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Background Liver resection is a well-established treatment for colorectal, neuroendocrine and sarcomatous metastases but remains ill-defined for metastases from other primary sites. This study aimed to analyze the outcomes of hepatic resection for metastases not of colorectal, neuroendocrine, sarcomatous, or ovarian (NCNSO) origin and to identify predictors of outcome. Methods Retrospective analysis of patients undergoing resection for NCNSO metastases in three western centers. Patients were analyzed according to the primary cancer. Outcomes were recurrence and survival. Results We analyzed 188 patients, divided in: gastrointestinal (59), breast (59) and “others” (70). Median time to recurrence was 15.3 months, while median survival was 52 months. Survival at 1, 3, and 5 years was 78%, 60.4% and 47.8%, respectively. In term of prognostic factors, metastases >35 mm from gastrointestinal tumors were associated with lower survival (p = 0.029) and age>60 years was associated with better survival in breast metastases (p = 0.018). Conclusions Liver resection for NCNSO metastases is feasible and results in long-term survival are similar to colorectal metastases. In gastrointestinal metastases, size (

Background. We report the histopathological results of a novel ‘‘inversed’’ strategy designed to manage patients with colorectal cancer (CRC) who have synchronous liver metastases by using chemotherapy first, liver surgery second, and resection of the primary tumor as a final step. This study was designed to compare the response to chemotherapy in liver metastases, primary tumors, and locoregional lymph nodes. Methods. Twenty-nine patients with stage IV CRC received a combination of oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin (OCFL) for 3–4 months. Histological response to chemotherapy was assessed by using a tumor regression grading (TRG) score based on presence of residual tumor cells and extent of fibrosis. Results. Median age of patients was 56 (range, 37–69) years. Primary tumor location was right colon ( n= 5), left colon ( n= 7), and rectum ( n= 17 patients). TRG scores correlated across disease sites (Spearman correlation coefficients for TRG in the primary tumor and lymph nodes was 0.59 [ P= 0.005]; for the primary tumor and metastases 0.44 [ P= 0.021]; and for lymph nodes and metastases 0.58 [ P= 0.006]). Complete absence or poor tumor response (TRG4/5) was significantly more frequent in primary tumors (35.7%) and locoregional lymph nodes (38%) than in liver metastases (6.9%; McNemar test, P= 0.02). Two patients had a complete pathologic response (pT0N0M0). Conclusions. In patients with stage IV colorectal cancer, liver metastases exhibit a better histological response than primary tumors to OCFL neoadjuvant chemotherapy.

Objective: The purpose of the study was to analyze clinical presentation, surgical management, and long-term outcome of patients suffering from biliary diverticulum, namely Todani type II congenital bile duct cyst (BDC). Background: The disease incidence ranges between 0.8% and 5% of all reported BDC cases with a lack of information about clinical presentation, management, and outcome. Methods: A multicenter European retrospective study was conducted by the French Surgical Association. The patients' medical records were included in a Web site database. Diagnostic imaging studies, operative and pathology reports underwent central revision. Results: Among 350 patients with congenital BDC, 19 type II were identified (5.4%), 17 in adults (89.5%) and 2 in children. The biliary diverticulum was located at the upper, middle, and lower part of the extrahepatic biliary tree in 11, 4, and 4 patients (58%, 21%, and 21%, respectively). Complicated presentation occurred in 6 patients (31.6%), including one case of synchronous carcinoma. Surgical techniques included diverticulum excision in all patients. Associated resection of the extrahepatic biliary tree was required in 11 cases (58%) and could be predicted by the presence of complicated clinical presentation. There was no mortality. Long-term outcome was excellent in 89.5% of patients (median follow-uptime: 52 months). Conclusions: According to the present largest Western series of Todani type II BDC, the type of clinical presentation rather than BDC location, was able to guide the extent of biliary resection. Excellent long-term outcome can be achieved in expert centers.

Background: In advanced metastatic colorectal adenocarcinoma, the addition of a neo-adjuvant systemic treatment to surgery might translate into a survival advantage, although this is yet to be confirmed by ongoing randomized trials. The objective of this study was to assess the effects of preoperative systemic chemotherapy on the morphology of non-tumoral liver. Patients and methods: A large series of surgically resected liver metastases (n = 153) was selected. Light microscopy, electron microscopy, and immunohistochemistry using antibodies against endothelial cells (CD31) and hepatic stellate cells (α-SM actin, CRBP-1) were performed to identify sinusoidal wall integrity. Results: We found that 44 (51%) of the 87 post-chemotherapic liver resection specimens had sinusoidal dilatation and hemorrhage, related to rupture of the sinusoidal barrier. In contrast, the 66 livers treated by surgery alone remained normal. In 21 out of the 44 post-chemotherapy patients (48%), perisinusoidal and veno-occlusive fibrosis also developed. Sinusoidal injury persisted several months after end of chemotherapy, and fibrosis may progress. Development of lesions was strongly correlated to the use of oxaliplatin; 34 out of 43 patients (78%) treated with this drug showed striking sinusoidal alterations. Conclusions: Systemic neo-adjuvant chemotherapy in metastatic colorectal cancer frequently causes morphological lesions involving hepatic microvasculature. Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non-tumoral liver revealed by this study, should be included in the list of the adverse side-effects of colorectal systemic chemotherapy, in particular related to the use of oxaliplatin

BC are a common source of morbidity after pediatric LT. Knowledge about risk factors may help to reduce their incidence. Retrospective analysis of BC in 116 pediatric patients (123 LT) (single institution, 05/1990-12/2011, medium follow-up 7.9 yr). One-, five-, and 10-yr survival was 91.1%, no patient died of BC. Prevalence and risk factors for anastomotic and intrahepatic BC were examined. There were 29 BC in 123 LT (23.6%), with three main categories: 10 (8.1%) primary anastomotic strictures, eight (6.5%) anastomotic leaks, and three (2.4%) intrahepatic strictures. Significant risk factors for anastomotic leaks were total operation time (increase 1.26-fold) and early HAT (48 yr (increase 1.09-fold) and MELD score >30 (increase 1.2-fold). To avoid morbidity from anastomotic BC in pediatric LT, the preferred biliary anastomosis appears to be biliary-enteric. Operation time should be kept to a minimum, and HAT must by all means be prevented. Children with a high MELD score or receiving livers from older donors are at increased risk for intrahepatic strictures.

Liver resection is generally restricted to patients without clinically significant portal hypertension (Hepatic Venous Pressure Gradient - HVPG - ⩽10mmHg) and several teams perform transjugular HVPG measurements as part of the pre-operative work-up. The present study investigates whether a non-invasive Computed Tomography (CT)-based assessment could be as accurate as the invasive transjugular measurement.A cohort of patients with hepatocellular carcinoma (HCC) treated by resection (n=36) or transplantation (n=39) was selected (mean age: 61±9.2years, male/female ratio: 4/1). Pre-operative CTs were read by two independent investigators, and potential CT-based HVPG predictors were compared to the transjugular HVPG measurements. A validation was conducted on another cohort of 70 non-surgical patients.The invasive HVPG values were significantly correlated to liver/spleen volume ratio, spleen volume, platelet count, and peri-hepatic ascites (p0.001), which all showed high inter-observer agreements (intra-class correlation coefficients ⩾0.927, Kappa ⩾0.945). The presence of a HVPG10mmHg was best predicted by the liver/spleen volume ratio (AUC: 0.883 [0.805-0.960]) and the peri-hepatic ascites (p0.001). These two variables were combined into an accurate model for predicting HVPG10mmHg (AUC: 0.911 [0.847-0.975]), with sensitivity, specificity, and positive and negative predictive values of 92%, 79%, 91%, and 81%. The model was also accurate in the validation cohort with an AUC of 0.820 [0.719-0.921]. The computed formula was:The proposed CT-based model showed a high accuracy in the prediction of HVPG and, if further confirmed by prospective validation, could replace the invasive transjugular assessment in patients not requiring a biopsy of the non-tumoral liver.

