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Background Choledochalmalformation (CM) is a rare medical condition of which 80% are diagnosed in pediatric patients. There are several important controversies regarding diagnostic workup, management, and follow-up in these pediatric patients. To assess preferences and practices of Dutch pediatric surgeons regarding the diagnostic procedures, management, and follow-up of children with CM we conducted an electronic survey.Methods A questionnaire was sent to all the pediatric surgeons working in the academic centers and the only community hospital with a pediatric surgery service. The questionnaire included, items regarding incidence, diagnostic workup, interval between diagnosis and surgery, surgical techniques, and follow-up. We also assessed whether personal exposure influenced the preferences and practices.Results Overall 22 out of the 31 (71%) Dutch pediatric surgeons returned the questionnaire. Total 15 out of 22 (68%) encountered CM up to 2 times/y, whereas 7 out of 22 (32%) encountered it more than 2 times/y. Indications for surgery were significantly different between surgeons who encountered CM > 2 time/y versus those who did not: 6/6 (100%) of surgeons encountering CM > 2 times/y considered the presence of an asymptomatic CM an indication for surgery versus 5/14 (36%) of the pediatric surgeons who encountered a CM up to 2 times/y (p = 0.01). Overall 12 out of the 22 (55%) respondents preferred surgery between 6 months and 2 years of age. The amount of exposure did not differ in preferred age at surgery or surgical technique. In the symptomatic child 10/22 (45%) of respondents preferred surgery within 3 months. Overall 7/22 (32%) favored laparoscopic resection. Hepaticojejunostomy with Roux-en-Y reconstruction was the preferred reconstruction for all the respondents. One-third stated that they never performed a parenchyma resection. Follow-up was limited to 10 years in almost half of the respondents.Conclusion Dutch pediatric surgeons demonstrate a wide variety of opinions regarding diagnostic workup, treatment, and follow-up of CM. Whilemost surgeons encounter CM up to 2 times/y, there is an association between exposure and several of the outcome parameters. Some of the answers are not in line with the expert opinion. This demonstrates that there is a need for evidence-based (inter)national guidelines regarding the diagnostic approach, management, and follow-up.

Little is known about the achievement of developmental milestones (i.e., COL) after pediatric liver transplantation. The aim of this study was to examine the COL of young adults who underwent a liver transplantation during childhood and to compare it to healthy peers. Furthermore, we studied factors possibly related to their COL. COL was assessed using the CLQ, which assesses the achievement of developmental milestones (autonomy, psychosexual, social, and antisocial development) and risk behavior (substance abuse and gambling). Sociodemographic characteristics and clinical data were collected using the prospective institutional liver transplantation database. A total of 39 young adults who underwent a liver transplantation at the UMCG in their childhood completed the CLQ. They achieved fewer milestones with regard to autonomy, psychosexual, and social development compared to healthy peers, and they reported less risk behavior. Neither age at the time of study nor age at the time of transplantation was significantly correlated with any of the COL subscales. Young adults show delay in reaching developmental milestones in every dimension after a liver transplantation during their childhood.

INTRODUCTION: Choledochal malformations (CMs) are increasingly diagnosed antenatally. There is a dilemma between early surgery to prevent CM-related symptoms and postponing surgery to reduce complications. We aimed to identify the optimal timing of surgery in asymptomatic neonates with antenatally diagnosed CM and to identify predictors for development of symptoms.METHODS: Using the Netherlands Study group on CHoledochal Cyst/malformation (NeSCHoc) we retrospectively collected demographic, biochemical and surgical data from all Dutch patients with an antenatally detected CM.RESULTS: Between 1989 and 2014, antenatally suspected CM was confirmed in 17 patients at a median age of 10days (1day-2months). Four patients developed symptoms directly after birth (24%). Thirteen patients (76%) remained asymptomatic. Two of these progressed to symptoms before surgical intervention at 0.7 and 2.1months resp. Postoperatively, four patients developed short-term complications and three developed long-term complications. Patients 5.6kg (0%, p=0.02).CONCLUSION: When not symptomatic within the first days of life, the majority of children with antenatally detected CM remains asymptomatic. Surgery might safely be delayed to the age of 6months or a weight of 6kg. Postponing surgery in the clinically and biochemical asymptomatic patient might decrease the complication rate.LEVELS OF EVIDENCE: Level III.

Frozen section analysis (FS) during cancer surgery is widely used to assess resection margins. However, in hilar cholangiocarcinoma (HCCA), FS may be less reliable because of the specific growth characteristics of the tumor. The aim of this study was to determine the accuracy and consequences of intraoperative FS of the proximal bile duct margins in HCCA. Between 1990 and 2014, 67 patients underwent combined extrahepatic bile duct resection and partial liver resection for HCCA with the use of FS. Sensitivity and specificity of FS was 68% and 97%, respectively. Seventeen of 67 patients (25%) displayed a positive bile duct margin at FS. The false‐negative rate was 16% (eight patients). Ten patients (15%) with a positive bile duct margin underwent an additional resection in an attempt to achieve negative margins, which succeeded in three patients (4%). However, only one of these three patients did not have concomitant lymph node metastases, which are associated with a poor prognosis by itself. The use of FS of the proximal bile duct is of limited clinical value because of the relatively low sensitivity, high risk of false‐negative results, and the low rate of secondary obtained tumor‐free resection margins. Supported by the literature, a new approach to the use of FS in HCCA should be adopted, reserving the technique only for cases in which a substantial additional resection is possible.

