Hepatic Brucelloma Diagnosis and Long-Term Treatment, France.

We report a case of hepatic brucelloma in France. This diagnosis may be suspected in any patient who has a liver abscess after traveling to a brucellosis-endemic area. Brucella spp. may be detected by PCR in the liver tissue or suppuration. Abscess drainage and prolonged antimicrobial therapy help achieve healing.

Damage Control Surgery for Non-traumatic Abdominal Emergencies.

BACKGROUND: Damage control surgery (DCS) was a major paradigm change in the management of critically ill trauma patients and has gradually expanded in the general surgery arena, but data in this setting are still scarce. The study aim was to evaluate outcomes of DCS in patients with general surgery emergencies. METHODS: Between 2005 and 2015, 164 patients (104 men, age 66) underwent DCS for non-traumatic abdominal emergencies. The decision to perform DCS was triggered by the presence of at least one trauma DCS criterion: hypotension (<70 mmHg), hypothermia (<35 °C), acidosis (pH < 7.25), coagulopathy (INR ≥ 1.7) and massive (>5 RBC) transfusion. Statistical tests were performed to identify risk factors for operative mortality. Observed outcomes were compared to those predicted by commonly employed scores (APACHE II, POSSUM, P-POSSUM, SAPS II). RESULTS: DCS was performed for acute mesenteric ischemia (n = 68), peritonitis (n = 44), pancreatitis (n = 28), bleeding (n = 14) and other (n = 10). Abdominal compartment syndrome was associated in 52 patients (32%). Seventy-four (45%) patients died and 150 patients (91%) experienced complications. On multivariate analysis, age (p = 0.018) and INR ≥ 1.7 (p = 0.001) were independent predictors of mortality. Mortality was 24% (13/55), 48% (22/46) and 62% (39/63) in patients with one, two and ≥3 DCS criteria, respectively. Comparison of observed and score-predicted mortality suggested DCS use resulted in significant survival benefit of the whole cohort and of patients with pancreatitis and postoperative peritonitis. CONCLUSIONS: DCS can be lifesaving in critically ill patients with general surgery emergencies. Patients with peritonitis and acute pancreatitis are those who benefit most of the DCS approach.

Internal biliary stenting in liver transplantation.

PURPOSE: Internal biliary stenting (IBS) was reported to decrease biliary complications after liver transplantation (LT) but data in literature is scarce. The aim of the present study was to evaluate our experience with end-to-end choledoco-choledocostomy during liver transplantation with special focus on the influence of IBS on patient and biliary outcomes. METHODS: Between 2009 and 2013, 175 patients underwent deceased donor LT with end-to-end choledoco-choledocostomy and were included in the study. Supra-papillary silastic stent was inserted in 67 patients (38%) with small-size (< 5 mm) bile ducts (recipient or donor). Endoscopic retrograde cholangiopancreatography (ERCP) was scheduled for IBS removal, 6 months after LT. Operative outcomes and survival of patients who received internal stenting (IBS group) were compared with those of patients who did not (no-IBS group). Risk factors for biliary anastomotic complications were identified. RESULTS: Ten patients died (6%) and 104 (59%) experienced postoperative complications. Five-year patient and graft survival rates were 77 and 74%, respectively. Biliary complications were recorded in 61 patients (35%) and were significantly decreased by IBS insertion (p = 0.0003). Anastomotic fistulas occurred in 23 patients (13%) and stenoses in 44 patients (25%). On multivariate analysis, high preoperative MELD scores (p = 0.02) and hepatic artery thrombosis (p < 0.0001) were predictors of fistula; absence of IBS was associated with both fistula (p = 0.014) and stricture (p = 0.003) formation. CONCLUSIONS: IBS insertion during LT decreases anastomotic complication.

Sorafenib vs surgical resection for hepatocellular carcinoma with macrovascular invasion: A propensity score analysis.