Background To date, studies assessing the risk of post-transplant hepatocellular carcinoma (HCC) recurrence have focused on tumour characteristics. This study investigated the impact of donor characteristics and graft quality on post-transplant HCC recurrence. Methods Using the Scientific Registry of Transplant Recipients patients with HCC who received a liver transplant between 2004 and 2011 were included, and post-transplant HCC recurrence was assessed. A multivariable competing risk regression model was fitted, adjusting for confounders such as recipient sex, age, tumour volume, α-fetoprotein, time on the waiting list and transplant centre. Results A total of 9724 liver transplant recipients were included. Patients receiving a graft procured from a donor older than 60 years (adjusted hazard ratio (HR) 1·38, 95 per cent c.i. 1·10 to 1·73; P = 0·006), a donor with a history of diabetes (adjusted HR 1·43, 1·11 to 1·83; P = 0·006) and a donor with a body mass index of 35 kg/m2 or more (adjusted HR 1·36, 1·04 to 1·77; P = 0·023) had an increased rate of post-transplant HCC recurrence. In 3007 patients with documented steatosis, severe graft steatosis (more than 60 per cent) was also linked to an increased risk of recurrence (adjusted HR 1·65, 1·03 to 2·64; P = 0·037). Recipients of organs from donation after cardiac death donors with prolonged warm ischaemia had higher recurrence rates (adjusted HR 4·26, 1·20 to 15·1; P = 0·025). Conclusion Donor-related factors such as donor age, body mass index, diabetes and steatosis are associated with an increased rate of HCC recurrence after liver transplantation.

Background: Central pontine and extrapontine myelinolysis (CPEPM) is a rare but potentially fatal complication after orthotopic liver transplantation (OLT). The aim of this study was to identify risk factors for development of CPEPM after OLT and to assess patient outcome. Methods: We reviewed the clinical data of 1,378 patients who underwent OLT between 1987 and 2009 in Geneva, Switzerland and Edmonton, Canada. Nineteen patients (1.4%) developed CPEPM. We compared their characteristics with control patients, matched by age, gender, date of OLT, and MELD score. Results: The 19 patients with CPEPM (7F, mean age 52.1±2years) had a mean MELD score of 26±2.2. Before OLT, patients who develop CPEPM presented more frequently low (2 of these conditions were strongly associated with CPEPM (p=0.00015). Mortality at 1 year of patients developing CPEPM was higher (63 vs. 13%, p

We analyzed the impact of chemotherapy-related liver injuries (CALI), pathological tumor regression grade (TRG), and micrometastases on long-term prognosis in patients undergoing liver resection for colorectal metastases after preoperative chemotherapy.CALI worsen the short-term outcomes of liver resection, but their impact on long-term prognosis is unknown. Recently, a prognostic role of TRG has been suggested. Micrometastases (microscopic vascular or biliary invasion) are reduced by preoperative chemotherapy, but their impact on survival is unclear.Patients undergoing liver resection for colorectal metastases between 1998 and 2011 and treated with oxaliplatin and/or irinotecan-based preoperative chemotherapy were eligible for the study. Patients with operative mortality or incomplete resection (R2) were excluded. All specimens were reviewed to assess CALI, TRG, and micrometastases.A total of 323 patients were included. Grade 2-3 sinusoidal obstruction syndrome (SOS) was present in 124 patients (38.4%), grade 2-3 steatosis in 73 (22.6%), and steatohepatitis in 30 (9.3%). Among all patients, 22.9% had TRG 1-2 (major response), whereas 55.7% had TRG 4-5 (no response). Microvascular invasion was detected in 37.8% of patients and microscopic biliary infiltration in 5.6%.The higher the SOS grade the lower the pathological response: TRG 1-2 occurred in 16.9% of patients with grade 2-3 SOS versus 26.6% of patients with grade 0-1 SOS (P = 0.032).After a median follow-up of 36.9 months, 5-year survival was 38.6%. CALI did not negatively impact survival. Multivariate analysis showed that grade 2-3 steatosis was associated with better survival than grade 0-1 steatosis (5-year survival rate of 52.5% vs 35.2%, P = 0.002). TRG better than the percentage of viable cells stratified patient prognosis: 5-year survival rate of 60.4% in TRG 1-2, 40.2% in TRG 3, and 29.8% in TRG 4-5 (P = 0.0001). Microscopic vascular and biliary invasion negatively impacted outcome (5-year survival rate of 23.3% vs 45.7% if absent, P = 0.017; 0% vs 42.3%, P = 0.032, respectively).TRG was confirmed to be a crucial prognostic determinant. CALI do not negatively impact long-term prognosis, but the tumor response is reduced in patients with grade 2-3 SOS. Steatosis was found to have a protective effect on survival. Micrometastases significantly impacted prognosis assessment.

Obesity is associated with poor health outcomes in the general population, but the evidence surrounding the effect of body mass index (BMI) on postliver transplantation survival is contradictory. The aim of this study was to assess the impact of wait list BMI and BMI changes on the outcomes after liver transplantation. Using the Scientific Registry of Transplant Recipients, we compared survival among different BMI categories and examined the impact of wait list BMI changes on post-transplantation mortality for patients undergoing liver transplantation. Cox proportional hazards multivariate regression was carried out to adjust for confounding factors. Among 38 194 recipients, underweight patients had a poorer survival compared with normal weight (HR = 1.3, 95% CI: 1.13-1.49). Conversely, overweight and mildly obese men experienced better survival rates compared with their lean counterparts (HR = 0.9, 95% CI: 0.84-0.96, and HR = 0.86, 95% CI: 0.79-0.93 respectively). Female patients gaining weight over 18.5 kg/m(2) while on the wait list showed improving outcomes (HR = 0.46, (95% CI: 0.28-0.76)) compared with those remaining underweight. This study supports the harmful impact of underweight on postliver transplant survival, and highlights the need for a specific monitoring and management of candidates with BMIs close to 18.5 kg/m(2) . Obesity does not constitute an absolute contraindication to liver transplantation.

International audience; 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.

The aim of the present study was to assess the efficiency of cell-based immune assays in the detection of alloreactivity after islet transplantation and to correlate these results with clinical outcome. Mixed lymphocyte cultures were performed with peripheral blood mononuclear cells from recipients ( n = 14), donors, or third party. The immune reactivity was assessed by the release of IFN-γ (ELISpot), cell proliferation (FACS analysis for Ki67), and cytokine quantification (Bioplex). Islet function correlated with the number of IFN-γ-secreting cells following incubation with donor cells ( p = 0.007, r = –0.50), but not with third party cells ( p = 0.61). Similarly, a high number of donor-specific proliferating cells was associated with a low islet function ( p = 0.006, r = −0.51). Proliferating cells were mainly CD3+CD4+ lymphocytes and CD3-CD56+ natural killer cells (with low levels of CD3+CD8+ lymphocytes). Patients with low islet function had increased levels of CD4+Ki67+cells ( p ≤ 0.0001), while no difference was observed in CD8+Ki67+ and CD56+Ki67+ cells. IFN-γ, IL-5, and IL-17 levels were increased in patients with low islet function, but IL-10 levels tended to be lower. IFN-γ-ELISpot, proliferation, and cytokines were similarly accurate in predicting clinical outcome (AUC = 0.77 ± 0.088, 0.85 ± 0.084, and 0.88 ± 0.074, respectively). Cellular immune reactivity against donor cells correlates with posttransplant islet function. The tested assays have the potential to be of substantial help in the management of islet graft recipients and deserve prospective validation.

