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Background Since 2006, surgery combined with perioperative chemotherapy is the standard of care for resectable gastric adenocarcinoma in Europe. Specific effects of neoadjuvant chemotherapy remain unknown. The aim was to evaluate the rate of tumor downstaging and its impact on survival in patients undergoing curative resection after neoadjuvant chemotherapy (NeoCT) for gastric adenocarcinoma. Material and Methods All patients treated in a curative intent for gastric or esophagogastric junction adenocarcinomas between 1996 and 2016 in our high-volume center were retrospectively included. Tumor downstaging after NeoCT was defined as ypTN inferior to cTN. The accuracy of clinical staging was evaluated in patients treated by upfront surgery before 2006. Results During the study period, 491 patients were operated for gastric adenocarcinoma, and 449 patients were finally analyzed. Among the 163 (36.3%) patients who received NeoCT, 61 (37.4%) had tumor downstaging. Overall survival and disease-free survival were longer in patients with tumor downstaging compared to patients without it (5-year survival: 84.8% vs 49.7%; P = .002 and 61.7% vs 43.4%; P = .054). In multivariate analysis tumor downstaging was an independent prognosis factor for better overall survival (HR = 5.258; P = .002) and disease-free survival (HR = 2.286; P = .028). Moreover, 45.5% of patients staged cT1-T2N0, in whom upfront surgery was performed, were understaged and ultimately had a more advanced tumor on pathological analysis. Conclusion Response to neoadjuvant chemotherapy constitutes a major prognostic factor for overall and disease-free survival. In the absence of predictive factors for tumor downstaging, the indication for perioperative chemotherapy should remain broad, in particular because of the low accuracy of pretherapeutic staging and therefore the high risk of understaging tumors.

Intrahepatic cholangiocarcinoma is a rare disease with a poor prognosis. In patients where surgical resection is possible, outcome is influenced by perioperative morbidity and lymph node status. Laparoscopic liver resection is associated with improved clinical and oncological outcomes in primary and metastatic liver cancer compared with open liver resection, but evidence on intrahepatic cholangiocarcinoma is still insufficient. The primary aim of this study was to compare overall survival for a large series of patients treated for intrahepatic cholangiocarcinoma by open or laparoscopic approach. Secondary objectives were to compare disease-free survival, predictors of death, and recurrence.Patients treated with laparoscopic or open liver resection for intrahepatic cholangiocarcinoma from 2000 to 2018 from 3 large international databases were analyzed retrospectively. Each patient in the laparoscopic resection group (case) was matched with 1 open resection control (1:1 ratio), through a propensity score calculated on clinically relevant preoperative covariates. Overall and disease-free survival were compared between the matched groups. Predictors of mortality and recurrence were analyzed with Cox regression, and the Textbook Outcomes were described.During the study period, 855 patients met the inclusion criteria (open liver resection = 709, 82.9%; laparoscopic liver resection = 146, 17.1%). Two groups of 89 patients each were analyzed after propensity score matching, with no significant difference regarding pre- and postoperative variables. Overall survival at 1, 3, and 5 years was 92%, 75%, and 63% in the laparoscopic liver resection group versus 92%, 58%, and 49% in the open liver resection group (P = .0043). Adjusted Cox regression revealed severe postoperative complications (hazard ratio: 10.5, 95% confidence interval [1.01-109] P = .049) and steatosis (hazard ratio: 13.8, 95% confidence interval [1.23-154] P = .033) as predictors of death, and transfusion (hazard ratio: 19.2, 95% confidence interval [4.04-91.4] P.001) and severe postoperative complications (hazard ratio: 4.07, 95% confidence interval [1.15-14.4] P = .030) as predictors of recurrence.The survival advantage of laparoscopic liver resection over open liver resection for intrahepatic cholangiocarcinoma is equivocal, given historical bias and missing data.

Background Patients affected by HCC represent a vulnerable population during the COVID-19 pandemic and may suffer from the unusual allocation of healthcare resources. The aim of this study was to determine the impact of the COVID-19 pandemic on the management of HCC patients within six French referral centers of the metropolitan area of Paris. Materials and methods We performed a multicenter, retrospective, cross-sectional study on the management of patients affected by HCC during the first six weeks of COVID-19 pandemic (exposed), compared to the same period in 2019 (unexposed). Were included all patients discussed in multidisciplinary tumor meeting (MTB) and/or undergoing radiological or surgical programmed procedure during the study period, in a curative or palliative intent. Endpoints were the number of patients with a modification in the treatment strategy, or a delay in decision-to-treatment. Results After screening, n=670 patients were included (n=293 Exposed to COVID, n=377 Unexposed to COVID). A decrease of the numbers of patients with HCC presented in MTB in 2020 (p=0.034) and with a first diagnosis of HCC (n=104 Exposed to COVID, n=143 Unexposed to COVID, p=0.083) was find. Modification in the treatment strategy was observed in 13.1% of patients, with no differences between the two periods. Nevertheless 21.5% versus 9.5% of patients experienced a treatment delay longer than 1 month in 2020 compared to 2019 (p, Graphical abstract, Highlights • In COVID period, a decrease of the numbers of patients with hepatocellular carcinoma presented in Multidisciplinary Tumour Board and, in particular, with a first diagnosis of HCC was find. • Globally, modification in the treatment strategy was observed in 13.1% of patients, with no differences between the two periods but the main reason was significantly different in 2020 compared to 2019: COVID-19 in 2020 vs tumour progression in 2019. • More than 21% of patients experienced a treatment delay longer than 1 month in COVID period compared to 9.5% in 2019 , specially, in subgroup with active, recurrent HCC. The main reasons for the delay of treatment in 2020 was COVID-19 infection related • In 2020, 7.1% of patients had a diagnosis of an active COVID-19 infection and 4/21 (19.1%) died., During COVID pandemic era, less patients with hepatocellular carcinoma (HCC) have been presented in multidisciplinary tumor bord, specially with a first diagnosis of HCC

Background This study aimed to evaluate the controversial benefit of a pancreaticoduodenectomy (PD) in patients with PALN metastasis intraoperatively detected by systematic frozen section examination in pancreatic adenocarcinoma. Methods PALN intraoperative examination by frozen section was systematically performed from January 2006 to February 2018 prior to performing PD for pancreatic adenocarcinoma. Until June 2012, PALN + patients still underwent PD (PALN+/PD group) in the framework of a prospective study. Since July 2012, PALN+ was considered as contraindicating the planned PD (PALN+/No-PD group). Post-operative morbidity and survival were compared between these two groups. Results Of the 32 PALN + patients intraoperatively detected, the first 13 underwent a PD, while the last 19 did not undergo resection. Seven patients (54%) among 13 PALN+/PD patients developed a post-operative complication against 3 (16%) among 19 PALN+/No-PD patients (p = 0.049). The median length of stay was 5 days longer for PALN+/PD patients (p = 0.001). The median survival did not differ between PALN+/No-PD and PALN+/PD groups (respectively 13.4 months (95%CI:7.6–19.3) and 11.5 months (95%CI:5.9–17.1), p = 0.471). No patient was alive 4 years after surgery in both the PALN+/No-PD or PALN+/PD groups. Conclusion In case of PALN detected intraoperatively in pancreatic adenocarcinoma, PD does not improve survival compared to current palliative treatment.