Objective: To evaluate whether a low postoperative platelet count is associated with a poor recovery of liver function in patients after partial liver resection.Background: Experimental studies in rodents have recently suggested that blood platelets play a critical role in the initiation of liver regeneration. It remains unclear whether platelets are also involved in liver regeneration in humans.Methods: In a series of 216 consecutive patients who underwent partial liver resection for colorectal liver metastases. we studied postoperative mortality and liver dysfunction in relation to the immediate postoperative platelet count. All patients had normal preoperative liver function and none of them had liver fibrosis or cirrhosis. Delayed postoperative recovery of liver function was defined as serum bilirubin > 50 mu mol/L or prothrombin time > 20 seconds at any time point between postoperative day I and 5.Results: Patients with a low ( 100(9)/L). A low immediate postoperative platelet count was identified as an independent risk factor of delayed postoperative recovery of liver function (OR, 11.5; 95% CL, 1.1-122.4; P = 0.04 in multivariate analysis).Conclusion: After partial liver resection, a low platelet count is an independent predictor of delayed postoperative liver function recovery and is associated with increased risk of postoperative mortality. These clinical findings are in accordance with the accumulating evidence from experimental studies, indicating that platelets play a critical role in liver regeneration.

Hox transcription factors play an essential role in patterning the anteroposterior axis during embryogenesis and exhibit a complex array of spatial and temporal patterns of expression. Their earliest onset of expression in vertebrates is during gastrulation in a temporally collinear sequence in the presomitic/ventrolateral mesoderm, and it is not clear which upstream signal transduction events initiate this expression. Using Xenopus, we present evidence that Xwnt8 is necessary for initiation of this collinear sequence by activating Hox-1 expression in three Hox clusters: hoxd, hoxa, and hoxb. All three labial genes appear to be direct targets of canonical Wnt signaling through Tcf/Lef. In addition, Xwnt8 loss- and gain-of-function leads to indirect regulation of other Hox genes: Hoxb4, Hoxd4, Hoxa7, Hoxc6, and Hoxc8. These findings shed new light on the early role of Wnt8 as well as of a proposed WNT gradient in patterning the Xenopus central nervous system (Kiecker and Niehrs [2001] Development 128:4189-4201). Developmental Dynamics 239:126-139, 2010. (c) 2009 Wiley-Liss, Inc.

This study assesses the relation between the anhepatic phase duration and the outcome after liver transplantation. Of 645 patients who underwent transplantation between 1994 and 2006, 194 were recipients of consecutive adult primary piggyback liver transplants using heart-beating donors. The anhepatic phase was defined as the time from the physical removal of the liver from the recipient to recirculation of the graft. Other noted study variables were the cold and warm ischemia times, donor and recipient age, donor and recipient body mass index, perioperative red blood cell (RBC) transfusion, indication for transplantation, and Model for End-Stage Liver Disease score. The primary outcome parameter was graft dysfunction, which was defined as either primary nonfunction or initial poor function according to the Ploeg-Maring criteria. The median anhepatic phase was 71 minutes (37-321 minutes). Graft dysfunction occurred in 27 patients (14%). Logistic regression analysis showed an anhepatic phase over 100 minutes [odds ratio (OR), 4.28], a recipient body mass index over 25 kg/m(2) (OR, 3.21), and perioperative RBC transfusion (OR, 3.04) to be independently significant predictive factors for graft dysfunction. One-year patient survival in patients with graft dysfunction was 67% versus 92% in patients without graft dysfunction (P

Currently, liver transplantation (LT) is an accepted method of treatment of end-stage liver disease, metabolic diseases with their primary defect in the liver and unresectable primary liver tumors. Surgical techniques in LT have evolved considerably over the past 40 yr. The developments have led to a safer procedure for the recipient reflected by continuously improving survival figures after LT. Also the new techniques offer the possibility of tailoring the operation to the needs and condition of the recipient as in partial grafting or in different revascularization techniques, or in techniques of biliary reconstructions. In addition, the new techniques such as split LT, domino transplantation and living donor LT have brought about an increase in the available grafts. In this review the evolution of surgical techniques in LT over the past 40 yr and their contribution to the current results are discussed.