BACKGROUND. Surgical strategy for hilar cholangiocarcinoma often includes hepatectomy, but the role of portal vein resection (PVR) remains controversial. In this study, the authors sought to identify factors associated with outcome after surgical management of hilar cholangiocarcinoma and examined the impact of PVR on survival.Three hundred five patients who underwent curative-intent surgery for hilar cholangiocarcinoma between 1984 and 2010 were identified from an international, multi-institutional database. Clinicopathologic data were evaluated using univariate and multivariate analyses.Most patients had hilar cholangiocarcinoma with tumors classified as T3/T4 (51.1%) and Bismuth-Corlette type II/III (60.9%). Resection involved extrahepatic bile duct resection (EHBR) alone (26.6%); or hepatectomy and EHBR without PVR (56.7%); or combined hepatectomy, EHBR, and PVR (16.7%). Negative resection (R0) margin status was higher among the patients who underwent hepatectomy plus EHBR (without PVR, 64.2%; with PVR, 66.7%) versus EHBR alone (54.3%; P.001). The median number of lymph nodes assessed was higher among the patients who underwent hepatectomy plus EHBR (without PVR, 6 lymph nodes; with PVR, 4 lymph nodes) versus EHBR alone (2 lymph nodes; P.001). The 90-day mortality rate was lower for patients who underwent EHBR alone (1.2%) compared with the rate for patients who underwent hepatectomy plus EHBR (without PVR, 10.6%, with PVR, 17.6%; P.001). The overall 5-year survival rate was 20.2%. Factors that were associated with an adverse prognosis included lymph node metastasis (hazard ratio [HR], 1.79; P = .002) and R1 margin status (HR, 1.81; P.001). Microscopic vascular invasion did not influence survival (HR, 1.23; P = .19). Among the patients who underwent hepatectomy plus EHBR, PVR was not associated with a worse long-term outcome (P = .76).EHBR alone was associated with a greater risk of positive surgical margins and worse lymph node clearance. The current results indicated that hepatectomy should be considered the standard treatment for hilar cholangiocarcinoma, and PVR should be undertaken when necessary to extirpate all disease. Combined hepatectomy, EHBR, and PVR can offer long-term survival in some patients with advanced hilar cholangiocarcinoma.

BACKGROUND: Resection of hepatic metastases is indicated in selected stage IV colorectal cancer (CRC) patients. A minority will eventually develop pulmonary metastases and may undergo lung surgery with curative intent. The aims of the present study were to assess clinical outcome and identify parameters predicting survival after pulmonary metastasectomy in patients who underwent prior resection of hepatic CRC metastases.¦METHODS: We performed a retrospective analysis of 27 consecutive patients (median age 62 years; range: 33-75 years) who underwent resection of pulmonary metastases after previous hepatic metastasectomy from CRC in two institutions from 1996 to 2009. All patients underwent complete resection (R0) for both colorectal and hepatic metastases.¦RESULTS: Median follow-up was 32 months (range: 3-69 months) after resection of lung metastases and 65 months (range: 19-146 months) after resection of primary CRC. Three- and 5-year overall survival rates after lung surgery were 56 and 39%, respectively, and median survival was 46 months (95% CI 35-57). Median disease-free survival after pulmonary metastasectomy was 13 months (95% CI 5-21). At the time of last follow-up, seven patients (26%) had no evidence of recurrent disease and 6 of these 7 patients presented initially with a single lung metastasis.¦CONCLUSIONS: Resection of lung metastases from CRC patients may result in prolonged survival, even after previous hepatic metastasectomy. Yet, prolonged disease-free survival remains the exception, and seems to occur only in patients with a single lung lesion.

Background & Aims Herpes simplex virus hepatitis is a rare, but severe disease, thus far only documented by case reports and short series. The present study was based on the SRTR registry, and included all listed patients for liver transplantation from 1985 to 2009 with a diagnosis of HSV hepatitis. Methods We assessed demographics and outcome of all listed patients, and further conducted a case–control study, matching each transplanted patient with 10 controls. Matching criteria included: transplant status, MELD score ±5, transplant date ±6months, and age at transplant ±5years. During the study period, 30 patients were listed for HSV hepatitis. Of the 30 listed patients, seven recovered spontaneously and five died, prior to transplantation. The remaining 10 children and eight adults were transplanted. Results The chance of recovery was significantly higher in children than in adults (7/19 vs. 0/11, p =0.02). In children, survival was similar between HSV patients and the matched controls (5-year survival: 69% vs. 64%, p =0.89). Conversely, survival was poor in adult HSV (5-year survival: 38% vs. 65%, p =0.006), with 62% of them dying within the first 12months. All three reported post-transplant deaths in children were independent from HSV. Among the seven adult post-transplant deaths, four were related to infection (bacterial, fungal, or viral). Conclusions Children listed for HSV hepatitis have a significantly better survival than adults both prior and after liver transplantation. While HSV fulminant hepatitis is an appropriate indication for liver transplantation in children, it should only be performed in selected adult patients in otherwise good condition.

Herpes simplex virus (HSV) hepatitis is an uncommon cause of acute liver failure (ALF), primarily affecting immunocompromised patients. So far, 148 cases have been published, of which 9 underwent liver transplantation (LT). The reported post-transplant survival is poor, with over 60% dying in the first year. Dosing and duration of antiviral therapy after LT are not established. Concerns include both the risk of hepatic recurrence after LT and emergence of viral resistance during prolonged therapy. HSV DNA plasma levels might be helpful to monitor therapeutic response and guide duration of therapy. We present a case of ALF complicating a primary HSV-1 infection in an immunocompetent host, who required emergency LT. We further discuss the value of measuring serial HSV DNA plasma loads to monitor antiviral therapy.

BACKGROUND: Traditionally, survival estimates have been reported solely as survival from the time of surgery, but future survival probability likely changes based on the survival time already accumulated after therapy-otherwise known as conditional survival (CS). We sought to assess the comparative performance of various colorectal liver metastasis prognostic scoring systems, as well as to investigate the CS of patients who underwent resection of colorectal liver metastasis. STUDY DESIGN: Between 1982 and 2008, 949 patients who underwent colorectal liver metastasis resection were identified from an international multi-institutional database. Various prognostic scoring systems were evaluated using Cox proportional hazards models and calculated concordance index (c). CS estimates were calculated as CS = S(x+5)/S-(x). RESULTS: Overall survival after liver resection was 65% at 3 years and 45% at 5 years, with a median survival of 52 months. All of the prognostic scoring systems had poor-to-moderate prognostic discriminatory ability (Fong c = 0.57, Nordlinger c = 0.56, Memorial Sloan-Kettering Cancer Center nomogram c = 0.58). Using CS, the probability of surviving an additional 5 years, given that the patient had already survived 1, 3, or 5 years, was 41%, 40%, or 50%, respectively. The inadequate performance of the prognostic scoring systems was explained by the fact that as survival from liver resection increased from 0 to 5 years, the 5-year observed CS improved substantially for patients who were initially predicted to have poor survival at the time of surgery. CONCLUSIONS: Colorectal liver metastasis prognostic scoring systems have fair-to-moderate performance. CS can provide more accurate prognostic information for patients and physicians after colorectal liver metastasis resection and should be incorporated into the quantification of survival. (I Am Coll Surg 2010;210:755-766. (C) 2010 by the American College of Surgeons)