International audience; BackgroundPostoperative peritonitis (POP) following gastrointestinal surgery is associated with significant morbidity and mortality, with no clear management option proposed. The aim of this study was to report our surgical management of POP and identify pre- and perioperative risk factors for morbidity and mortality.MethodsAll patients with POP undergoing relaparotomy in our department between January 2004 and December 2013 were included. Pre- and perioperative data were analyzed to identify predictors of morbidity and mortality.ResultsA total of 191 patients required relaparotomy for POP, of which 16.8% required >1 reinterventions. The commonest cause of POP was anastomotic leakage (66.5%) followed by perforation (20.9%). POP was mostly treated by anastomotic takedown (51.8%), suture with derivative stoma (11.5%), enteral resection and stoma (12%), drainage of the leak (8.9%), stoma on perforation (8.4%), duodenal intubation (7.3%) or intubation of the leak (3.1%). The overall mortality rate was 14%, of which 40% died within the first 48 h. Major complications (Dindo–Clavien > 2) were seen in 47% of the cohort. Stoma formation occurred in 81.6% of patients following relaparotomy. Independent risk factors for mortality were: ASA > 2 (OR = 2.75, 95% CI = 1.07–7.62, p = 0.037), multiorgan failure (MOF) (OR = 5.22, 95% CI = 2.11–13.5, p = 0.0037), perioperative transfusion (OR = 2.7, 95% CI = 1.05–7.47, p = 0.04) and upper GI origin (OR = 3.55, 95% CI = 1.32–9.56, p = 0.013). Independent risk factors for morbidity were: MOF (OR = 2.74, 95% CI = 1.26–6.19, p = 0.013), upper GI origin (OR = 3.74, 95% CI = 1.59–9.44, p = 0.0034) and delayed extubation (OR = 0.27, 95% CI = 0.14–0.55, p = 0.0027).ConclusionMortality following POP remains a significant issue; however, it is decreasing due to effective and aggressive surgical intervention. Predictors of poor outcomes will help tailor management options.

Resume Le kyste mucineux simple du pancreas est une forme rare de kyste pancreatique, decrite pour la premiere fois en 2002 par Kosmahl et al. a partir de l’analyse de 5 cas. Nous en rapportons un cas observe dans notre centre, suivi d’une revue de la litterature. Cette lesion, de physiopathologie mal connue, correspond a un kyste epithelial mucineux, et se presente generalement sous la forme d’un kyste uniloculaire du corps ou de la queue du pancreas a contenu clair, ne communiquant pas avec les canaux pancreatiques. Histologiquement, le kyste est revetu par un epithelium mucosecretant peu atypique surmontant une paroi fibreuse, sans stroma de type pseudo-ovarien. Cette entite est d’excellent pronostic, sans aucun cas de recidive ou de transformation maligne decrit. La nature non neoplasique de cette lesion, admise auparavant, a ete recemment remise en question par la description, dans certains cas, de mutations de KRAS et de lesions de neoplasie intra-epitheliale. Cette lesion doit etre distinguee des cystadenomes sereux macrokystiques, des tumeurs kystiques mucineuses et des tumeurs intra-canalaires papillaires et mucineuses, a partir d’un faisceau d’arguments cliniques, radiologiques et pathologiques. En effet, le traitement de ces lesions kystiques pancreatiques va d’une simple surveillance a une exerese chirurgicale, et depend de leur nature histologique.

Background Patients with familial adenomatous polyposis (FAP) carry a risk of duodenal adenocarcinoma. These patients, who already have an ileal pouch-anal anastomosis (IPAA), sometimes require pancreaticoduodenectomy (PD). This work aims to evaluate the long-term consequences of the combination of PD + IPAA. Methods All patients with IPAA due to FAP who underwent PD from 1991 to 2017 were included (PD + IPAA group). Patients were matched 1:1 according to age, sex, ASA score and presence of colorectal cancer. Fecal continence and quality of life (QoL) were assessed using the Wexner score and the EORTC-QLQ-C30 questionnaire. Results Thirty-two PD + IPAA patients were matched with thirty-two IPAA-only patients. In each group, the response rate to the questionnaire was 78% (25/32). No differences were noted between PD + IPAA and IPAA-only groups in terms of daytime fecal frequency (6.0 vs 6.0; p = 0.362), Wexner score (3/20 vs 4/20; p = 0.984) and global QoL score (83.3/100 vs 83.3/100; p = 0.401). In the PD + IPAA group, 26% of patients developed diabetes a median period of 10.0 years after PD. The global QoL for these patients was significantly altered (p = 0.011), while daytime fecal frequency was unaffected (p = 0.092) as fecal continence (p = 0.475). Conclusion In FAP patients with IPAA, PD does not affect bowel function or QoL.

Simple mucinous cyst of the pancreas is an unusual pancreatic cyst, first described by Kosmahl et al. in 2002 with 5 cases. We describe a case of simple mucinous cyst of the pancreas, followed by a literature review. The physiopathology of this cyst is still unclear. It is an epithelial cyst, presenting as unilocular cystic lesion of the pancreatic body or tail, with a clear content, and no communication with the pancreatic duct. Microscopically, the cyst is lined by mucin-producing cells with mild atypia, and contains a fibrous wall without ovarian-like stroma. The prognosis is excellent, as no recurrent disease and progression to malignancy have been described. The non neoplastic origin of this lesion is debated, as cases with KRAS mutation and intra-epithelial neoplastic lesions have been recently reported. It is important to distinguish this lesion from macrocystic serous cystadenoma, mucinous cystic neoplasms and intraductal papillary mucinous neoplasms, by clinical, radiological and pathological features, as the treatment varies from simple surveillance to surgical resection.

International audience; Aims: The aims of this study were to compare short-and long-term outcomes for clinical T2N0 oesophageal cancer with analysis of (i) primary surgery (S) versus neoadjuvant therapy plus surgery (NS), (ii) squamous cell carcinoma and adenocarcinoma subsets; and (iii) neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy.Methods: Data were collected from 30 European centres from 2000 to 2010. Among 2944 included patients, 355 patients (12.1%) had cT2N0 disease; 285 (S) and 70 (NS), were compared in terms of short-and long-term outcomes. Propensity score matching analyses were used to compensate for differences in baseline characteristics.Results: No significant differences between the groups were shown in terms of in hospital morbidity and mortality. Nodal disease was observed in 50% of S-group at the time of surgery, with 20% pN2/N3. Utilisation of neoadjuvant therapy was associated with significant tumour downstaging as reflected by increases in pT0, pN0 and pTNM stage 0 disease, this effect was further enhanced with neoadjuvant chemoradiotherapy. After adjustment on propensity score and confounding factors, for all patients and subset analysis of squamous cell and adenocarcinoma, neoadjuvant therapy had no significant effect upon survival or recurrence (overall, loco-regional, distant or mixed) compared to surgery alone. There were no significant differences between neoadjuvant chemotherapy and chemoradiotherapy in short-or long-term outcomes.Conclusion: The results of this study suggest that a surgery alone treatment approach should be recommended as the primary treatment approach for cT2N0 oesophageal cancer despite 50% of patients having nodal disease at the time of surgery.