Between November 1982 and March 2006, 67 children with body weight 4.0 was 44%, 38%, 38%, and 30%, respectively (p = 0.02). In summary, patient survival in children with body weight

Fibrosis is a pervasive disease in which the excessive deposition of extracellular matrix (ECM) compromises tissue function. Although the underlying mechanisms are mostly unknown, matrix stiffness is increasingly appreciated as a contributor to fibrosis rather than merely a manifestation of the disease. Here we show that the loss of Fibulin-5, an elastic fibre component, not only decreases tissue stiffness, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis. These results suggest that Fibulin-5 may be a therapeutic target to short-circuit this profibrotic feedback loop., Stiffness in the extracellular matrix is thought to contribute to pathological cutaneous fibrosis. Here, the authors identify the elastic fibre protein Fibulin-5 as a link and potential therapeutic target mediating the transition of cutaneous stiffening to fibrosis.

The exact frequency and clinical consequences of surgical hepatic injuries during organ procurement are unknown. We analyzed the incidence, risk factors, and clinical outcome of surgical injuries in 241 adult liver grafts. Hepatic injuries were categorized as parenchymal, vascular, or biliary. Outcome variables were bleeding complications, hepatic artery thrombosis (HAT), and graft survival. In 82 livers (34%), 96 injuries were detected. Most injuries were minor, but clinically relevant injuries were detected in 6.6% (16/241) of the livers. Fifty (21%) liver grafts had some degree of parenchymal or capsular injury, 40 (17%) had vascular injury, and 6 (2%) had an injury to the bile duct. Procurement region was the only risk factor significantly associated with surgical injury. The rate of hepatic artery injury was significantly higher in livers with aberrant arterial anatomy. Bleeding complications were found in 18% of patients who received livers with a parenchymal or capsular injury in contrast to 9% without parenchymal injury (P = 0.065). HAT was found in 23% of the patients who received a liver with arterial injury compared to 4% without arterial injury (P = 0.001). Overall graft survival rates were not significantly different for grafts with or without anatomical injury. In conclusion, surgical injuries of donor livers are an underestimated problem in liver transplantation and can be observed in about one-third of all cases. Clinically relevant injuries are detected in 6.6% of all liver grafts. Arterial injuries are associated with an increased risk of HAT.

No consensus exists regarding the optimal reconstruction of the cavo-caval anastomosis in piggyback orthotopic liver transplantation (PB-LT). The aim of this study was to analyze our experience with end-to-side (ES) cavo-cavostomy. Outcome parameters were patient and graft survival and surgical complications. During the period 1995-2002 146 full-size PB-LT in 137 adult patients were performed with ES cavo-cavostomy without the routine use of temporary portocaval shunt (TPCS). In 12 patients (8%) this technique was used for implantation of second or third grafts. Veno-venous bypass was not used in any case and TPCS was performed only in eight patients (6%). One-, three- and five-yr patient and graft survival were 84%, 79% and 75%, and 81%, 74% and 69%, respectively. The median number of intraoperative transfusion of packed red blood cells (RBC) was 2.0 (range 0-33) and 30% of the patients (n = 43) did not require any RBC transfusion. Surgical complications of various types were observed after 49 LT (34%) and none of the complications was specifically related to the technique of ES cavo-cavostomy. Our experience indicates that PB-LT with ES cavo-cavostomy is a safe procedure, can safely be performed without the routine use of a TPCS, has a very low risk of venous outflow obstruction and can also be used effectively during retransplantations.

Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1-, 3- and 5-year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, per-operative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni- and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, peri-operative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.

The aim of this study was to analyze the effect of human leukocyte antigen (HLA) class I and HLA-DR mismatching, sharing cross-reactive antigen groups (CREGs), and sharing HLA-DR antigens on the outcome after pediatric liver transplantation. Outcome parameters were graft survival, acute rejection, and portal fibrosis. A distinction was made between full-size (FSLTx) and technical-variant liver transplantation (TVLTx). A total of 136 primary transplants were analyzed. The effect of HLA on the outcome parameters was analyzed by adjusted multivariate logistic and Cox regression analysis. HLA mismatches, shared CREGs, and shared HLA-DR antigens affected neither overall graft survival nor survival after FSLTx. Survival after TVLTx was superior in case of 2 mismatches at the HLA-DR locus compared to 0 or 1 mismatch (P = 0.01) and in case of no shared HLA-DR antigen compared to I shared HLA-DR antigen (P = 0.004). The incidence of acute rejection was not influenced by HLA. The incidence of portal fibrosis could be analyzed in 62 1-yr biopsies and was higher after TVLTx than FSLTx (P = 0.04). The incidence of portal fibrosis after TVLTx with 0 or 1 mismatch at the HLA-DR locus was 100% compared to 43% with 2 mismatches (P = 0.004). After multivariate analysis, matching for HLA-DR and matching for TVLTx were independent risk factors for portal fibrosis. In conclusion, an overall beneficial effect of HLA matching, sharing CREGs, or sharing HLA-DR antigens was not observed. A negative effect was present for HLA-DR matching and sharing HLA-DR antigens on survival after TVLTx. HLA-DR matching might be associated with portal fibrosis in these grafts.