AIMS: Because of its efficacy, oxaliplatin (OX) is increasingly used as a chemotherapeutic agent in the treatment of colorectal liver metastases (CRLM). Oxaliplatin-associated liver toxicity has been reported and can affect clinical practice, but studies on its prevalence and a full pathological description are lacking. The aims of this study were to fill this gap by providing, from a pathologist's perspective, a detailed assessment of the spectrum of hepatic lesions associated with OX, to suggest a scoring system to quantify them, and to investigate the protective effect of bevacizumab against OX-associated damage. METHODS AND RESULTS: The spectrum of oxaliplatin-associated liver lesions was investigated in a multi-institutional series of surgically resected CRLM (n = 385). Among 274 patients treated by OX, 54% had moderate/severe sinusoidal obstruction syndrome (SOS). Peliosis, centrilobular perisinusoidal/venular fibrosis and nodular regenerative hyperplasia (NRH) developed in 10.6%, 47% and 24.5%, respectively. The 111 patients treated by surgery alone had no lesions. Hepatic lesions were less severe in patients treated with OX/bevacizumab (n = 70) compared with the group treated by OX alone (n = 204), with an incidence of moderate/severe SOS (31.4% versus 62.2%), peliosis (4.3% versus 14.6%), NRH (11.4% versus 28.9%, respectively) and centrilobular/venular fibrosis (31.4% versus 52%, respectively) (P < 0.001). CONCLUSIONS: Pathologists should be aware of the distinctive lesions associated with OX and of their high prevalence. OX-related lesions are less frequent in patients treated with bevacizumab, suggesting that this drug has a preventive effect. Uniform criteria for diagnosis and grading of OX-associated lesions should help to include histological data in the optimal multidisciplinary management of CRLM.

Objective(s): To investigate rates and patterns of recurrence in patients following curative intent surgery for colorectal liver metastasis. Background: Outcomes following surgical management of colorectal liver metastasis have largely focused on overall survival. Contemporary data on rates and patterns of recurrence following surgery for colorectal liver metastasis are limited. Methods: One thousand six hundred sixty-nine patients treated with surgery (resection +/- radiofirequency ablation [RFA]) for colorectal liver metastasis between 1982 and 2008 were identified from an international multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. Results: At the time of the initial liver-directed surgery, surgical treatment was resection only (90.2%), resection plus RFA (8.0%), or RFA alone (1.8%). While 5-year overall survival was 47.3%, 947 (56.7%) patients recurred with a median RFS time of 16.3 months. First recurrence site was intrahepatic only (43.2%), extrahepatic only (35.8%), intra- and extrahepatic (21.0%). There was no difference in RFS based on site of recurrence (intrahepatic: 16.9 months; extrahepatic: 16.6 months; intra- and extrahepatic: 16.2 month; P > 0.05). Receipt of adjuvant chemotherapy was associated with overall recurrence risk (hazard ratio [HR] = 0.56), while history of RFA (HR = 2.39, P = 0.001) and RI margin status (HR = 1.36) were predictive of intrahepatic recurrence. Pattern of recurrence and RYS remained similar following repeat surgery for recurrent disease. Conclusions: While 5-year survival following surgery for colorectal liver metastasis approaches 50%, over one-half of patients develop recurrence within 2 years. The pattern of failure is distributed relatively equally among intrahepatic, extrahepatic, and intra-plus extrahepatic sites. Patients undergoing repeat surgery for recurrent metastasis have similar patterns of recurrence and RFS time.

BACKGROUND: The surgical management of hepatocellular carcinoma in patients with well-compensated cirrhosis is controversial. The purpose of the current study was to compare the outcome of patients with well-compensated cirrhosis and early stage hepatocellular carcinoma treated with initial hepatic resection versus transplantation. METHODS: Between 1985 and 2008, 245 patients underwent hepatic resection, and 134 patients underwent liver transplantation for early stage hepatocellular carcinoma. All patients had well-compensated cirrhosis. Prognostic factors were evaluated using univariate and multivariate analyses; survival was calculated using the Kaplan-Meier method. RESULTS: Compared with transplantation, patients undergoing resection had larger tumors and a higher incidence of microscopic vascular invasion. Transplantation was associated with better 5-year disease-free and overall survival compared with resection. Hepatitis status, presence of microscopic vascular invasion, and tumor size were predictors for recurrence, while the presence of microscopic vascular invasion and tumor size conferred an increased risk of death. The disease-free survival advantage with transplantation was more pronounced in hepatitis C patients compared with non-hepatitis and hepatitis B patients. The overall survival advantage with transplantation persisted in cases of solitary lesions < or = 3 cm, but was attenuated in patients with a MELD score < or = 8. CONCLUSION: In well-compensated cirrhotic patients with early stage hepatocellular carcinoma, transplantation was associated with longer disease-free and overall survival. Patients undergoing resection did, however, have tumors with more advanced pathologic features. Patients best suited for initial resection as the treatment of hepatocellular carcinoma were those with a MELD score

BACKGROUND: The outcome of liver resection for colorectal liver metastases (CRLM) appears to be improving despite the fact that surgery is offered to patients with more-severe disease. To quantify this assumption and to understand its causes we analyzed a series of patients on the basis of a standardized severity score and changes in management occurring over the years. METHODS: Patients' characteristics, operative data, chemotherapies and follow-up were recorded. CRLM severity was quantified according to Fong's clinical risk score (CRS), modified to take into account the presence of bilateral liver metastases. Three periods were analyzed, in which different indications, surgical strategies and uses of chemotherapy were applied: 1984-1992, 1993-1998, and 1999-2005. RESULTS: Between January 1984 and December 2005, 210 liver resections were performed in 180 patients (1984-1992, 43 patients; 1993-1998, 42 patients; 1999-2005, 95 patients). CRLM severity increased throughout the time periods, as did the use of neoadjuvant chemotherapies, repeat resections, and multistep procedures. While the disease-free survival did not improve over time, the 1-, 3- and 5-year overall survival rate increased from 85%, 30%, and 23% in the first period, to 88%, 60%, and 34% in the second period, and to 94%, 69%, and 46% in the third period. CONCLUSIONS: Analysis according to the CRS showed that despite the fact that patients had more severe disease, the overall survival improved over the years, mainly thanks to more aggressive treatment of recurrent disease. Management of advanced CRLM should, from the start, take into account the likelihood of secondary procedures.

To examine clinical features and outcome of patients who underwent hepatic resection for colorectal liver metastases (LM) involving the caudate lobe.Consecutive patients who underwent hepatic resection for LM from May 1990 to September 2004 were analyzed from a multicenter database. Demographics, operative data, pathologic margin status, recurrence, and survival were analyzed.Of 580 patients, 40 (7%) had LM involving the caudate. Six had isolated caudate LM and 34 had LM involving the caudate plus one or more other hepatic segments. Patients with caudate LM were more likely to have synchronous primary colorectal cancer (63% vs. 36%; P = 0.01), multiple LM (70% vs. 51%; P = 0.02) and required extended hepatic resection more often than patients with non-caudate LM (60% vs. 18%; P0.001). Only four patients with caudate LM underwent a vascular resection; three at first operation, one after recurrence of a resected caudate tumor. All had primary repair (vena cava, n = 3; portal vein, n = 1). Perioperative complications (43% vs. 28%) and 60-day operative mortality (0% vs. 1%) were similar (caudate vs. non-caudate LM, both P0.05). Pathological margins were positive in 15 (38%) patients with caudate LM and in 43 (8%) with non-caudate LM (P0.001). At a median follow-up of 40 months, 25 (64%) patients with caudate LM recurred compared with 219 (40%) patients with non-caudate LM (P = 0.01). Patients with caudate LM were more likely to have intrahepatic disease as a component of recurrence (caudate: 51% vs. non-caudate: 25%; P = 0.001). No patient recurred on the vena cava or portal vein. Patients with caudate LM had shorter 5-year disease-free and overall survival than patients with non-caudate LM (disease-free: 24% vs. 44%; P = 0.02; overall: 41% vs. 58%; P = 0.02).Patients who undergo hepatic resection for caudate LM often present with multiple hepatic tumors and tumors in proximity to the major hepatic veins. Extended hepatectomy is required in the majority, although vascular resection is not frequently necessary; when performed, primary repair is usually possible. Despite resection in this population of patients with multiple and bilateral tumors, and despite close-margin and positive-margin resection in a significant proportion, recurrence on the portal vein or vena cava was not observed, and long-term survival is accomplished (41% 5-year overall survival).