BACKGROUND & AIM: Sorafenib is the standard of care for patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI), with limited survival. Retrospective surgical studies have reported prolonged survival in this situation. This study aimed to compare the overall survival of patients with HCC and MVI treated with surgical resection or sorafenib. METHODS: A total of 143 patients with HCC and MVI but no extra-hepatic spread, treated with surgical resection (SR-patients; n=75) or sorafenib (SOR-patients; n=68) in four French centres between 1990 and 2013 were reviewed retrospectively. A propensity score analysis was performed to reduce bias. RESULTS: SR-patients were significantly younger and had a lower tumour burden than SOR-patients. Median overall survival (OS) rates were 10.1 months [95% CI: 4.1-16.1] in SR-patients and 12.9 months [95% CI: 7.9-17.9] in SOR-patients (P=.959). The 90-day mortality rate was 16% (n=12) in SR-patients and 7.5% (n=5) in SOR-patients (P=.196). SR-patients had a median disease-free survival of 4.60 months [95% CI: 3.3-5.9]. Under the propensity analysis, median OS was 12.0 months [95% CI: 5.5-18.5] in SR-patients vs 9.7 months [95% CI: 6.1-13.3] in SOR-patients (P=.682). Under multivariate analysis, extensive MVI (HR=1.956, P=.024) and bilirubin >17 µmol/L (HR=1.738, P=.011) were the two factors significantly associated with mortality. CONCLUSION: Under a propensity score analysis, the overall survival of patients with HCC and MVI undergoing surgical resection was similar to that achieved with sorafenib. We were not able to identify a patient subgroup experiencing a surgery-related improvement in survival, and quality of life was not evaluable.

Pancreaticobiliary Maljunctions in European Patients with Bile Duct Cysts: Results of the Multicenter Study of the French Surgical Association (AFC).

BACKGROUND: Pancreaticobiliary maljunctions (PBMs) are congenital anomalies of the junction between pancreatic and bile ducts, frequently associated with bile duct cyst (BDC). BDC is congenital biliary tree diseases that are characterized by distinctive dilatation types of the extra- and/or intrahepatic bile ducts. Todani's types I and IVa, in which dilatation involves principally the main bile duct, are the most frequent. PBM induces pancreatic juice reflux into the biliary tract that is supposed to be one of the main factors of biliary cancer degeneration, although the diagnostic criteria of PBM that can be either morphological and/or functional are not well defined especially in Western series. OBJECTIVE: The aim of this study was to assess the relative prevalence of PBM in BDC in a large European multicenter study, to analyze the characteristics of PBM and try to propose diagnostic criteria of PBMs based on morphological and/or functional criteria and define the positive, negative predictive values, sensibility and specificity of either criteria. RESULTS: From 1975 to 2012, 263 patients with BDC were analyzed. Among them, 190 (72.2 %) were considered to present PBM. Types I and IVa had a similar rate of PBM association. According to the "AFC classification," 57.2 % had a C-P type, 34.5 % a P-C type and 8.3 % a complex type ("anse-de-seau"). The median length of the common channel in patients with PBM was 15.8 ± 6.8 mm (range 5-40 mm). The median intrabiliary amylase and lipase levels were 65,249 and 172,104 UI/L, respectively. For the diagnostic of PBM, a common channel length of more than 8 mm and an intrabiliary amylase level superior to 8000 UI/L were associated with a predictive positive value and a specificity of more than 90 %. Synchronous biliary cancer had an incidence of 8.7 % in all patients with BDC and PBM 11.1 % in adults. Compared to type IV, the type I BDC was associated with statistically more cancer patients in the presence of PBM. CONCLUSIONS: Characteristics of PBM associated with BDC in Western population are quite close to reported Eastern series. The results suggest considering both the intrabiliary value of amylase >8000 UI/L and a length of a common channel >8 mm as appropriate values for positive diagnosis of PBM.