The adenosine triphosphate (ATP)-binding cassette (ABC)-transporters ABCG5 and ABCG8 have been shown to mediate hepatic and intestinal excretion of cholesterol. In various (genetically modified) marine models, a strong relationship was found between hepatic expression of ABCG5/ABCG8 and biliary cholesterol content. Our study aimed to relate levels of hepatic expression of ABCG5 and ABCG8 to biliary excretion of cholesterol in man. From 24 patients who had received a liver transplant, bile samples were collected daily after transplantation over a 2-week period to determine biliary composition. Expression of ABCG5, ABCG8, MDR3, and BSEP was assessed by real-time polymerase chain reaction (PCR) in liver biopsy specimens collected before and after transplantation. Levels of hepatic ABCG5, ABCG8, and MDR3 messenger RNA (mRNA) were strongly correlated. After transplantation, the biliary secretion rate of cholesterol continuously increased, coinciding with gradual increases in bile salt and phospholipid secretion. In contrast, hepatic levels of ABCG5 and ABCG8 mRNA remained unchanged. Surprisingly, no correlation was found between the hepatic expression of ABCG5 and ABCG8 and rates of biliary cholesterol secretion, normalized for biliary phospholipid. secretion. As expected, the concentration of biliary phospholipids correlated well with MDR3 expression. In conclusion the strong relationship between ABCG5 and ABCG8 gene expression is consistent with the coordinate regulation of both genes, and in line with heterodimerization of both proteins into a functional transporter. Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans. This finding suggests the existence of alternative pathways for the hepatobiliary transport of cholesterol that are not controlled by ABCG5/ABCG8.

Background/Aims: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation.Methods: In 28 liver transplant recipients, bile samples were collected daily posttransplantation for determination of bile composition. Hepatic expression of bile transporters was studied before and after transplantation. Histopathological criteria as well as biliary concentrations of alkaline phosphatase (ALP) and gamma-glutamyltransferase (gamma-GT) were used to quantify bile duct injury.Results: Early after transplantation, bile salt secretion increased more rapidly than phospholipid secretion, resulting in high biliary bile salt/phospholipid ratio (BA/PL). In parallel with this, mRNA levels of the bile salt transporters NTCP and BSEP increased significantly after transplantation, whereas phospholipid translocator MDR3 mRNA levels remained unchanged. Bile duct injury correlated significantly with bile salt secretion and was associated with a high biliary BA/PL ratio.Conclusions: Bile salt secretion after human liver transplantation recovers more rapidly than phospholipid secretion. This results in cytotoxic bile formation and correlates with bile duct injury. These findings suggest that endogenous bile salts have a role in the pathogenesis of bile duct injury after liver transplantation. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The aim of this study is to analyse a single centre's experience with two techniques of liver transplantation (OLT), conventional (CON-OLT) and piggyback (PB-ES), and to compare outcome in terms of survival, morbidity, mortality and post-operative liver function as well as operative characteristics. A consecutive series (1994-2000) of 167 adult primary OLT were analysed. Ninety-six patients had CON-OLT and 71 patients had PB-ES. In PB-ES group two revascularization protocols were used. In the first protocol reperfusion of the graft was performed first via the portal vein followed by the arterial anastomosis (PB-seq). In the second protocol the graft was reperfused simultaneously via portal vein and hepatic artery (PB-sim). One-, 3- and 5-yr patient survival in the CON-OLT and PB-ES groups were 90, 83 and 80%, and 83, 78 and 78%, respectively (p = ns). Graft survival at the same time points was 81, 73 and 69%, and 78, 69 and 65%, respectively (p = ns). Apart from the higher number of patients with cholangitis and sepsis in CON-OLT group, morbidity, retransplantation rate and post-operative liver and kidney function were not different between the two groups. The total operation time was not different between both groups (9.4 h in PB-ES vs. 10.0 h in CON-OLT), but in PB-ES group cold and warm ischaemia time (CIT and WIT), revascularization time (REVT), functional and anatomic anhepatic phases (FAHP and AAHP) were significantly shorter (8.9 h vs. 10.7 h, 54 min vs. 63 min, 82 min vs. 114 min, 118 min vs. 160 min and 87 min vs. 114 min, respectively, p

slug gene expression is associated with the specification and migration of neural crest cells in the African clawed frog Xenopus laevis. We provide evidence that the protein Ying-Yang 1 (YY1) regulates the slug gene expression both indirectly and directly, via a YY1 cis-element in the slug promoter, during Xenopus development. The ability of the YY1 to bind this YY1 cis-element was confirmed by electromobility shift assays and reporter assays. YY1 was detected in the nuclei of ectodermal cells contemporaneously with the process of neural crest specification. The injection of anti-YY1 morpholino, which targeted both YY1alpha and YY1beta gene products, depleted YY1 expression below 20% and was lethal at gastrulation. Sublethal depletion of YY1 reduced the length of the anterior-posterior axis and severely inhibited the expression of the neural marker Nrp1 and of the slug gene. Overexpression of YY1 or mutation of the YY1 cis-element reduced the restricted spatial expression of the slug reporter gene in the neural ectoderm border and provoked its expression in the nonneural ectoderm. Chromatin immunoprecipitation indicated that endogenous YY1 interacts directly with the YY1 cis-element of the endogenous slug gene and with the slug gene reporter sequence injected into embryos. The results suggest that YY1 is essential for Xenopus development; is necessary for neural ectoderm differentiation, a prerequisite for neural crest specification; and restricts which cells can form neural crest mesenchyme through directly blocking slug gene activity.