Background Major oncologic surgery is associated with a high incidence of venous thromboembolic events (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE). However, the incidence and risk factors for symptomatic VTE during curative treatment for patients with esophageal cancer are poorly documented. Methods Data were collected from 30 European centers from 2000 to 2010. The incidence of in-hospital VTE was assessed in 2,944 patients with esophageal cancer having surgery with curative intent, and 50 clinically relevant parameters were assessed as potential risk factors for VTE. Patients received low molecular weight heparin prophylaxis during hospital stay and for 4 weeks after surgery. Results Eighty-four patients (2.9%) developed a symptomatic VTE; all of them had a DVT and 44 were also diagnosed with a PE. In the VTE group there were 19 postoperative deaths recorded, 5 of which (26.3%) were directly caused by PE at postoperative days 7, 10, 21, 45, and 48 despite VTE prophylaxis. In-hospital postoperative mortality was significantly higher in VTE patients (23% versus 7%, p 0.001) and mean hospital stay was also longer in this group (33 ± 24 versus 25 ± 21 days, p 0.001). Multivariable analysis showed that high American Society of Anesthesiologists (ASA) class ( p = 0.008), pneumopathy ( p = 0.002), or an acute respiratory distress syndrome (ARDS) ( p = 0.015) were significantly associated with VTE. Conclusions Patients with ASA class III or IV and those who present a postoperative pneumopathy or ARDS seem to be at higher risk for VTE. Thus, current VTE screening and thromboprophylaxis for these patients might be inadequate and needs further investigation.

Aim To compare clinical presentation, operative management and short- and long-term outcomes of congenital bile duct cysts (BDC) in adults with children. Methods Retrospective multi-institutional Association Francaise de Chirurgie study of Todani types I+IVB and IVA BDC. Results During the 37-year period to 2011, 33 centers included 314 patients (98 children; 216 adults). The adult population included more high-risk patients, with more active, more frequent prior treatment (47.7% vs 11.2%; p < 0.0001), more complicated presentation (50.5% vs 35.7%; p = 0.015), more synchronous biliary cancer (11.6% vs 0%; p = 0.0118) and more major surgery (23.6% vs 2%; p < 0.0001), but this latter feature was only true for type I+IVB BDC. Compared to children, the postoperative morbidity (48.1% vs 20.4%; p < 0.0001), the need for repeat procedures and the status at follow-up were worse in adults (27% vs 8.8%; p = 0.0009). However, severe postoperative morbidity and fair or poor status at follow-up were not statistically different for type IVA BDC, irrespective of patients' age. Synchronous cancer, prior HBP surgery and Todani type IVA BDC were independent predictive factors of poor or fair long-term outcome. Conclusion BDC is a more indolent disease in children compared to adults, except for Todani type IV-A BDC.

Resume Nous rapportons le cas d’un malade de 73 ans, aux antecedents d’adenocarcinome du pancreas opere par laparotomie mediane, se presentant aux urgences pour un tableau d’occlusion aigue du grele secondaire a une hernie anterolaterale de l’abdomen (ou hernie de Spiegel) etranglee. A la tomodensitometrie, la hernie siegeait au bord lateral du muscle droit a droite et se developpait a travers un orifice etroit des aponevroses des muscles oblique interne et transverse de l’abdomen sans traverser l’aponevrose du muscle oblique externe. Une hernie de Spiegel ou hernie de la ligne semi-lunaire s’exteriorisera le plus souvent au niveau du point faible situe a l’intersection entre la ligne semi-lunaire et l’extremite laterale de la ligne arquee, au niveau d’une zone de transition dans la constitution du feuillet posterieur de la gaine rectusienne. Ce point faible est limite en bas par l’artere epigastrique inferieure. Devant une occlusion du grele chez un malade ayant un antecedent de laparotomie, il conviendra de rechercher systematiquement une hernie anterolaterale de l’abdomen etranglee, avant d’evoquer une occlusion sur brides et adherences postoperatoires. Les hernies de Spiegel sont asymptomatiques dans neuf cas sur dix mais le risque d’etranglement est eleve imposant un traitement chirurgical systematique. La prise en charge pourra se faire, en chirurgie programmee comme en urgence, par abord direct ou par laparoscopie, avec ou sans pose de materiel prothetique.

Objectives Metastatic tumors to the pancreas are rare and usually present a part of an advanced metastatic disease. Isolated metastasis is even rarer and may be difficult to differentiate from primary pancreatic neoplasm. The leading sources of metastases are breast, lung, kidney, and skin (melanoma). We present our experience with 12 cases of isolated pancreatic metastasis. Methods We made a retrospective review from a series of pancreatic resections for metastatic disease, which occurred during the last decade. Results The sites of origin were as follows: kidney (8 cases), lung (2 cases), bone (1 case), and breast (1 case). Only 4 patients were symptomatic (abdominal pain, 3 cases; melena, 1 case). The metastasis was metachronous in 11 cases, with mean disease-free interval of 9 years. The preoperative diagnosis was endocrine tumor in 4 cases. All patients underwent complete extirpation. At the time of follow-up, 3 patients had died of malignancy and 9 were still alive and free of disease, with a mean follow-up of 3 years. Conclusions Isolated metastatic tumors to the pancreas may be detected decades after the initial diagnosis and can be asymptomatic, emphasizing the need for lifelong surveillance in this population. Surgical extirpation of these lesions may offer the chance of long-term survival.

Background Stoma reversal can be performed during liver resection (LR) in patients with colorectal liver metastases (CRCLM) whose primary colorectal tumor has been previously resected with a diverting loop ileostomy. This combined procedure is reputed to be associated with an increased morbidity. This study investigates the impact of simultaneous loop ileostomy closure (LIC) on the postoperative outcome of LR for CRCLM. Methods From November 1996 to April 2012, 408 patients who underwent LR for CRCLM were retrospectively studied from a prospective database. Patients who underwent simultaneous LR and LIC were matched for the type of the main liver procedure, the use of preoperative chemotherapy and the need for greater than or equal to 6 cycles of preoperative chemotherapy with LR only patients. Intraoperative and postoperative complications were recorded and compared. Results Twenty-four patients (6%) with simultaneous LR and LIC were matched with 72 patients with LR only. Both groups were comparable for patients' demographics and intraoperative findings. Liver related ( P = .957) and overall postoperative morbidity ( P = .643) rates did not differ between groups. Conclusion The combined procedure appeared to be safe when strict surgical technique is used.