Liver-infiltrating CD8(+) lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND: Chronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV-related cirrhosis in patients with hepatocellular carcinoma (HCV-HCC) as compared to HCV patients without hepatocellular carcinoma. METHOD: Immune markers (CD3, CD4, CD8, CD20, CD56, TCRγδ, FoxP3) and gene expression profiles (CD8α, CD8ß, FoxP3, IL-6, IFN-γ, perforin, RANTES) were analysed in a test cohort by immunohistochemistry and quantitative RT-PCR analysis on serial non-tumorous and tumorous tissues. RESULTS: Immune micro-environment was more inflammatory in HCV-HCC than HCV cirrhotic livers. The number of CD3(+) , CD4(+) , CD8(+) and CD20(+) liver-infiltrating lymphocytes was significantly higher, whereas the number of CD56(+) cells was significantly lower in HCV-HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4(+) and CD20(+) cells and to nodular parenchyma for CD8(+) cells. Gene expressions of CD8α, FoxP3 and RANTES were also significantly higher in HCV-HCC than in HCV cirrhosis. Interestingly, in a large cohort of 63 HCV-HCC patients. The number of CD8(+) cells ≥100/field was associated with significant higher tumour recurrence (P = 0.003) and lower overall survival (P = 0.05) at 5 years. CONCLUSION: High densities of liver-infiltrating lymphocytes in HCV-HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumour recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery.

European experience of 573 liver resections for hepatocellular adenoma: a cross-sectional study by the AFC-HCA-2013 study group.

BACKGROUND: Hepatocellular adenoma (HCA) is a benign hepatic lesion that may be complicated by bleeding and malignant transformation. The aim of the present study is to report on large series of liver resections for HCA and assess the incidence of hemorrhage and malignant transformation. METHODS: A retrospective cross-sectional study, from 27 European high-volume HPB units. RESULTS: 573 patients were analyzed. The female: male gender ratio was 8:2, mean age: 37 ± 10 years. Of the 84 (14%) patients whose initial presentation was hemorrhagic shock (Hemorrhagic HCAs), hemostatic intervention was urgently required in 25 (30%) patients. No patients died after intervention. Tumor size was >5 cm in 74% in hemorrhagic HCAs and 64% in non-hemorrhagic HCAs (p < 0.001). In non-hemorrhagic HCAs (n = 489), 5% presented with malignant transformation. Male status and tumor size >10 cm were the two predictive factors. Liver resections included major hepatectomy in 25% and a laparoscopic approach in 37% of the patients. In non-hemorrhagic HCAs, there was no mortality and major complications occurred in 9% of patients. DISCUSSION: Liver resection for HCA is safe. Presentation with hemorrhage was associated with larger tumor size. In males with a HCA >10 cm, a HCC should be suspected. In such situation, a preoperative biopsy is preferable and an oncological liver resection should be considered.

Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria.

In France, decisions regarding superurgent (SU) liver transplantation (LT) for patients with acute liver failure (ALF) are principally based on the Clichy-Villejuif (CV) criteria. The aims of the present study were to study the outcomes of patients registered for SU LT and the factors that were predictive of spontaneous improvement and to determine the usefulness of the CV criteria. All patients listed in France for SU LT between 1997 and 2010 who were 15 years old or older with ALF were included. In all, 808 patients were listed for SU transplantation: 22% with paracetamol-induced ALF and 78% with non-paracetamol-induced ALF. Of these 808 patients, 112 improved spontaneously, 587 underwent LT, and 109 died or left the waiting list because of a worsening condition. The 1-year survival rate according to an intention-to-treat analysis and the survival after LT were 66.3% [interquartile range (IQR), 62.7%-69.7%] and 74.2% (IQR, 70.5%-77.6%), respectively. The factors that were predictive of a spontaneous recovery with ALF-related paracetamol hepatotoxicity were as follows: hepatic encephalopathy grade 0, 1, or 2 [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.99-11.6]; creatinine clearance≥60 mL/minute/1.73 m2 (OR, 4.77; 95% CI, 1.96-11.63), a bilirubin level<200 µmol/L (OR, 21.64; 95% CI, 1.76-265.7); and a factor V level>20% (OR, 5.79; 95% CI, 1.66-20.29). For ALF-related nonparacetamol hepatotoxicity, the factor that was predictive of a spontaneous recovery was a bilirubin level<200 µmol/L (OR, 10.38; 95% CI, 4.71-22.86). The sensitivity, specificity, and positive and negative predictive values for the CV criteria were 75%, 56%, 50%, and 79%, respectively, for ALF due to paracetamol and 69%, 50%, 64%, and 55%, respectively, for ALF not related to paracetamol. The performance of current criteria for SU transplantation could be improved if paracetamol-induced ALF and non-paracetamol-induced ALF were split and 2 other items were included in this model: the bilirubin level and creatinine clearance.

