flanked by lox sites. A cell line has been established for 2 years, which is not tumorigenic when injected subcutaneously into nude mice and display characteristics of bipotent hepatoblasts, precursors of hepatocytes and biliary cells. After orthotopic transplantation into nude mice via the portal vein, these cells expressed albumin until the sacrifice of the animals (17 days). The next steps will be to define conditions for transplantation of retrovirally transduced fetal primary and/or immortalized hepatocytes into young foetuses (60 days of gestation) and post-natally.