From September 1986 until December 2001, 42 patients (20 males and 22 females) underwent a combined extrahepatic bile duct resection (EHBDR) and liver resection (LR) for hilar cholangiocarcinoma (HC). The aim of this study was to analyze patient survival, morbidity, and mortality as well as to seek predictive factors. The 1-, 3, and 5-year actuarial patient survival was 72%, 37%, and 22%, respectively. Median survival was 19 months. Hospital mortality, all due to septic complications, was 12%. Morbidity was observed in 32 patients (76%). Infections were the most dominant complication. Patients (n = 11) with American Joint Committee on Cancer (AJCC) stage I or stage II tumors exhibited a superior survival compared with patients (n = 3 1) with stage III or IV tumors (p = 0.023). Patients with tumor-free lymph nodes (n 26) indicated a greater survival compared with patients with tumor-positive lymph nodes (n = 16) = 0.004). Patients undergoing vascular reconstructions indicated a trend toward higher mortality and lower survival (p = 0.068). Over 20% of the patients with hilar cholangiocarcinoma can survive more than 5 years after a combined EHBDR and LR at the cost of 12% perioperative mortality and a 76% morbidity. Results might improve with the prevention of infectious complications and improved selection of patients to avoid vascular reconstruction and to predict a negative nodal state. (C) 2004 The Society for Surgery of the Alimentary Tract.

Hyperlipidemia is a common side effect of cyclosporine A (CsA) after solid organ transplantation. CsA also markedly reduces the synthesis rate of bile salts in rats and can inhibit biliary bile salt secretion. It is not known, however, whether CsA inhibits the synthesis of bile salts in humans, and whether the hyperlipidemic effects of CsA are related to bile salt metabolism. Our objective was to assess the effects of CsA on the synthesis rate of bile salts and on plasma triglycerides and cholesterol levels in pediatric liver transplant patients. Before and after discontinuation of CsA treatment after liver transplantation, synthesis rate and pool size of the primary bile salts cholate and chenodeoxycholate were determined using a stable isotope dilution technique and related to plasma lipids. In 6 children (age: 3–16 years) CsA treatment was discontinued at 2 years (median 2.3 years) after liver transplantation. Discontinuation of CsA increased synthesis rate of chenodeoxycholate (+38%, P < .001) and cholate (+21%, P < .05) and the pool size of chenodeoxycholate (+54%, P < .001). Discontinuation of CsA decreased plasma levels of cholesterol (–18%, P < .05) and triglycerides (–23%, P < .05). Bile salt synthesis rate appeared to be inversely correlated with plasma cholesterol (Spearman rank correlation coefficient [rs] = −0.82, P < .01) and plasma triglyceride levels (rs = −0.62, P < .05). In conclusion, CsA inhibits bile salt synthesis and increases plasma concentration of cholesterol and triglycerides in pediatric liver transplant patients. Suppression of bile salt synthesis by long-term CsA treatment may contribute to hyperlipidemia and thus to increased risk for cardiovascular disease. (Liver Transpl 2004;10:872–880.)

To compare early foveal and peripheral information extraction, visual scenes were masked either foveally or peripherally during the initial part of fixations, using an eye-movement contingent display-change technique. The sequential attention model of eye-movement control predicts a substantial effect of early foveal masking, and early peripheral masking should not affect the ongoing processing. Foveal masking indeed postponed foveal processing as reflected by a considerable increase of average fixation durations with longer masking (Experiments 1 and 3). However, there was also an effect of peripheral masking, mainly on the saccade target selections with an increased number of fixations (Experiment 3) in conjunction with smaller saccade amplitudes (Experiments 2 and 3). Overall, scene perception was more influenced by early foveal masking than by early peripheral masking, and this is partly in agreement with the sequential attention model of eye-movement control.