Tumour size over 3 cm predicts poor short-term outcomes after major liver resection for hilar cholangiocarcinoma. By the HC-AFC-2009 group.

INTRODUCTION: As mortality and morbidity after a curative resection remains high, it is essential to identify pre-operative factors associated with an early death after a major resection. METHODS: Between 1998 and 2008, we selected a population of 331 patients having undergone a major hepatectomy including segment I with a lymphadenectomy and a common bile duct resection for a proven hilar cholangiocarcinoma in 21 tertiary centres. The study's objective was to identify pre-operative predictors of early death (<12 months) after a resection. RESULTS: The study cohort consisted of 221 men and 110 women, with a median age of 61 years (range: 24-85). The post-operative mortality and morbidity rates were 8.2% and 61%, respectively. The 1-, 3- and 5-year overall survival rates were 85%, 64% and 53%, respectively. The median tumour size was 23 mm on pathology, ranging from 8 to 40. A tumour size >30 mm [odds ratio (OR) 2.471 (95% confidence interval (CI) 1.136-7.339), P = 0.001] and major post-operative complication [OR 3.369 (95% CI 1.038-10.938), P = 0.004] were independently associated with death <12 months in a multivariate analysis. CONCLUSION: The present analysis of a series of 331 patients with hilar cholangiocarcinoma showed that tumour size >30 mm was independently associated with death <12 months.

Early liver transplantation for severe alcoholic hepatitis.

BACKGROUND: A 6-month abstinence from alcohol is usually required before patients with severe alcoholic hepatitis are considered for liver transplantation. Patients whose hepatitis is not responding to medical therapy have a 6-month survival rate of approximately 30%. Since most alcoholic hepatitis deaths occur within 2 months, early liver transplantation is attractive but controversial. METHODS: We selected patients from seven centers for early liver transplantation. The patients had no prior episodes of alcoholic hepatitis and had scores of 0.45 or higher according to the Lille model (which calculates scores ranging from 0 to 1, with a score ≥ 0.45 indicating nonresponse to medical therapy and an increased risk of death in the absence of transplantation) or rapid worsening of liver function despite medical therapy. Selected patients also had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence. Survival was compared between patients who underwent early liver transplantation and matched patients who did not. RESULTS: In all, 26 patients with severe alcoholic hepatitis at high risk of death (median Lille score, 0.88) were selected and placed on the list for a liver transplant within a median of 13 days after nonresponse to medical therapy. Fewer than 2% of patients admitted for an episode of severe alcoholic hepatitis were selected. The centers used 2.9% of available grafts for this indication. The cumulative 6-month survival rate (±SE) was higher among patients who received early transplantation than among those who did not (77 ± 8% vs. 23 ± 8%, P<0.001). This benefit of early transplantation was maintained through 2 years of follow-up (hazard ratio, 6.08; P = 0.004). Three patients resumed drinking alcohol: one at 720 days, one at 740 days, and one at 1140 days after transplantation. CONCLUSIONS: Early liver transplantation can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. (Funded by Société Nationale Française de Gastroentérologie.).

Surgical management of congenital intrahepatic bile duct dilatation, Caroli's disease and syndrome: long-term results of the French Association of Surgery Multicenter Study.