Sirolimus (SRL) has been proposed to replace calcineurin inhibitors (CNI) in case of CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of conversion from CNI to SRL in maintenance liver transplantation (LT) patients. Between 2002 and 2006, conversion was performed in 48 patients (17 female, 31 male; mean age 57 +/- 10 yr) after a median delay of 19.4 months (range 0.2-173 months) after LT. Indication for conversion was renal impairment (RI) (78%), CNI neurotoxicity (13%), or post-LT cancer (9%). Median follow-up was 22.6 +/- 11 months. Median SRL dosage and trough levels were 2.4 +/- 1.3 mg and 8.1 +/- 2.7 microg/L. Immunosuppression consisted of SRL alone (33%), or SRL + mycophenolate mofetil (MMF) (39%), SRL + prednisone (15%), SRL + CNI (4%), or SRL + MMF + prednisone (8%). Mean glomerular filtration rate (GFR) improved from 33 to 48 mL/minute in patients with severe RI (P = 0.022) and from 56 to 74 mL/minute in patients with moderate RI (P = 0.0001). After conversion, main complications were albuminuria (36%), hyperlipidemia (49%), dermatitis (14%), edema (14%), oral ulcers (12%), joint pain (4%), infection (2%), and pneumonia (2%). Acute rejection (AR) occurred in 17% of the patients. SRL was withdrawn in 17% of the patients. In conclusion, conversion from CNI to SRL is safe and is associated with significant renal function improvement.

Background. Simultaneous pancreas-kidney (SPK) transplantation has become the therapy of choice for type 1 diabetic patients with end-stage renal disease. The current analysis examined the impact of human leukocyte antigen (HLA) matching on graft outcome following SPK transplantation. The study population was obtained from patients enrolled in the Euro-SPK 001 study. Methods. The effect of HLA matching on graft function and survival was assessed in 180 SPK recipients in whom complete donor recipient HLA data were available. A group of 45 patients with 0-3 HLA mismatches (MM) was compared with a group of 135 patients with 4-6 MM. Results. There were no differences in 3-year kidney, pancreas or patient survival between the 0-3 and 4-6 MM groups. Biological parameters of kidney and pancreas graft function were similar in both groups. Significantly more patients with 0-3 MM (66%) were rejection-free at 3 years than was the case among those with 4-6 MM (41%; P = 0.003). The relative risk of acute rejection was 2.6 times higher among patients with 4-6 MM than among those with 0-3 MM. Conclusions. There was no evidence that HLA matching was associated with improved kidney or pancreas survival. However, a higher rate of acute rejection was observed with poor HLA match, which may impact long-term survival.

The objective of our study was to prospectively evaluate whether a second-generation sonography contrast agent (SonoVue) can improve the conspicuity of solid organ injuries (liver; spleen; or kidney, including adrenal glands) in patients with blunt abdominal trauma.Two hundred ten consecutive hemodynamically stable trauma patients underwent both abdominal sonography and CT at admission. The presence of solid organ injuries and the quality of sonography examinations were recorded. Patients with false-negative sonography findings for solid organ injuries in comparison with CT results underwent control sonography. If a solid organ injury was still undetectable, contrast-enhanced sonography was performed. Findings of admission, control, and contrast-enhanced sonograms were compared with CT results for their ability to depict solid organ injuries. Contrast-enhanced sonography was also performed in patients in whom a vascular injury (pseudoaneurysm) was shown on admission or control CT.CT findings were positive for 88 solid organ injuries in 71 (34%) of the 210 patients. Admission, control, and contrast-enhanced sonograms had a detection rate for solid organ injury of 40% (35/88), 57% (50/88), and 80% (70/88), respectively. The improvement in the detection rate between control and contrast-enhanced sonography was statistically significant (p = 0.001). After exclusion of low-quality examinations, contrast-enhanced sonography still missed 18% of solid organ injuries. Five vascular liver (n = 1) and spleen (n = 4) injuries (pseudoaneurysms) were detected on CT; all were visible on contrast-enhanced sonography.Contrast-enhanced sonography misses a large percentage of solid organ injuries and cannot be recommended to replace CT in the triage of hemodynamically stable trauma patients. However, contrast-enhanced sonography could play a role in the detection of pseudoaneurysms.

Percutaneous radio-frequency (RF) ablation of liver tumors is usually performed under guidance of real-time US, but some tumor nodules in some patients cannot be adequately visualized with this technique. We report our preliminary results with an MR-compatible, internally perfused 17-G RF probe adapted to a standard RF generator for impedance-controlled RF ablation under MR guidance. Following initial testing of the probe for MR compatibility, artifacts and macroscopic effects on an ex vivo pig liver, four patients with eight neoplastic liver nodules (five metastatic and three primary), which could not be properly targeted by US, were treated with the cooled-tip technique under MRI guidance in an open 0.23-T magnet. Metallic artifacts produced by the probe were useful for accurate placement and did not interfere with MRI monitoring at the end of the procedure. Based on imaging findings, the immediate result of RF was considered adequate in all instances. Local recurrence occurred in one instance after 6 months, requiring repeat treatment. No adverse effects were noted. Initial experience suggests that the probe we used allows to perform impedance-controlled cooled-tip RF ablation of liver tumors under open-magnet MR guidance.

Background / Aims : Little information is available regarding the effect of cold storage and hyperthermic preconditioning on the contractile responses of hepatic vessels. We then studied, after cold preservation, the in vitro contractile responses of rat portal veins (RPV) isolated from normal rats or from rats previously subjected to hyperthermia. Methods : Rats were or were not subjected to hyperthermia 24h before the RPV isolation. Then, RPV were stored at 4°C in Krebs–Henseleit bicarbonate (KHB) or University of Wisconsin solution or conserved at 20°C in KHB solution. Control RPV were tested after rat sacrifice. Results : The contractile responses were importantly decreased in RPV conserved at room temperature. The morphology of the vessels was altered and the heat shock protein 70 (Hsp70) protein expression disappeared. These abnormalities were prevented by cold preservation. The type of preservation solution did not interfere with the beneficial effect. Hyperthermic preconditioning increased the expression of Hsp70 protein in freshly isolated and cold preserved RPV but decreased the contractile responses. In RPV conserved at room temperature, hyperthermic preconditioning further worsened the decreased contractile response. Conclusions : Thus, hyperthermic preconditioning, which is beneficial in protecting hepatic injury following cold preservation, alters the contractile responses of RPV.