Objective To describe the epidemiology and causes of graft loss after pediatric liver transplantation and to identify risk factors. Summary Background Data Graft failure after transplantation remains an important problem. It results in patient death or retransplantation, resulting in lower survival rates. Methods A series of 157 transplantations in 120 children was analyzed. Graft loss was categorized as early (within 1 month) and late (after 1 month). Risk factors were identified by analyzing recipient, donor, and transplantation variables. Results Kaplan-Meier 1-month and 1 -, 3-, and 5-year patient survival rates were 85%, 82%, 77%, and 71%, respectively, Graft survival rates were 71%, 64%, 59%, and 53%, respectively. Seventy-one of 157 grafts (45%) were lost 18 (25%) by death of patients with functioning grafts and 53 (75%) by graft-related complications. Forty-five grafts (63%) were lost early after transplantation. Main causes of early loss were vascular complications, primary nonfunction, and patient death. Main cause of late graft loss was fibrosis/cirrhosis, mainly as a result of biliary complications or unknown causes, Child-Pugh score, anhepatic phase, and urgent transplantation were risk factors for early loss, Donor age, clonor/recipient weight ratio, blood loss, and technical-variant liver grafts were risk factors for late loss, Conclusions To prevent graft loss after pediatric liver transplantation, potential recipients should be referred early so they can be transplanted in an earlier phase of their disease, Technical-variant liver grafts are risk factors for graft survival. The logistics of the operation need to be optimized to minimize the length of the anhepatic phase.

471 Background: In patients with T3 RCC with venous tumor thrombus reaching the inferior vena cava, without metastatic disease, a nephrectomy with cavotomy is performed. Before 2000, surgical approach of level 3-4 caval tumorthrombus included sternotomy and cardiopulmonary bypass with circulatory arrest, with high morbidity and mortality rates. After the routine use of liver mobilization around 2000, sternotomy became less necessary. We compared perioperative characteristics, complications and survival pre- and post-2000. Methods: We retrospectively studied 91 patients, operated between 1984 and 2016 in a referral hospital. Patients with a T3 RCC and caval thrombus underwent a radical nephrectomy with thrombectomy. Data on patient and tumor characteristics, operation approach, complications (Clavien-Dindo classification), hospital stay, progression and survival were collected and analyzed using Mann-Whitney U, Chi-Square, and Log-Rank tests. Results: 91 patients (56 male) with a mean age of 65 years were included. 33% had a level 3 or 4 cava thrombus. Surgical management before 2000 included sternotomy with circulation arrest in 32% and liver mobilization in 10%. After 2000, the number of sternotomies lowered to 8% while liver mobilization increased to 74%. See table 1 for perioperative outcomes and complications. Disease specific survival was significant longer in patients operated after 2000 (estimated mean 70 vs. 94 months, p = 0.03). Only N stage influenced progression free survival, patients N+ showed worse survival (p < 0.01). Conclusions: The change in surgical approach including liver mobilization significantly decreased complication rates, blood loss, transfusion rate, hospital stay and increased disease specific survival. [Table: see text]

Vascular complications have a detrimental effect on the outcome after liver transplantation. Most studies focus exclusively on hepatic artery thrombosis (HAT). The current study analyzed the incidence, consequences, and risk factors for HAT, portal vein thrombosis (PVT), and venous outflow tract obstruction (VOTO) in a consecutive series of 157 pediatric liver transplantations. The overall incidence of vascular complications was 21%. The incidences of HAT, PVT, and VOTO were 10%, 4%, and 6%, respectively. Patient survival after PVT and VOTO and graft survival after HAT and PVT were less compared with survival of grafts without vascular complications. To identify risk factors for vascular complications, factors related to recipient, donor, and surgical techniques were analyzed. A low donor-recipient (D/R) age ratio, long surgical time, and use of the proper hepatic artery of the recipient for arterial reconstruction were risk factors for HAT. Young age, low weight, segmental grafts, and piggyback technique were risk factors for PVT. Fulminant hepatic failure, high D/R age and weight ratios, and use of segmental grafts were related to VOTO. Vascular complications, which occurred in 21% of the pediatric liver transplantations, had a significant impact on patient and graft survival. Size disparity between donor and recipient was an important risk factor for vascular complications, especially in the case of transplantation of segmental grafts. Patient and graft survival might improve by avoiding the identified risk factors.

Background/Aims: The purpose of the study was to investigate the incidence of and risk factors for splenic artery aneurysms in liver transplant patients. Methods: Medical records and the pre- and 1-year postoperative angiograms of 337 liver transplant patients were reviewed to assess the presence and characteristics of these aneurysms. Results: Forty-five patients with aneurysms were identified (13%): 41 cases in 242 adult patients (17%) and four (4%) in 95 children ( p p p Conclusions: The incidence of splenic artery aneurysms in liver transplant patients is 13%. They are generally multiple and located in the distal third of the splenic artery. The incidence is higher in women and in patients with parenchymal liver disease and portal hypertension. The incidence of rupture was 4%.

Growth after pediatric liver transplantation is an important factor in determining the quality of life. We collected data on height, skeletal age, and liver function of 45 consecutive pediatric transplant recipients and assessed the influence of primary diagnosis, liver function, and immunosuppressive regimen on their growth. Height and skeletal age were plotted as median standard deviation scores versus years post-transplantation. Growth, in terms of both height and skeletal age, were continuous without catch-up growth. Primary diagnosis was found to have no influence on height and poor liver function had a negative effect on both height and skeletal growth. A higher alternate day prednisolone maintenance dose also had a negative effect on skeletal growth. Thus, it can be concluded that a pretransplant lack of growth will not be restored and is an indication for early transplantation in endstage liver disease, especially in younger children.