OBJECTIVE: To assess clinical presentation and long-term results of surgical management of congenital intrahepatic bile duct dilatation (IHBDD) (Caroli disease and syndrome) in a multicenter setting. BACKGROUND: Congenital IHBDD predisposes to biliary stasis, resulting in intrahepatic lithiasis, septic complications, and cholangiocarcinoma. Although liver resection (LR) is considered to be the treatment of choice for unilobar disease extent into the liver, the management of bilobar disease and/or associated congenital hepatic fibrosis remains challenging. METHODS: From 1978 to 2011, a total of 155 patients (median age: 55.7 years) were enrolled from 26 centers. Bilobar disease, Caroli syndrome, liver atrophy, and intrahepatic stones were encountered in 31.0%, 19.4%, 27.7%, and 48.4% of patients, respectively. A complete resection of congenital intrahepatic bile ducts was achieved in 90.5% of the 148 patients who underwent surgery. RESULTS: Postoperative mortality was nil after anatomical LR (n = 111) and 10.7% after liver transplantation (LT) (n = 28). Grade 3 or higher postoperative morbidity occurred in 15.3% of patients after LR and 39.3% after LT. After a median follow-up of 35 months, the 5-year overall survival rate was 88.5% (88.7% after LT), and the Mayo Clinic score was considered as excellent or good in 86.0% of patients. The 1-year survival rate was 33.3% for the 8 patients (5.2%) who presented with coexistent cholangiocarcinoma. CONCLUSIONS: LR for unilobar and LT for diffuse bilobar congenital IHBDD complicated with cholangitis and/or portal hypertension achieved excellent long-term patient outcomes and survival. Because of the bad prognosis of cholangiocarcinoma and the sizeable morbidity-mortality after LT, timely indication for surgical treatment is of major importance.

A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial.

PURPOSE: This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC). METHODS: Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25-30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI-HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively. CONCLUSIONS: FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.

Progression while receiving preoperative chemotherapy should not be an absolute contraindication to liver resection for colorectal metastases.

PURPOSE: Tumor progression while receiving neoadjuvant chemotherapy (PD) has been associated with poor outcome and is commonly considered a contraindication to liver resection (LR). This study aims to clarify in a large multicenter setting whether PD is always a contraindication to LR. METHODS: Data from the LiverMetSurvey international registry were analyzed. Patients undergoing LR for colorectal metastases without extrahepatic disease after neoadjuvant chemotherapy between 1990 and 2009 were reviewed. RESULTS: Among 2143 patients, PD occurred in 176 (8.2 %). Risk of progression was increased after 5-FU or irinotecan (22.7 % vs. 6.8 % after other regimens, p < 0.0001; 14.9 % vs. 7.2 %, p < 0.0001), while it was reduced after oxaliplatin (5.6 % vs. 12.0 %, p < 0.0001) and still diminished among patients receiving targeted therapies (2.6 %). PD was an independent prognostic factor of survival at multivariate analysis (35 % vs. 49 %, p = 0.0006). In the PD group, 3 independent prognostic factors were identified: carcinoembryonic antigen (CEA) ≥ 200 ng/mL (p = 0.003), >3 metastases (p = 0.028), and tumor diameter ≥ 5 0 mm (p = 0.002). A survival predictive model showed that patients without any risk factors had 5-year survival rates of 53.3 %; good survival results were still observed if metastases were >3 or ≥ 50 mm (29.9 and 19.1 %, respectively). On the contrary, survival was less than 10 % at 3 years in the presence of >1 prognostic factor or CEA of ≥ 200 ng/mL. CONCLUSIONS: PD is a negative prognostic factor, but it is not an absolute contraindication to LR. Patients with PD could be scheduled for LR except for those with >3 metastases and ≥ 50 mm, or CEA ≥ 200 ng/mL in whom further chemotherapy is recommended.

Hepatic arterial embolization in the management of blunt hepatic trauma: indications and complications.

BACKGROUND: The objective was to clarify the role of hepatic arterial embolization (AE) in the management of blunt hepatic trauma. METHODS: Retrospective observational study of 183 patients with blunt hepatic trauma admitted to a trauma referral center over a 9-year period. The charts of 29 patients (16%) who underwent hepatic angiography were reviewed for demographics, injury specific data, management strategy, angiographic indication, efficacy and complications of embolization, and outcome. RESULTS: AE was performed in 23 (79%) of the patients requiring angiography. Thirteen patients managed conservatively underwent emergency embolization after preliminary computed tomography scan. Six had postoperative embolization after damage control laparotomy and four had delayed embolization. Arterial bleeding was controlled in all the cases. Sixteen patients (70%) had one or more liver-related complications; temporary biliary leak (n=11), intra-abdominal hypertension (n=14), inflammatory peritonitis (n=3), hepatic necrosis (n=3), gallbladder infarction (n=2), and compressive subcapsular hematoma (n=1). Unrecognized hepatic necrosis could have contributed to the late posttraumatic death of one patient. CONCLUSION: AE is a key element in modern management of high-grade liver injuries. Two principal indications exist in the acute postinjury phase: primary hemostatic control in hemodynamically stable or stabilized patients with radiologic computed tomography evidence of active arterial bleeding and adjunctive hemostatic control in patients with uncontrolled suspected arterial bleeding despite emergency laparotomy. Successful management of injuries of grade III upward often entails a combined angiographic and surgical approach. Awareness of the ischemic complications due to angioembolization is important.