The role of surgical resection for patients with large or multifocal intrahepatic cholangiocarcinoma (ICC) remains unclear. This study evaluated the long-term outcome of patients who underwent hepatic resection for large (a parts per thousand yen7 cm) or multifocal (a parts per thousand yen2) ICC. Between 1990 and 2013, 557 patients who underwent liver resection for ICC were identified from a multi-institutional database. Clinicopathologic characteristics, operative details, and long-term survival data were evaluated. Of the 557 patients, 215 (38.6 %) had a small, solitary ICC (group A) and 342 (61.4 %) had a large or multifocal ICC (group B). The patients in group B underwent an extended hepatectomy more frequently (16.9 vs. 30.4 %; P < 0.001). At the final pathology exam, the patients in group B were more likely to show evidence of vascular invasion (22.5 vs. 38.5 %), direct invasion of contiguous organs (6.5 vs. 12.9 %), and nodal metastasis (13.3 vs. 21.0 %) (all P < 0.05). Interestingly, the incidences of postoperative complications (39.3 vs. 46.8 %) and hospital mortality (1.1 vs. 3.7 %) were similar between the two groups (both P > 0.05). The group A patients had better rates for 5-year overall survival (OS) (30.5 vs. 18.7 %; P < 0.05) and disease-free survival (DFS) (22.6 vs. 8.2 %; P < 0.05) than the group B patients. For the patients in group B, the factors associated with a worse OS included more than three tumor nodules [hazard ratio (HR), 1.56], nodal metastasis (HR, 1.47), and poor differentiation (HR, 1.48). Liver resection can be performed safely for patients with large or multifocal ICC. The long-term outcome for these patients can be stratified on the basis of a prognostic score that includes tumor number, nodal metastasis, and poor differentiation.

BACKGROUND The treatment of patients with metastatic rectal cancer remains controversial. We developed a reverse strategy the liver first approach to optimize the chance of a curative resection. The aim of this study was to assess rectal outcomes after reverse treatment of patients with metastatic rectal cancer. METHODS From May 2000 to November 2013 a total of 34 consecutive selected patients with histology proven adenocarcinoma of the rectum and liver metastases were prospectively entered into a dedicated computerized database. All patients were treated via our reverse strategy. Rectal and overall survival outcomes were analyzed. RESULTS Most patients presented with advanced disease (median Fong clinical risk score of 3; range 2 5). One patient failed to complete the whole treatment (3 ). Rectal surgery was performed after a median of 3.9 months (range 0.4 17.8 months). A total of 73.3 patients received preoperative radiotherapy. Perioperative mortality and morbidity rates were 0 and 27.3 after rectal surgery. Severe complications were reported in two patients (6.1 ): one anastomotic leak and one systemic inflammatory response syndrome. The median hospital stay was 11 days (range 5 23 days). Complete local pathological response was observed in three patients (9.1 ). The median number of lymph nodes collected was 14. The R0 rate was 93.9 . There was no positive circumferential margin. After a mean follow up of 36 months after rectal surgery 5 year overall survival was 52.5 . Five patients experienced pelvic recurrence. CONCLUSIONS In our cohort of selected patients with stage IV rectal cancer the reverse strategy was not only safe and effective but also oncologically promising with a low morbidity rate and high long term survival.

The association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) undergoing surgical resection is controversial. We sought to define the incidence of major and microscopic vascular invasion relative to ICC tumor size, and identify predictors of microscopic vascular invasion in patients with ICC a parts per thousand yen5 cm. A total of 443 patients undergoing surgical resection for ICC between 1973 and 2011 at one of 11 participating institutions were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. As tumor sized increased, the incidence of microscopic vascular invasion increased: < 3 cm, 3.6 %; 3-5 cm, 24.7 %; 5-7 cm, 38.3 %; 7-15 cm, 32.9 %, a parts per thousand yen15 cm, 55.6 %; (p < 0.001). Increasing tumor size was also found to be associated with worsening tumor grade. The incidence of poorly differentiated tumors increased with increasing ICC tumor size: < 3 cm, 9.7 %; 3-5 cm, 19.8 %; 5-7 cm, 24.2 %; 7-15 cm, 21.1 %; > 15 cm, 31.6 % (p = 0.04). The presence of perineural invasion (odds ratio [OR] = 2.98) and regional lymph node metastasis (OR = 4.43) were independently associated with an increased risk of microscopic vascular invasion in tumors a parts per thousand yen5 cm (both p < 0.05). Risk of microscopic vascular invasion and worse tumor grade increased with tumor size. Large tumors likely harbor worse pathologic features; this information should be considered when determining therapy and prognosis of patients with large ICC.

Background & Aims Liver transplantation from marginal donors is associated with ischemia/reperfusion (I/R) lesions, which may increase the risk of post-transplant hepatocellular carcinoma (HCC) recurrence. Graft reperfusion prior to retrieval (as for extracorporeal membrane oxygenation – ECMO) can prevent I/R lesions. The impact of I/R on the risk of cancer recurrence was assessed on a syngeneic Fischer-rat liver transplantation model. Methods HCC cells were injected into the vena porta of all recipients at the end of an orthotopic liver transplantation (OLT). Control donors were standard heart-beating, ischemic ones (ISC), underwent 10min or 30min inflow liver clamping prior to retrieval, and ischemic/reperfused (ISC/R) donors underwent 2h liver reperfusion after the clamping. Results I/R lesions were confirmed in the ISC group, with the presence of endothelial and hepatocyte injury, and increased liver function tests. These lesions were in part reversed by the 2h reperfusion in the ISC/R group. HCC growth was higher in the 10min and 30min ISC recipients ( p =0.018 and 0.004 vs. control, as assessed by MRI difference between weeks one and two), and was prevented in the ISC/Rs ( p =0.04 and 0.01 vs. ISC). These observations were associated with a stronger pro-inflammatory cytokine profile in the ISC recipients only, and the expression of hypoxia and HCC growth-enhancer genes, including Hmox1 , Hif1a and Serpine1 . Conclusions This experiment suggests that ischemia/reperfusion lesions lead to an increased risk of post-transplant HCC recurrence and growth. This observation can be reversed by graft reperfusion prior to retrieval.

To evaluate the consequences of laparoscopy during hemorrhage, we studied the respiratory, renal, and hepatic blood flow changes induced by abdominal Co2 insufflation during severe hemorrhage in anesthetized pigs.Prospective animal study.University research laboratory.Anesthetized and ventilated pigs (n = 18).The right carotid artery was cannulated to measure mean arterial pressure. A pulmonary artery catheter was inserted to measure mean pulmonary arterial pressure and cardiac output. After a midline abdominal incision, three flow probes were positioned around the portal vein, the hepatic artery, and the renal artery to measure portal vein blood flow, hepatic artery blood flow, and renal blood flow. To induce hemorrhage, blood was withdrawn until mean arterial pressure reached 50 mm Hg. Laparoscopy was mimicked by insufflating Co2 until intra-abdominal pressure reached approximately 15 mm Hg. Measurements were collected during hemorrhage, Co2 abdominal insufflation, and the combination of both interventions.Severe pulmonary hypertension and hypercapnic acidosis occurred during abdominal Co2 insufflation. However, the abdominal Co2 insufflation did not aggravate the cardiac output and total hepatic blood flow changes induced by acute hemorrhage, whereas the combination of hemorrhage and abdominal Co2 insufflation markedly altered renal blood flow.These results suggest that renal function must be monitored carefully when performing laparoscopy in trauma patients. In contrast, hepatic perfusion seems well preserved.

Background/Aims: Patients infected with the hepatitis C virus (HCV) often have liver steatosis, suggesting the possibility of a viral cytopathic effect. The aim of this study was to correlate the occurrence and severity of liver steatosis with HCV RNA type, level and sequence of the core-encoding region. Methods: We scored the liver steatosis in 101 HCV-infected individuals carefully selected to exclude other risk factors of a fatty liver. Results were compared with HCV RNA genotype and level in serum and liver. In selected patients, we assessed the effect of antiviral therapy on steatosis and the relationship between nucleocapsid sequence heterogeneity and fat infiltration. Results: Steatosis was found in 41 (40.6%) patients, irrespective of sex, age or route of infection. HCV genotype 3 was associated with higher steatosis scores than other genotypes. A significant correlation between steatosis score and titer of intrahepatic HCV RNA was found in patients infected with genotype 3, but not in those infected with genotype 1. In selected patients, response to alpha-interferon was associated with the disappearance of steatosis. Analysis of the nucleocapsid of 14 HCV isolates failed to identify a sequence specifically associated with the development of steatosis. Conclusions: We provide virological and clinical evidence that the steatosis of the liver is the morphological expression of a viral cytopathic effect in patients infected with HCV genotype 3. At variance with published evidence from experimental models, the HCV nucleocapsid protein does not seem to fully explain the lipid accumulation in these patients.