Purpose. To examine the potential of cultured human liver slices to predict cytochrome P450 (CYP) inducibility, regarding global and zonal CYP expression, together with drug-induced histologic changes. Methods. We first assessed whether CYP2B6, 3A4, and 2C9 expression was maintained in cultured liver slices. Cultured hepatocytes were used as the reference culture system. Then we tested the effects of phenobarbital and cyclophosphamide on CYP expression in both models. Results. Morphologic features are preserved in slices. Basal CYP expression declines with time in culture in both models. Slices display the same region specificity of CYP2B6, 2C9, and 3A4 expression as intact liver. CYP2B6 and 3A4 mRNA, apoprotein, and enzyme-related activities were induced by phenobarbital and cyclophosphamide, whereas CYP2C9 apoprotein was not. Their immunoreactivities were also increased, while their zonal distribution was preserved on slice tissue sections. Microsomal enzyme induction was confirmed by histology. Conclusions. Cultured human liver slices are an attractive alternative to hepatocyte culture for the prediction of human CYP isoenzyme induction by xenobiotics.

We tested the effects of low 20% O2) and high (70% O2) oxygen tension on the morphological and biochemical integrity of human liver slices incubated for up to 72 h in supplemented Williams' E medium in a dynamic rotating culture system. High oxygen tension was more effective than low oxygen tension for preserving morphological integrity in long-term culture 48–72 h). After 72 h of culture with 70% O2, the lobular pattern was well preserved, and the survival of hepatocytes approximately 80%) and other cell types was good. Immunohistochemical studies showed good preservation of the region-specific expression of CYP2E1 and CYP3A4 isoenzymes for up to 72 h of incubation in 70% O2. As compared to 20% O2, the oxidized glutathione content and reactive oxygen species production were slightly increased in 70% O2, suggesting that minimal oxidative stress occurred with the high oxygen tension. In conclusion, despite slight oxidative stress associated with high oxygen tension, 70% O2 appeared more appropriate than 20% O2 for preserving the morphological and biochemical integrity of human liver slices cultured in a dynamic organ culture system for up to 72 h.

Objectifs Si l’impact de la chimiotherapie preoperatoire (CTPO) sur l’histologie du foie non tumoral et la morbidite postoperatoire est bien etudie, son influence eventuelle sur la regeneration hepatique reste imprecise. Ce travail etudie donc l’impact de la CTPO sur la regeneration hepatique apres hepatectomie droite. Patients et methodes Etude monocentrique retrospective incluant 40 hepatectomies droites consecutives pour MCCR. Trois groupes etaient definis : (A) pas de CTPO (n = 9) ; (B) 1 a 6 cycles (n = 25) ; (C) 7 cycles ou plus (n = 6). La regeneration hepatique etait appreciee par volumetries, realisees en aveugle du traitement preoperatoire par un seul radiologue sur l’imagerie pre- et postoperatoire (1 a 12 mois). Resultats L’hypertrophie du foie gauche restant etait significativement reduite chez les patients du groupe C versus groupe A + B (471 mL versus 706 mL ; p = 0,015). En revanche, cette hypertrophie gauche ne differait pas entre les patients du groupe B versus groupe A. La CTPO ne majorait pas ici significativement la morbidite postoperatoire. Conclusion Une CTPO prolongee (plus de 6 cycles) reduit la regeneration hepatique apres hepatectomie droite. Ceci pourrait impacter les strategies neoadjuvantes et l’usage des chimiotherapies d’intervalle dans les hepatectomies en 2 temps.

We have previously demonstrated that fresh or cryopreserved xenogeneic hepatocytes manually macroencapsulated in AN69 polymer and transplanted intraperitoneally in rats were able to improve the survival rate after 95% hepatectomy without immunosuppression. In addition, we developed a semiautomatic device where porcine hepatocytes were coextruded with AN69 hydrogel in order to macroencapsulate large amounts of cells. The purpose of the present study was to 1) test whether transplanted porcine hepatocytes macroencapsulated in this device remained functional as evaluated by their ability to prevent death from acute liver failure, and 2) compare the efficiency of cryopreserved or freshly isolated hepatocytes. Fresh or cryopreserved porcine hepatocytes were macroencapsulated in the semiautomatic device by coextrusion in AN69 polymer in 2-m minitubes containing 6 x 10(7) cells. Acute liver failure was induced in rats by two-step 95% hepatectomy. At the time of completion of liver resection, rats were either not transplanted with minitubes (control group I, n = 13), or were implanted with two minitubes containing culture medium (control group II, n = 11), hepatocytes killed by heat treatment (control group III, n = 10), coextruded fresh hepatocytes (group IV, n = 11), or coextruded cryopreserved hepatocytes (group V, n = 11), without immunosuppression. The survival rate at day 7 was between 0% and 31% in the three control groups. By contrast, coextruded fresh hepatocytes significantly improved the survival rate (group IV, 82%) as did cryopreserved cells (group V, 91% survival). In surviving rats, minitubes were explanted after 20 days; either fresh or cryopreserved hepatocytes appeared morphologically viable and their ultrastructure was preserved. Their detoxification capacities evaluated by the activity of the cyt P450 CYP3A4 were partly maintained. In conclusion, porcine hepatocytes macroencapsulated by coextrusion using a semiautomatic device and transplanted without immunosuppression were able to prevent death from acute liver failure in rats. Cryopreserved cells were as efficient as fresh hepatocytes.

Flucloxacillin, an isoxazolyl-penicillin, causes cholestasis and biliary epithelium injury. The aim of the study was to determine whether flucloxacillin, either directly or through metabolite formation, may induce cytotoxicity in hepatic or biliary cells. Cytotoxicity was assessed by lactate dehydrogenase release in primary cultures of human hepatocytes and of gallbladder-derived biliary epithelial cells (BEC). Metabolite production in microsome and cell preparations was analyzed by chromatography, nuclear magnetic resonance spectroscopy, and mass spectrometry. While flucloxacillin induced no direct cytotoxicity in any of the hepatocyte (n = 12) and BEC (n = 19) preparations, the conditioned media from cultured hepatocytes preincubated with flucloxacillin (50-500 mg/L) triggered a significant increase in lactate dehydrogenase release over controls in approximately 50% of BEC preparations (7/12), and this effect depended upon flucloxacillin concentration. Remaining BEC preparations exhibited no toxic response. Cytotoxicity in BEC preparations (9/13) was also induced by the supernatants of human liver microsomes and of recombinant human cytochrome P450 (CYP)3A4 preincubated with flucloxacillin (500 mg/L). Supernatants from both liver microsome and CYP3A4 preparations contained one major metabolite which was identified as 5'-hydroxymethylflucloxacillin. The production of this metabolite was inhibited following CYP3A4 inhibition by troleandomycin in human liver microsomes, and markedly enhanced following CYP3A induction by dexamethasone in rat liver microsomes. As opposed to BEC, cultured hepatocytes displayed significant CYP3A activity and produced low amounts of this metabolite. The purified metabolite (0.01-5 mg/L) exerted toxic effects in BEC but not in hepatocytes. In conclusion, hepatocytes mainly via CYP3A4 activity, generate flucloxacillin metabolite(s) including 5'-hydroxymethylflucloxacillin that may induce cytotoxicity in susceptible BEC. These metabolic events may contribute to the pathogenesis of drug-induced cholangiopathies.