Evaluation of a biodegradable PLA-PEG-PLA internal biliary stent for liver transplantation: in vitro degradation and mechanical properties.

Internal biliary stenting during biliary reconstruction in liver transplantation decrease anastomotic biliary complications. Implantation of a resorbable internal biliary stent (RIBS) is interesting since it would avoid an ablation gesture. The objective of present work was to evaluate adequacy of selected PLA-b-PEG-b-PLA copolymers for RIBS aimed to secure biliary anastomose during healing and prevent complications, such as bile leak and stricture. The kinetics of degradation and mechanical properties of a RIBS prototype were evaluated with respect to the main bile duct stenting requirements in liver transplantation. For this purpose, RIBS degradation under biliary mimicking solution versus standard phosphate buffer control solution was discussed. Morphological changes, mass loss, water uptake, molecular weight, permeability, pH variations, and mechanical properties were examined over time. The permeability and mechanical properties were evaluated under simulated biliary conditions to explore the usefulness of a PLA-b-PEG-b-PLA RIBS to secure biliary anastomosis. Results showed no pH influence on the kinetics of degradation, with degradable RIBS remaining impermeable for at least 8 weeks, and keeping its mechanical properties for 10 weeks. Complete degradation is reached at 6 months. PLA-b-PEG-b-PLA RIBS have the required in vitro degradation characteristics to secure biliary anastomosis in liver transplantation and envision in vivo applications.

K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy.

PURPOSE: K-Ras mutations predict resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy. EXPERIMENTAL DESIGN: This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G>C mutation), methylenetetrahydrofolate reductase polymorphism (677C>T, 1298A>C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression. RESULTS: Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors. The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival. CONCLUSIONS: The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.

[How to predict the relapse after surgery or radiofrequency of liver metastases of colorectal cancer? Interest of the serum kinetic variation of a matrix metalloproteinase cluster]. / Cinétique de variation sérique des métalloprotéïnases matricielles (MMP-1, -2, -7 et -9) et de TIMP-1 : un facteur prédictif de récidive après traitement radical des métastases hépatiques de cancers colorectaux ?

INTRODUCTION: Recurrence after liver surgery or radiofrequency is a clinical and biological challenge because it worsens the colorectal cancer prognosis. To date, no biomarker is yet validated to predict the recurrence in order to intensify adjuvant therapy for patients with higher risk. Matrix metalloproteinases play a major role in the metastasis dissemination and tumoral microenvironment and could be a potential biomarker of interest. METHODS: Forty-four patients with liver metastasis treated by surgery or radiofrequency were enrolled in this study. Serum levels of MMP-1, MMP-2, MMP-7, MMP-9 and TIMP-1 were monitored in Elisa after therapy and correlated to the recurrence from January 2004 to December 2007. After the curative treatment, patients were assessed for the recurence for two years by CT-scan and examination. RESULTS: Post-operative serum level of MMP-9 was significantly higher between J0, J1 and J45 after liver surgery or radiofrequency (***P≤0.001). Level of MMP-2 was significantly increased at M3 and M6 (***P≤0.001) but does not appear to be a risk factor of liver recurrence. The level of TIMP-1 at J0 is a deleterious factor (HR=1.76, P=0.042*). CONCLUSION: This is the first study wich correlates the post-operative level of 4 MMPs and TIMP-1 with the risk of liver recurrence after surgery or radiofrequency. Serum TIMP-1 level at J0 could be helpful to identify patients with higher risk but these results need to be confirmed in a large-scale study.