OBJECTIVE: To review the authors' recent experience and that of the literature since 1973 and to provide management guidelines for true aneurysms of the pancreaticoduodenal arteries (PDA). SUMMARY BACKGROUND DATA: True aneurysms of the PDA are rare, with a total of only 52 cases reported since 1973. METHODS: Six patients were admitted to the authors' institution between 1985 and 1995 for rupture of a true aneurysm of the PDA. They were analyzed with regard to the mode of presentation, preoperative workup, management, and outcome. RESULTS: All patients had severe epigastric pain from retroperitoneal hemorrhage. Computed tomography scanning and angiography were performed in all cases. Aneurysms ranged from 0.7 to 1.2 cm (median 0.9 cm). The celiac axis was stenotic or occluded in five cases. Three patients underwent emergency pancreatoduodenectomy. Two of them survived. In one case, section of the median arcuate ligament was associated with the procedure, and the patient died from an aortic dissection. Embolization was performed in the last three patients. The procedure was definitive in two cases. In one, hemorrhage recurred 8 days later and required surgical ligation of the bleeding artery. CONCLUSIONS: The authors recommend rapid treatment of all true aneurysms of the PDA. Because most of these aneurysms result from a stenosis of the celiac axis, selective embolization may help to preserve patency of the PDA and should, therefore, be the primary therapeutic choice in ruptured aneurysms. Close follow-up is mandatory because of possible recurrent bleeding. Appropriate and expeditious management of true PDA aneurysms should help reduce the mortality rate.

Esophageal squamous-cell carcinoma is relatively common in alcohol and tobacco abusers, and it can develop rapidly after liver transplantation. We report the early detection of an esophageal squamous-cell carcinoma in a patient with alcoholic cirrhosis, diagnosed during the pre-enlistment work-up that he was undergoing before liver transplantation. This lesion had not been detected at standard endoscopy, but was well characterized using in vivo staining and microscopic examination with an "endocytoscopy" system.

BACKGROUND: The goal of this study was to investigate the surgical management and outcomes of patients with primary colorectal cancer (CRC) and synchronous liver metastasis (sCRLM). STUDY DESIGN: Using a multi-institutional database, we identified 1,004 patients treated for sCRLM between 1982 and 2011. Clinicopathologic and outcomes data were evaluated with uni- and multivariable analyses. RESULTS: A simultaneous CRC and liver operation was performed in 329 (33%) patients; 675 (67%) underwent a staged approach ("classic" staged approach, n = 647; liver-first strategy, n = 28). Patients managed with the liver-first approach had more hepatic lesions and were more likely to have bilateral disease than those in the other 2 groups (p < 0.05). The use of staged operative strategies increased over the time of the study from 58% to 75% (p < 0.001). Liver-directed therapy included hepatectomy (90%) or combined resection + ablation (10%). A major resection (>3 segments) was more common with a staged approach (39% vs 24%; p < 0.001). Overall, 509 patients (50%) received chemotherapy in either the preoperative (22%) or adjuvant (28%) settings, with 11% of patients having both. There were 197 patients (20%) who had a complication in the postoperative period, with no difference in morbidity between staged and simultaneous groups or major vs minor hepatectomies (p > 0.05). Ninety-day postoperative mortality was 3.0%, with no difference between simultaneous and staged approaches (p = 0.94). The overall median and 5-year survivals were 50.9 months and 44%, respectively; long-term survival was the same regardless of the operative approach (p > 0.05). CONCLUSIONS: Simultaneous and staged resections for sCRLM can be performed with comparable morbidity, mortality, and long-term oncologic outcomes. (J Am Coll Surg 2013; 216: 707-718. (C) 2013 by the American College of Surgeons)

BACKGROUND The aims of this study were to assess sexual function and conjugal satisfaction in patients prior to and after liver transplantation and in comparison to healthy individuals. MATERIAL AND METHODS A cross sectional cohort questionnaire assessment was performed in adult liver recipients including the International Index of Erectile Function (IIEF) for men or the Female Sexual Function Index (FSFI) for women. Conjugal satisfaction was assessed with the Locke Wallace Marital Adjustment Test. Waitlist candidates and age matched healthy individuals were used as controls. RESULTS Questionnaires of 136 patients were assessed (45 women/91 men mean age: 57 ± 11 years). Overall sexual function improved after transplantation (male: p=0.065 and female: p=0.072) but remained lower than in aged matched healthy individuals. The post transplant level of conjugal satisfaction was stable and similar to healthy controls in men but improved significantly in women (p=0.008) with higher levels than in healthy subjects (p=0.05). CONCLUSIONS The present study shows that sexual function improves after transplantation yet not to the level of healthy controls. It also demonstrates for the first time that post transplant conjugal satisfaction is at least similar to the one of healthy controls.

Introduction: Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. Methods: We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. Results: During the median follow up duration of 31 months (range 1-208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34-3.21; P

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.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.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.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.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.

BACKGROUND:: Liver first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver directed chemotherapy the resection of the CRLM and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80 of patients can successfully undergo a complete RM whereas less than 30 of those undergoing classical management (CM) do so. This registry based study compared the 2 approaches. METHODS:: The study was based on the LiverMetSurvey (January 1 2000 to December 31 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. RESULTS:: A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM P = 0.231) and Fong scores of 3 or more (79 vs 87 P = 0.164). Rectal cancer neoadjuvant rectal radiotherapy and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001) whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease free survival were similar in the RM and CM groups (48 vs 46 at 5 years P = 0.965 and 30 vs 26 P = 0.992). CONCLUSIONS:: Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed.

Important predictor of survival

Clinical progress in the field of liver transplantation has been largely supported by animal models(1,2). Since the publication of the first orthotopic rat liver transplantation in 1979 by Kamada et al.(3), this model has remained the gold standard despite various proposed alternative techniques(4). Nevertheless, its broader use is limited by its steep learning curve(5). In this video paper, we show a simple and easy-to-establish revision of Kamada's two-cuff technique. The suprahepatic vena cava anastomosis is performed manually with a running suture, and the vena porta and infrahepatic vena cava anastomoses are performed utilizing a quick-linker cuff system(6). Manufacturing the quick-linker kit is shown in a separate video paper.

Approximately one fourth of patients transplanted for hepatitis C virus (HCV)-induced liver failure progress to cirrhosis within 5 years, potentially requiring retransplantation. Although the relisting decision can be difficult in these patients, a score could help in selection of candidates with the best potential outcomes.A total of 1422 HCV-positive patients having undergone a retransplantation were included in this registry-based study. A multivariate Cox regression was performed, and an Akaike procedure was applied to design a score predicting survival after retransplantation and to allow an internal validation. Retained variables were donor age (DnAge), serum creatinine (Creat), International Normalized Ratio (INR), and serum albumin (Alb) at the second transplantation, recipient age (RecAge) at the first transplantation, and the interval between both transplantations (Int).The score was designed as 0.23×DnAge+4.86×log Creat-2.45×log Int+2.69×INR+0.10×RecAge-3.27× Alb+40. The receiver operating characteristic area under curve was 0.643 at 3 years, and survivals were 71%, 56%, and 37% for scores30, 30 to 40, and40, respectively (log rank0.0001).Overall, the proposed score is specifically designed for HCV-positive patients, accurately predicts survival after a liver retransplantation, and is helpful in the selection of candidates with the best potential outcomes.