The ability of ultrasound to detect biliary obstruction, bile leakage and generalized ductal changes after orthotopic liver transplantation (OLT) was compared to cholangiography. Cholangiography was considered to be the gold standard. Adequate opacification of the biliary tree was achieved in 139 cholangiograms. Biliary obstruction, intermediate or large bile leakage, and generalized ductal changes were diagnosed with cholangiography in 15% (21/139), 14% (20/139), and 16% (22/139), respectively. Normal ultrasound findings could not exclude biliary stricture, generalized ductal changes, or bile leakage, and fluid collections were not correlated with bile leakage. Abnormal ultrasound findings were highly predictive of the cholangiographic diagnosis of biliary obstruction or generalized ductal changes (specificity of 98% and 100%, respectively). An irregular appearance of the bile ducts and increased periductal echogenicity proved to be characteristic features for generalized ductal changes. (C) 1996 John Wiley & Sons, Inc.

RATIONALE AND OBJECTIVES. To analyze changes in Doppler ultrasound variables in relation to liver biopsy findings for the diagnosis of acute rejection after orthotopic liver transplantation (OLT), the authors performed in a prospective study 316 Doppler ultrasound examinations in the first 2 weeks after OLT on 23 patients. METHODS. Recordings were obtained daily from the hepatic artery (resistive index [RI]) and hepatic vein (damping index [DI]). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS. Serial Doppler ultrasound examinations showed a significant increase in the RI in 11 of 22 patients (50%); the 23rd patient was excluded because of hepatic artery thrombosis, Despite an agreement in 15 of 22 patients (68%) no statistically significant correlation could be found (positive predictive value 6/11 = 55%; negative predictive value 9/11 = 82%; chi-square = 3.14; P > 0.05). A significant increase in the DI was observed in 14 of 23 patients (61%). However, no statistically significant correlation could be found as well with this parameter (positive predictive value 6/14 = 43%; negative predictive value 6/9 = 67%; chi-square = 0.00; P > 0.05). CONCLUSION. Serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

The aim of this study was to analyze the influence of intraoperative blood loss, expressed as an index of the circulating blood volume (BL), on patient and graft survival and on morbidity after primary orthotopic liver transplantation (OLT) in a series of 40 consequetive children (Mann-Whitney test, Pearson test). The influence on patient survival could not be assessed due to the low mortality. Graft survival and overall morbidity were not affected. Increased BL led only to a higher incidence of postoperative bleeding, with a subsequent higher intervention rate. In the group of children aged 3.75 years or less, significantly higher BL was found compared to the older children. In addition, prolonged intensive care unit stays and ventilator times were observed in this younger age group. The BL thus has limited repercussions on graft survival and morbidity after primary pediatric OLT.

Hox transcription factors provide positional information during patterning of the anteroposterior axis. Hox transcription factors can co-operatively bind with PBC-class co-factors, enhancing specificity and affinity for their appropriate binding sites. The nuclear localisation of these co-factors is regulated by the Meis-class of homeodomain proteins. During development of the zebrafish hindbrain, Meis3 has previously been shown to synergise with Hoxb1 in the autoregulation of Hoxb1. In Xenopus XMeis3 posteriorises the embryo upon ectopic expression. Recently, an early temporally collinear expression sequence of Hox genes was detected in Xenopus gastrula mesoderm (see intro. P3). There is evidence that this sequence sets up the embryo's later axial Hox expression pattern by time-space translation. We investigated whether XMeis3 is involved in regulation of this early mesodermal Hox gene expression. Here, we present evidence that XMeis3 is necessary for expression of Hoxd1, Hoxb4 and Hoxc6 in mesoderm during gastrulation. In addition, we show that XMeis3 function is necessary for the progression of gastrulation. Finally, we present evidence for synergy between XMeis3 and Hoxd1 in Hoxd1 autoregulation in mesoderm during gastrulation.

Objective: To study the impact of perineural growth as a prognostic factor in periampullary adenocarcinorna (pancreatic head, ampulla of Vater, distal bile duct, and duodenal carcinoma).Summary Background Data: Pancreatic head carcinoma is considered to have the worst prognosis of the periampullary carcinomas. Several other prognostic factors for periampullary tumors have been identified, eg, lyrnph node status, free resection margins, tumor size and differentiation, and vascular invasion. The impact of perineural growth as a prognostic factor in relation to the site of origin of periampullary carcinomas is unknown.Methods: Data of 205 patients with periampullary carcinomas were retrieved from our prospective database. Pancreaticoduodenectomy was performed in 121 patients. Their clinicopathological data were reviewed and analyzed in a multivariate analysis.Results: Perineural growth was present in 49% of the cases (37 of the 5 1 patients with pancreatic head carcinoma; 7 of the 30 patients with ampulla of Vater carcinoma; 7 of the 19 with distal bile duct carcinoma,- and 8 of the 21 with duodenal carcinoma). Overall 5-year survival was 32.6% with a median survival of 20.7 months. Median Survival in tumors with perineural growth was 13.1 months compared with 36.0 months in tumors without perineural growth (P Conclusion: Perineural growth is a more important risk factor for survival than the primary site of periampullary carcinomas.