Lack of evidence of sustained hematopoietic reconstitution after transplantation of unmanipulated adult liver stem cells in monkeys.

The aim of this study was to search for hematopoietic potential in the liver of non-human primates. Lethally irradiated (2 x 5 Gy gamma) macaque monkeys were given autologous hepatic mononuclear cells (HMNC) isolated from a liver lobe by perfusion and digestion with 0.1% collagenase. Two monkeys were given intramedullary injections of HMNC (18.6 x 10(6)/kg, 20.4 x 10(6)/kg) and two others were co-transplanted with HMNC (14.35 x 10(6)/kg, 96.5 x 10(6)/kg) and bone marrow mesenchymal stem cells (0.42 x 10(6)/kg, 1.16 x 10(6)/kg). All monkeys exhibited a transient neutrophil recovery from day 22 for 10 days, but failed to produce platelets and remained transfusion-dependent. In conclusion, adult liver stem cells from a monkey model show a low level of in vivo hematopoietic potential, suggesting ex vivo manipulation will be required before clinical use of such cells.

Development of miniaturized light endoscope-holder robot for laparoscopic surgery.

PURPOSE: We have conducted experiments with an innovatively designed robot endoscope holder for laparoscopic surgery that is small and low cost. MATERIALS AND METHODS: A compact light endoscope robot (LER) that is placed on the patient's skin and can be used with the patient in the lateral or dorsal supine position was tested on cadavers and laboratory pigs in order to allow successive modifications. The current control system is based on voice recognition. The range of vision is 360 degrees with an angle of 160 degrees . Twenty-three procedures were performed. RESULTS: The tests made it possible to advance the prototype on a variety of aspects, including reliability, steadiness, ergonomics, and dimensions. The ease of installation of the robot, which takes only 5 minutes, and the easy handling made it possible for 21 of the 23 procedures to be performed without an assistant. CONCLUSION: The LER is a camera holder guided by the surgeon's voice that can eliminate the need for an assistant during laparoscopic surgery. The ease of installation and manufacture should make it an effective and inexpensive system for use on patients in the lateral and dorsal supine positions. Randomized clinical trials will soon validate a new version of this robot prior to marketing.

[Preclinical development of the TIMC LER (light endoscope robot)]. / Robot coelioscopique porte-endoscope miniaturisé LER (light endoscope robot) : développement pré-clinique.

INTRODUCTION: The authors participated in the development of an innovative endoscope robot in laparoscopic surgery designed by TIMC-GMCAO, providing a solution to the disadvantages of currently available systems, i.e. their cost and large dimensions. MATERIAL AND METHODS: A compact robot (LER) placed on the patient's skin that can be used in the lateral and dorsal supine position was tested on cadavres and laboratory pigs in order to allow successive modifications. The current control system is based on voice recognition. The amplitude of vision is 360 degrees with an angle of 160 degrees. Twenty three procedures were performed (2 radical prostatectomies, 4 pelvic lymph node dissections, 6 nephrectomies, 2 adrenalectomies, 3 cholecystectomies, 1 small bowel resection-anastomosis, 1 cystectomy, 1 splenectomy, and 3 appendicectomies). RESULTS: Among the various control systems tested, we adopted voice recognition on the basis of its intuitive nature and the fact that it leaves one hand free. In the light of these studies, several aspects of the prototype were modified: reliability, fixation, ergonomy and dimensions. The ease of installation, which takes only 5 minutes, and the easy handling of the robot allowed 21 out of 23 laparoscopic procedures to be performed without the need for an assistant. CONCLUSION: The LER robot is an endoscope robot guided by the surgeon's voice that can eliminate the need for an assistant to hold the camera during laparoscopic surgery in the lateral and dorsal supine positions. The ease of installation and manufacture should make this an effective and inexpensive system. The gain in operating time was not evaluated during these trials on cadavres and pigs, as various prototypes were tested and several problems of reliability were successively resolved. Ongoing randomized, prospective clinical trials should soon validate this robot prior to marketing.