Background Hepatic encephalopathy (HE) is a frequent and severe complication of cirrhosis. A single determination of ammonia in venous blood correlates poorly with neurological symptoms. Thus, a better biological marker is needed. Aim To make a diagnosis of HE, we explored the value of ammonia in capillary blood, an equivalent to arterial blood, measured at bedside following an oral glutamine challenge. Methods We included 57 patients (age 56 yrs; M/F: 37/20) with cirrhosis (alcoholic = 42; MELD score 13.8 [7-29], esophageal varices = 38) and previous episodes of HE (n = 19), but without neurological deficits at time of examination, and 13 healthy controls (age 54 yrs). After psychometric tests and capillary (ear lobe) blood ammonia measurements, 20 gr of glutamine was administered orally. Tests were repeated at 60 minutes (+ blood ammonia at 30'). Minimal HE was diagnosed if values were > 1.5 SD in at least 2 psychometric tests. Follow-up lasted 12 months. Results The test was well tolerated (nausea = 1; dizziness = 1). Patients showed higher values of capillary blood ammonia over time as compared to controls (0'-30'-60 minutes: 75, 117, 169 versus 52, 59, 78 umol/L, p < 0.05). At baseline, 25 patients (44%) had minimal HE, while 38 patients (67%) met the criteria for HE at 60 minutes (chi2: p < 0.01). For the diagnosis of minimal HE, using the ROC curve analysis, baseline capillary blood ammonia showed an AUC of 0.541 (CI: 0.38-0.7, p = 0.6), while at 60 minutes the AUC was 0.727 (CI: 0.58-0.87, p < 0.006). During follow-up, 18 patients (31%) developed clinical episodes of HE. At multivariate analysis, the MELD score (1.12 [1.018-1.236]), previous episodes of HE (3.2[1.069-9.58]), but not capillary blood ammonia, were independent predictors of event. Conclusions In patients with cirrhosis and normal neurological examination, bedside determination of ammonia in capillary blood following oral glutamine load is well tolerated and achieves a better diagnostic performance for minimal HE than basal capillary ammonia levels. However, capillary blood ammonia is a poor predictor of development of clinically overt HE.

Background Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra) during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration. Methods We performed 70%-hepatectomy in wild type (WT) mice, IL-1ra knock-out (KO) mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes. Results At 24h and at 48h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1) and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment. Conclusion IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.

Background Acinar cell carcinomas of the pancreas are rare neoplasms. Usually diagnosed at an advanced stage, in general they are large solid pancreatic tumours with an average size of more than 10 cm. Aims and results We report 3 cases of acinar cell carcinomas involving the peripancreatic lymph nodes, the liver hilum and the colon respectively, without clinical or pathological evidence of pancreatic tumours. These highly cellular neoplasms showed a predominantly acinar cell differentiation intermingled with a ductal component, with intracellular or extracellular mucin production by at least 25% of tumour cells. In addition, one case showed endocrine differentiation. Diffuse immunoreactivity for acinar enzymes trypsin and chymotrypsin was present in all cases. Conclusion The occurrence of acinar cell carcinomas outside the pancreas underlines the notion that acinar cell carcinomas may originate in extrapancreatic sites and probably develop from heterotopic or metaplastic pancreatic foci present along the biliary tract.

Management of patients with neuroendocrine liver metastasis (NELM) remains controversial. We sought to examine the relative efficacy of surgical management versus intra-arterial therapy (IAT) for NELM and determine factors predictive of survival. A total of 753 patients who had surgery (n = 339) or IAT (n = 414) for NELM from 1985 to 2010 were identified from nine hepatobiliary centers. Clinicopathologic data were assessed with regression modeling and propensity score matching. Most patients had a pancreatic (32%) or a small bowel (27%) primary tumor; 47% had a hormonally active tumor. There were statistically significant differences in characteristics between surgery versus IAT groups (hormonally active tumors: 28 vs. 48%; hepatic tumor burden > 25%: 52% vs. 76%) (all P < 0.001). Among surgical patients, most underwent hepatic resection alone without ablation (78%). The median number of IAT treatments was 1 (range, 1-4). Median and 5-year survival of patients treated with surgery was 123 months and 74% vs. 34 months and 30% for IAT (P < 0.001). In the propensity-adjusted multivariate Cox model, asymptomatic disease (hazard ratio 2.6) was strongly associated with worse outcome (P = 0.001). Although surgical management provided a survival benefit over IAT among symptomatic patients with > 25% hepatic tumor involvement, there was no difference in long-term outcome after surgery versus IAT among asymptomatic patients (P = 0.78). Asymptomatic patients with a large (> 25%) burden of liver disease benefited least from surgical management and IAT may be a more appropriate treatment strategy. Surgical management of NELM should be reserved for patients with low-volume disease or for those patients with symptomatic high-volume disease.

Background. No guidelines exist concerning treatment of asymptomatic bacteriuria in renal transplant recipients (RTR). Because of scarce clinical symptoms and fear of complications, such episodes are frequently treated based on subjective criteria without clear clinical benefit, with the risk of selecting resistant pathogens. Methods. We retrospectively analysed the outcome of 334 asymptomatic Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis) bacteriuria that occurred in 77 RTR later than 1 month post-transplantation. We distinguished: Type I, high-grade bacteriuria with pyuria; Type II, high-grade bacteriuria without pyuria; Type III, low-grade bacteriuria with pyuria and Type IV, low-grade bacteriuria without pyuria. Results. None of the 334 episodes was followed by acute rejection or chronic pyelonephritis. One hundred and one (30%) episodes were treated [32 (62%) Type I, 38 (45%) Type II, 13 (36%) Type III and 18 (11%) Type IV]. Evolution to symptomatic urinary tract infection (UTI) was similar between treated and untreated episodes (0/101 versus 4/233, P = 0.32). The four UTI resolved favourably without further complication upon treatment. Persistent asymptomatic bacteriuria occurred in 45 (46%) treated episodes (2 Type I, 27 Type II, 8 Type III and 9 Type IV), with selection of resistant pathogen in 35 cases (78%). Spontaneous bacterial clearance occurred in 138 (59%) untreated episodes (15 Type I, 23 Type II, 9 Type III and 91 Type IV). Negative control cultures tended to be more frequent in treated Type I (P = 0.09) and in untreated Type II episodes (P = 0.08). Conclusion. Restricting antibiotic treatments for asymptomatic low-grade bacteriuria and high-grade bacteriuria in the absence of pyuria, occurring later than 1 month posttransplantation, might be safe in RTR

Objective To develop a score predicting the morbidity of liver resections in a center with low mortality. Design, Setting, and Patients The study was based on a prospective database of all liver resections performed at the Geneva University Hospitals between January 1, 1991, and October 30, 2009 (a total of 726 elective liver resections in 689 patients). Perioperative complications and their severity were graded according to the original classification by Clavien et al. Variables independently associated with the occurrence of complications were identified using a linear regression analysis model. A score was computed with all independent variables in an assessment population including two-thirds of the liver resections and was further validated in a population including one-third of the liver resections. Results Overall mortality was 0.7% (5 of 726 liver resections). We recorded 375 different complications in 259 hepatic resections (36% of resections had ≥1 complication). In the assessment group, resection of 3 or more segments, an American Society of Anesthesiologists score of 3 or higher, and resection for a malignant neoplasm independently predicted the risk of complications. A score integrating these 3 factors significantly predicted the risk of postoperative complications. The score also correlated with the occurrence of major complications. Conclusion The score allows for identification of patients most susceptible to complications, in whom efforts against specific postoperative morbidities can be concentrated.