Background. This study evaluated the survival and functions of encapsulated porcine hepatocytes after intraperitoneal allotransplantation and xenotransplantation without immunosuppression. Methods. Isolated porcine hepatocytes were encapsulated in AN 69 polymer capsules (45·10 6 /capsule) and transplanted intraperitoneally in 12 rats and 12 pigs. Fifteen, 30, and 60 days after transplantation, capsules were removed and the viability and morphology of explanted hepatocytes were examined under light and electronic microscopy. The potential to produce albumin was assessed by evaluating the level of albumin messenger RNA, using semiquantitative reverse transcription—polymerase chain reaction. 6β-Hydroxylase activity was measured by high-performance liquid chromatography. In addition, cytochrome P450 3A proteins were detected by Western blot only in allogeneic hepatocytes. Results. Similar results were observed after allotransplantation and xenotransplantation. Histologic studies showed that hepatocytes were well-preserved and arranged in cords for up to 30 days. The expression of porcine albumin gene was maintained up to 15 days. 6β-Hydroxylase activity was 2.5-fold lower at day 15 than in freshly encapsulated hepatocytes, which were not transplanted. In allogeneic hepatocytes, the expression of CYP 3A protein was detected up to 60 days after transplantation. Conclusions. Encapsulated porcine hepatocytes remain viable and functional for at least 15 days after allotransplantation and xenotransplantation without immunosuppression. The demonstration of maintained hepatic functions in transplanted porcine hepatocytes up to 15 days is a first step toward application in the treatment of acute liver failure. (Surgery 2001;129:606-16.)

Aim The aim of this study was to analyse characteristics of patients who survived more than 5 years after liver resection of colorectal metastases. Methods A multicentre retrospective study collected 1818 patients who underwent curative resection of hepatic metastases between 1959 and 1991. Among the 747 patients operated on before 1987, 102 survived longer than 5 years, and were compared with patients who survived less than 5 years. Results Three risk factors proved independently significant in multivariate analysis between the two groups: serosa infiltration (P = 0·003), involvement of peritumoral lymph nodes around the primary colorectal tumour (P = 0·04), and a liver resection margin of less than 1 cm (P = 0·02). There was no significant difference for other parameters studied (location of primary tumour, location, number and size of metastases, type of resection). A trend towards a shorter survival of patients with increased carcinoembryonic antigen serum level was observed. Conclusion Resection of colorectal hepatic metastases can provide long-term survival even in patients with poor prognostic factors. It seems justified to undertake resection of colorectal liver metastases whenever it may be performed safely as a curative treatment.

Background. Hepatocyte transplantation could be an alternative to whole organ transplantation to correct enzymatic disorders. To this end, it would be of major importance to use xenogeneic cells without immunosuppression. The aim of this study was to investigate the survival and metabolic activity of encapsulated xenogeneic hepatocytes in the absence of immunosuppression. For this purpose, we used Gunn rats genetically incapable of bilirubin conjugation. Methods. Xenogeneic (from guinea pigs) and allogeneic (from Lewis rats) hepatocytes (2x 10 7 ) were isolated, macroencapsulated in hydrogel hollow fibers made with an acrylonitrile-sodium methallyl-sulfonate copolymer, and transplanted into the peritoneum of Gunn rats without any immunosuppression. Plasma bilirubin levels were evaluated weekly. Bilirubin conjugates in bile and cell morphology were studied after 5 and 12 weeks, respectively. Results. In Gunn rats transplanted with xenogeneic hepatocytes, a significant decrease in the serum bilirubin level was observed between 3 and 9 weeks after transplantation when compared with controls transplanted with empty hollow fibers: it fell to 62% of the initial level at weeks 5-7 (P

The purpose of the present study was to assess the prognostic impact of positive surgical margins (R1) after liver resection (LR) of colorectal liver metastases (CRLM) in the era of modern chemotherapy regimens. R1 resection is a negative prognostic factor after LR of CRLM. The significance of R1 margins in the era of effective chemotherapy is unknown.From January 2000 to December 2009, 215 patients (177 men: 62 %; median age 60 years; range 30-84 years) underwent LR of CRLM. The LR was considered R1 (margin1 mm) in 49 patients (23 %) and R0 in 166 patients (77 %). Overall, 108 (50 %) patients received preoperative chemotherapy and 156 (72 %) patients received postoperative chemotherapy.With a median follow-up of 36 months (range 1-141 months), the 5-year overall survival (OS) rate (47 vs 40 %; p = 0.05) and the disease-free survival (DFS) rate (36 vs 23 %; p = 0.006) were significantly lower in the R1 group. Recurrence developed in 152 patients (71 %) and the rate of recurrence was significantly higher (84 vs 67 %; p = 0.02) in the R1 group. On multivariate analysis, N+ status of the colorectal primary tumor (p = 0.008), presence of radiologically occult disease (p = 0.04), and R1 resection (p = 0.03) were independent adverse predictors of OS. The N+ status of the primary tumor (p = 0.003) and R1 resection (p = 0.02) were independent adverse predictors of DFS. On multivariate analysis use of postoperative chemotherapy was the only independent predictor of improved DFS (p = 0.02) in the R1 group.A positive resection margin remains a significant poor prognostic factor after LR of CRLM in the era of modern chemotherapy. Postoperative chemotherapy reduces recurrence rates after R1 resection of CRLM.

Evaluation of biomarkers and clinical factors associated with cancer-specific survival after curative resection for colorectal cancer liver metastases (LM).All patients who had an R0 resection for LM between 2000-2006 were reviewed. Clinical and histological data were assessed; p53 expression was studied by IHC. ERCC1 codon 118 and XRCC1 codon 399 were analyzed by PCR-RFLP using BsrDI and HpaII, respectively.Out of 119 patients included (80 synchronous LM (67.2%), median number 2 (1-18)), 104 patients (87.4%) received chemotherapy before recurrence; 60 patients (50.4%) had a p53 negative tumor. ERCC1 distribution was: 31(26%) AAC/AAC, 44(37%) AAC/AAT and 44(37%) AAT/AAT. XRCC1 distribution was: 46(39%) CGG/CGG, 53(44.9%) CGG/CAG and 19(16.1%) CAG/CAG. Three and 5-years disease free survival (DFS) and overall survival (OS) were 31%, 22.7%, 77.4%, and 66.6%, respectively. Node ratio0.2 (p = 0.0042), LM number3 (p0.0001), bilobar localization (p = 0.0074) and preoperative chemotherapy (p = 0.0036) were associated with a shorter DFS. None of the biomarkers was found to influence DFS. In multivariate analysis, a number of LM3 was the only independent factor. No factor was found to influence OS.The studied biomarkers had no significant impact on prognosis. For routine practice, clinical factors remain the only usable available tools.

BACKGROUND Five-year survival rates after resection of liver metastases from colorectal carcinoma are close to 25%. Recurrences occur in two-thirds of the patients after surgery. Selection of patients likely to benefit from surgery remains controversial and subjective. METHODS Data from 1568 patients with resected liver metastases from colorectal carcinoma were collected. The prognostic value of different factors was studied through uni- and multivariate analyses. A scoring system was developed including the most relevant factors. RESULTS Two- and 5-year survival rates were 64% and 28%, respectively, and were affected by: age; size of largest metastasis or CEA level; stage of the primary tumor; disease free interval; number of liver nodules; and resection margin. Giving one point to each factor, the population was divided into three risk groups with different 2-year survival rates: 0–2 (79%), 3–4 (60%), 5–7 (43%). CONCLUSIONS A simple prognostic scoring system was proposed to evaluate the chances for cure of patients after resection of liver metastases from colorectal carcinoma. The comparison between expected survival and estimated operative risk can help determine on an objective basis whether surgery is worthwhile. This system needs further prospective validation. Cancer 1996;77:1254-62.

A new high-water-content (83%) and highly permeable anionic polyelectrolyte hydrogel was obtained by phase inversion of a polymer solution containing 6% polyacrylonitrile-sodium methallylsulphonate, 91% dimethylsulphoxide and 3% physiological saline solution. Hydrogel-based hollow fibres (HFs) were fabricated with a co-extrusion apparatus in collaboration with Hospal (France). HFs have an internal diameter of 800 microns and a wall thickness of 100 microns. Experimental results demonstrated that hydrogel-based HFs were permeable to albumin (mol. wt 69,000) and human immunoglobulin G (150,000), but were impermeable to immunoglobulins A (170,000) and M (900,000) after 24 h of diffusion. In vitro, the viability of isolated rat hepatocytes injected into the HFs was 64 +/- 6% after 10 d versus 30 +/- 5% for hepatocytes cultured in Petri dishes (P = 0.0001). Under these conditions, the amount of albumin released by encapsulated hepatocytes was 12 +/- 3 micrograms/24 h/10(6) cells at day 10, whereas at that time no albumin was released by hepatocytes cultured in Petri dishes. In vivo, histological study of hydrogel HFs implanted up to 6 wk in the peritoneum of rats revealed a low inflammatory tissue reaction without giant multinucleate cells in the foreign tissue, which decreased after the third week. The survival rate of encapsulated hepatocytes was over 85% 45 d after transplantation in the peritoneum of syngeneic Lewis rats. Therefore, this hydrogel demonstrates highly favourable properties for encapsulation of hepatocytes with regard to its biocompatibility, permeability and ability to maintain hepatocytes in a functional state for prolonged periods.

Hepatocyte transplantation could be an alternative to whole liver transplantation. Allogeneic hepatocytes are rejected if transplanted without immunosuppression. The aim of this study was to transplant allogeneic hepatocytes in the peritoneum and to protect them from rejection by encapsulation in a new semipermeable membrane.Rat hepatocytes were encapsulated in hydrogel-based hollow fibers, obtained from AN69 copolymer, before being transplanted into the peritoneum of rats. Outcome of allogeneic hepatocytes encapsulated in hollow fibers was compared with that of syngeneic hepatocytes encapsulated in hollow fibers, with that of free allogeneic hepatocytes, and with allogeneic hepatocytes encapsulated in hollow fibers left open. Cell viability was assessed by erythrosin exclusion, structure by electron microscopy, and function by albumin release.Up to 90 days, viability of allogeneic hepatocytes in hollow fibers was greater than 80%. The structure remained normal at electron microscopy. Albumin release was 16.5 +/- 0.3 micrograms/24 hr/10(6) hepatocytes (day 15), 14.2 +/- 2.0 micrograms/24 hr/10(6) hepatocytes (day 30), 8.8 +/- 0.1 micrograms/24 hr/10(6) hepatocytes (day 60), and 11.4 +/- 0.3 micrograms/24 hr/10(6) hepatocytes (day 90). Free hepatocytes and hepatocytes in hollow fibers left open did not survive at day 15.Viability and function of encapsulated allogeneic hepatocytes were maintained up to 90 days after transplantation, without immunosuppression.

Experimental studies have shown that liver ischemia-reperfusion induces Kupffer cell activation and tumor necrosis factor- α (TNF α ) release. The aim of this work was to determine whether severe hepatic ischemia and subsequent reperfusion triggers TNF α release in man. Serum TNF α was measured before and 3, 10, 30, 60, 120 min after revascularization and postoperatively at day 1 and 2 in 11 patients with orthotopic liver transplantation (group 1 and 4 patients with liver resection with vascular occlusion (group 2). In group 1, TNF α levels decreased during the first few minutes of reperfusion, then increased slightly to peak at 120 min (40 ± 13 pg/ml). Primary non-function occurred in 1 patient in whom low peroperative levels of TNF α levels were measured. In group 2, no significant changes in TNF α levels were observed. These data, in a small number of patients: (a) show that hepatic ischemia reperfusion does not result in major TNF α production; (b) do not support a primary pathogenic role for TNF α in damage after ischemia-reperfusion in humans.

International audience; BackgroundChronic hepatitis C is a major cause of liver fibrosis and cirrhosis. It is generally accepted that inflammation that occurs in response to hepatocyte infection by the hepatitis C virus (HCV) is the main mechanism that triggers myofibroblast differentiation and stimulation in chronic hepatitis C. The aim of this study was to determine if HCV might infect human liver myofibroblasts (HLMF) and directly stimulate their fibrogenic activities.MethodsWe evaluated the expression of the viral entry receptors, levels of HCV-RNA and HCV-protein and the expression of fibrosis markers in HLMF by using quantitative PCR, western blot and immunofluorescence analyses. Pseudoparticles (HCVpp) and cell culture–derived HCV (HCVcc) were used to study the ability of HLMF to support viral entry, replication and fibrosis induction.ResultsWe showed that HLMF expressed all known molecules of the HCV receptor complex, i.e. CD81, LDL-R, scavenger receptor-BI, claudin-1 and occludin. These cells were also permissive to HCVpp entry. Inoculation with HCVcc caused short-term infection of these cells, as shown by their content in positive- and negative-strand HCV RNA, in core and NS3 viral proteins, and by their release of core protein levels in the culture supernatants. HCV infection stimulated myofibroblastic differentiation, proliferation and collagen production in these cells. In addition, evidence of in vivo infection was provided by the detection of positive- and negative-strand HCV RNA in preparations of HLMF obtained from HCV-infected patients.ConclusionThese findings indicate that HCV infection of HLMF can occur and trigger extracellular matrix overproduction, thereby contributing to the development of HCV-related liver fibrosis.

To examine the potential of cultured human liver slices to predict cytochrome P450 (CYP) inducibility, regarding global and zonal CYP expression, together with drug-induced histologic changes.We first assessed whether CYP2B6, 3A4, and 2C9 expression was maintained in cultured liver slices. Cultured hepatocytes were used as the reference culture system. Then we tested the effects of phenobarbital and cyclophosphamide on CYP expression in both models.Morphologic features are preserved in slices. Basal CYP expression declines with time in culture in both models. Slices display the same region specificity of CYP2B6, 2C9, and 3A4 expression as intact liver. CYP2B6 and 3A4 mRNA, apoprotein, and enzyme-related activities were induced by phenobarbital and cyclophosphamide, whereas CYP2C9 apoprotein was not. Their immunoreactivities were also increased, while their zonal distribution was preserved on slice tissue sections. Microsomal enzyme induction was confirmed by histology.Cultured human liver slices are an attractive alternative to hepatocyte culture for the prediction of human CYP isoenzyme induction by xenobiotics.

Purpose: In a pharmacoeconomic approach of anesthesia, postanesthesia care unit (PACU) occupancy can be chosen as a criteria of effectiveness to compare two anesthetic drugs with different rates of elimination and different costs of administration. Our objective was to develop a cost-effectiveness approach for the comparison of isoflurane (I) and desflurane (D). Method: In this prospective observational study, 68 patients aged 18–70 received either D or I for maintenance of anesthesia for inpatient abdominal procedures. Length of stay (LOS) in PACU was collected by a blinded observer. After the relationship between duration of surgery and LOS in PACU had been established in the 68 observed patients, we estimated the PACU occupancy according to duration of surgery and time of admission in PACU using a computer model of 204 consecutive patients, based on the hypothesis of an exclusive use of either D or I. Outcome measures were direct costs of the anesthesia procedure and occupancy of the PACU. Results: The direct cost of the anesthetic was significantly higher with D than with I. This represents an increase of CAN$ 2 708 for the 204 patients. PACU occupancy was reduced by at least one patient (out of five beds) during 26.1% of the time with D (P

Introduction La fermeture d’une ileostomie (FI) protegeant une anastomose colo-rectale basse ou colo-anale peut etre associee a la resection hepatique (RH) necessaire pour traitement secondaire de metastases hepatiques (MH) d’un cancer colo-rectal reseque. L’association d’une anastomose digestive a la RH est susceptible d’en majorer la morbidite, sans que ceci n’ait ete a ce jour bien evalue. Cette etude a analyse l’impact eventuel de la FI simultanee sur la morbidite des RH pour MH. Patients et methodes De 1996 a 2012, 408 patients ont beneficie d’une RH pour MH. Les 24 patients (6 %) ayant eu une RH associee a une FI (groupe RH + FI), effectuee avant l’hepatectomie, ont ete apparies un a un avec 3 patients operes d’une RH seule (groupe RH de 72 patients) sur les 3 criteres suivants : type de RH, realisation d’une chimiotherapie preoperatoire et la realisation de ≥ 6 cycles avant l’hepatectomie. Resultats Les deux groupes etaient comparables pour l’âge, le sexe, le score ASA, les taux de MH multiples, de MH bilaterales. Un seul patient est decede (groupe RH) en postoperatoire (1 %). L’usage du clampage pediculaire et sa duree, les taux de complications hepatiques et de morbidite globale et Clavien 3–5 etaient comparables dans les deux groupes. Aucun patient n’a developpe de fistule anastomotique sur le site de la FI. Conclusion La FI peut etre realisee simultanement a la RH et ne semble pas en majorer sa morbidite.

We have previously demonstrated that allogenic and xenogenic hepatocytes macroencapsulated manually in AN-69 polymer and transplanted intra-peritoneally in rats remained viable for several weeks. However, this manual technique is inadequate to encapsulate several billions of hepatocytes which would be required to correct hepatic failure in big animals or humans. In the present study, we developed an original semiautomatic device in which isolated pig hepatocytes and the polymer solution containing 6% poly(acrylonitrile-sodium methallylsulfonate), 91% dimethylsulfoxide and 3% 0.9% NaCl solution were coextruded through a double-lumen spinneret. The extruded minitube (inner diameter: 1.8 mm, wall thickness: 0.07-0.1 mm) containing the encapsulated hepatocytes fell and coiled up in a 0.9% NaCl solution at 4 degrees C and was cut down in 4 m units containing about 120 million hepatocytes. This process allowed to encapsulate 50 million hepatocytes by minute with a preserved immediate cell viability (92 +/- 5%). To test prolonged cell viability after coextrusion, the minitubes were implanted intraperitoneally in rats. Three and seven days after implantation, they were explanted and analyzed. Cells were viable and well-preserved. Therefore, the semiautomatic device appears able to efficiently macroencapsulate in a limited time several billions of porcine hepatocytes which remain viable after transplantation in xenogenic conditions.

To evaluate new therapies for human fulminant hepatic failure, a suitable large animal model is needed. The purpose of this study was to develop a reversible surgical model of acute hepatic liver failure by transient ischemia in pigs.Under general anesthesia, an end-to-side portacaval shunt was performed in 17 pigs and tape was laid around the hepatoduodenal ligament. Two days after construction of the functional portacaval shunt, 13 ambulant pigs underwent transient total liver ischemia by tightening of the tape around the hepatoduodenal ligament for 5.5 h. During ischemia, 10% glucose was continuously infused intravenously to prevent hypoglycemia.Ten animals (77%) died with hepatic coma after a mean duration of 22.5 +/- 1.9 h. The 3 remaining animals survived more than 5 days and were sacrificed. In dying animals, encephalopathy was observed 14 +/- 1.7 h after the onset of ischemia. During ischemia, similar progressive decrease of fibrinogen, platelets, prothrombin time, and factors V and VII activities was observed in dying and surviving animals. Just before death, mean prothrombin and factors V and VII activities were respectively 22 +/- 2, 21 +/- 4.4, and 24 +/- 5%. At 22 h, plasma ammonia and lactate levels were respectively 705 +/- 93 micromol/L and 10.5 +/- 0.4 mmol/L in dying animals and 249 +/- 75 micromol/L and 2.9 +/- 0.1 mmol/L in surviving animals (P0.01). Estimation of the percentage liver cells necrosed was 74 +/- 4.7% in the survivors and 86 +/- 5.5% in animals who died of hepatic coma (NS).This model is reproducible and reversible and should allow the quantitative evaluation of new technologies, such as bioartificial liver, for the support of hepatic failure in humans.

Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals, may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that biliary epithelial cells (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), alpha, mu, and pi glutathione S-transferase (GST), transcripts and proteins. We also identified CYP-associated steroid 6beta-hydroxylase activity in BEC. CYP and mEH expression was 5- to 20-fold lower in BEC than in autologous hepatocytes, and further differed by a higher ratio of CYP3A5/CYP3A4, and by CYP1A1 predominance over CYP1A2. alphaGST was highly expressed in both hepatocytes and BEC, while piGST was restricted to BEC. In approximately 50% of individuals, muGST was expressed in hepatocytes and at lower levels in BEC. By using the same antibodies as those used in immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH, alpha, mu, and piGST immunoreactivities are expressed and display a heterogeneous distribution in the epithelium lining the entire biliary tract except for small intrahepatic bile ducts that were devoid of CYP3A and alphaGST immunoreactivities. In conclusion, BEC contribute to phase II, and although to a lesser extent than hepatocytes, to phase I biotransformation. The distribution of drug-metabolizing enzymes in BEC suggest that they are heterogeneous in their ability to generate and detoxicate reactive metabolites, which may contribute to specific distributions of cholangiopathies.

BACKGROUND & AIMS: The cellular mechanisms that regulate biliary mucin secretion in humans are unknown. To address this question, human gallbladder epithelial cells were used in primary culture. METHODS: [1- (14)C]-glucosamine-labeled glycoproteins secreted in vitro were analyzed and quantified after exposing cells to activators and inhibitors of the main transduction pathways and to potential biologically active secretagogues. RESULTS: Secreted glycoproteins showed characteristics of biliary mucins. Activators of adenosine 3',5'- cyclic monophosphate-dependent pathway as well as secretin and vasoactive intestinal polypeptide did not significantly modify mucin secretion. By contrast, ionomycin and phorbol-12-myristate 13-acetate increased mucin secretion by 292% +/- 48% and 134% +/- 19% over basal level, respectively. The effects of these two agents were additive and were mediated by a calcium-dependent pathway implicating Ca2+/calmodulin-dependent protein kinase II (Ca2+/CaM-kinase II) and by the activation of protein kinase C (PKC), respectively, as ascertained by using inhibitors. Mucin secretion was stimulated by extracellular adenosine 5'-triphosphate via P2U receptors, cytosolic calcium increase, and PKC and by taurochenodeoxycholate via cytosolic calcium increase and Ca2+/CaM-kinase II. CONCLUSIONS: Mucin secretion in human gallbladder is regulated predominantly by calcium-dependent pathways implicating Ca2+/CaM-kinase II and PKC. Extracellular adenosine 5'- triphosphate and taurochenodeoxycholate may play a role in the regulation of biliary mucin secretion by activating these different signaling pathways. (Gastroenterology 1997 Mar;112(3):978-90)

The effects of liver transplantation on the pituitary-gonadal axis and sex-hormone metabolism were evaluated by studying hormonal status (androgens, oestrogens, and gonadotropins) and sex-hormone-binding globulin levels in men with advanced liver disease of both alcoholic and viral origins. Comparison of the results prior to and 6 months after liver transplantation showed that successful liver transplantation in men induced significant differences in sex-hormone levels and in pituitary-gonadal function in both alcoholic and post-hepatitis patients. Plasma testosterone and dihydrotestosterone levels increased, oestrogen (oestrone and oestradiol) and androstenedione levels fell while gonadotropin (FSH and LH) levels increased. There was also a fall in plasma prolactin levels. Sex-hormone binding globulin plasma levels were elevated prior to transplantation and decreased thereafter. These data show that male patients with advanced liver disease have biological hypogonadism and feminization, irrespective of the aetiology, and that these abnormalities rapidly improve after successful liver transplantation. Therefore in men with advanced liver disease the biochemical signs of sex hormone disturbance are reversible and may be largely related to the liver disease.

Hepatic resection is the only treatment that offers chances for cure in patients with hepatic metastases from colorectal cancer. However, even if some patients are still alive and disease-free 5 years after hepatic resection, most do not benefit from surgery due to early recurrences. Reliable selection criteria would be very useful for detecting before surgery the patients who can benefit from resection and for avoiding unprofitable resection or laparotomy in others.

French foreing trade between 1960 and 1970, by Jean-Pierre Balladur. French foreign trade in the last decade has been distinguished by a thorough geographic reorientation brought about by a progressive easing of French trade relations with members of the French franc area, a growing involvement with the European economic community and the opening of new frontiers in accordance with the regulations of G.A.T.T. Even though such a change has not come easily, France was generally able to balance its foreign trade until 1968. This was accomplished despite a change in the composition of industrial exports which resulted in a rise in the sales of industrial goods. This rise has been less rapid than that for exports. The balance proved to be delicate during the crisis of May-June 1968. However, the advantage of competitiveness gained through the 1969 devaluation should enable France during the Sixth Plan to set up an industrial structure capable of strengthening the trade equilibrium restored since 1970. In the last decade, the balance of current invisible operations deteriorated continuously as a result of the influx of foreign workers and the foreign aid policy to underdeveloped countries. Conversely, since 1963 the balance of long term capital movements has shown a surplus but this surplus has been diminishing., Los intercambios exteriores de Francia entre los años 1960 y 1970, por Jean-Pierre Balladur. Los intercambios exteriores de Francia en el transcurso del último decenio, se señalaron por una honda reorientación de su estructura geográfica especialmente facilitada por el aflojamiento progresivo de las reiaciones francesas con los países de la zona del franco, su integración en el seno de la Comunidad europea y la abertura de las fronteras en el concepto de la participación francesa al G.A.T.T. Semejante mutación no se Ilevó a cabo sin tropiezos, no obstante, Francia pudo en término medio mantener sus intercambios comerciales en las inmediaciones del equilibrio hasta el año 1968, pese a la transformación de la estructura de las exportaciones indus- triales, en el sentido de un incremento de las ventas de productos elaborados, el cual no fué tan rápido como el de las importaciones. Sin embargo, la inestabilidad de un tal equilibrio corner» cial se hizo patente cuando la crisis de 1968, pero las ventajas de competitividad que proporcionaba la devaluación de 1969 debe de permitir a Francia el dotarse en el transcurso del perfodo que abarca el VIe Plan de una estructura industrial capaz de fortalecer en forma duradera un equilibrio comercial restablecido desde 1970. Por su parte, el saldo de las operaciones invisibles corrientes no dejó de degradarse en el transcurso del perfodo debido al aporte de mano de obra extranjera y a la política de ayuda a los países en vías de desarrollo que Francia ha seguido durante el último decenio. Los movimientos de capitales a largo plazo se saldan, en cambio, por ingresos netos anuales desde 1963, los cuales tienden, no obstante, a reducirse. Las tendencias comprobadas para las operaciones invisibles y los movimientos de capitales a largo plazo, de proseguirse, accarrearán en particular la necesidad de conseguir un excedente comercial., Balladur Jean-Pierre. Les échanges extérieurs de la France entre 1960 et 1970. In: Economie et statistique, n°31, Février 1972. pp. 11-21.