We retrospectively studied the prevalence, presentation, results of treatment, and graft and patient survival of grafts developing an anastomotic biliary stricture (AS) in 531 adult liver transplantations performed between 1979 and 2003. Clinical and laboratory information was obtained from the hospital files, and radiological studies were re-evaluated. Twenty-one possible risk factors for the development of AS (variables of donor, recipient, surgical procedure, and postoperative course) were analyzed in a univariate and stepwise multivariate model. Forty-seven grafts showed an anastomotic stricture: 42 in duct-to-duct anastomoses, and 5 in hepaticojejunal Roux-en-Y anastomoses. The cumulative risk of AS after 1, 5, and 10 years was 6.6%,10.6%, and 12.3% respectively. Postoperative bile leakage (P = 0.001), a female donor/male recipient combination (P = 0.010), and the era of transplantation (P = 0.006) were independent risk factors for the development of an AS. In 47% of cases, additional (radiologically minor) nonanastomotic strictures were diagnosed. All patients were successfully treated by 1 or more treatment modalities. As primary treatment, encloscopic retrograde cholangiopancreaticography (ERCP) was successful in 24 of 36 (67%) cases and percutaneous transhepatic cholangiodrainage in 4 of 11 (36%). In the end 15 patients (32%) were operated, all with long-term success. AS presenting more than 6 months after transplantation needed more episodes of stenting by ERCP, and more stents per episode compared to those presenting within 6 months and recurred more often. Graft and patient survival were not impaired by AS.

Upregulation of heme oxygenase-1 (HO-1) has been proposed as an adaptive mechanism protecting against ischemia/reperfusion (I/R) injury. We investigated HO-1 expression in 38 human liver transplants and correlated this with I/R injury and graft function. Before transplantation, median HO-1 mRNA levels were 3.4-fold higher (range: 0.7-9.3) in donors than in normal controls. Based on the median value, livers were divided into two groups: low and high HO-1 expression. These groups had similar donor characteristics, donor serum transaminases, cold ischemia time, HSP-70 expression and the distribution of HO-1 promoter polymorphism. After reperfusion, HO-1 expression increased significantly further in the initial low HO-1 expression group, but not in the high HO-1 group. Postoperatively, serum transaminases were significantly lower and the bile salt secretion was higher in the initial low HO-1 group, compared to the high expression group. Immunofluorescence staining identified Kupffer cells as the main localization of HO-1.In conclusion, human livers with initial low HO-1 expression ( 3.4 times controls). These data suggest that an increase in HO-1 during transplantation is more protective than high HO-1 expression before transplantation.

Purpose: To correlate TP53 mutations with angiogenic status of the tumor and prognosis after liver surgery in patients with colorectal liver metastases and to correlate immunohistochemical staining of p53 protein with TP53 gene mutations. Experimental Design: Tumors of 44 patients with surgically treated colorectal liver metastases were analyzed for (a) TP53 mutations using denaturing gradient gel electrophoresis followed by sequencing, (b) microvessel density using the hot spot overlap technique, (c) apoptotic rate in tumor cells and endothelial cells of tumor microvessels using double immunostaining for anti–cleaved caspase 3 and anti-CD34, and (d) expression of p53 protein using immunohistochemistry. Results:TP53 mutations were detected in 36% of the metastases and occurred more frequently in liver metastases from left-sided colon tumors than from right-sided colon tumors (P = 0.04). In metastases with TP53 mutations, microvessel density was higher compared with tumors with wild-type p53. Endothelial cell apoptosis was not different in tumor microvessels from TP53-mutated versus nonmutated tumors. The 5-year actual survival was not influenced by TP53 mutational status, microvessel density, or endothelial cell apoptotic rate of the tumors. Based on immunohistochemical p53 overexpression, the positive and negative predictive values of TP53 mutations were 61% and 82%. Conclusions: In patients with surgically treated colorectal liver metastases, TP53 mutations and angiogenic status did not influence prognosis. Immunohistochemistry is not a reliable technique for detecting TP53 mutations.

Unlike the genetic code, the protein-DNA recognition modalities are degenerate in both directions. Consequently, how do transcription factors achieve their considerable specificity and selectivity in regulating the genetic programs that they ultimately influence? Here, we discuss the fact that different Hox gene-specific variants of retinoid response elements are not equivalent. Each particular variant occurs at a precise position along the vertebrate Hox clusters and this organization was present before the time when the ancestral vertebrate Hox cluster was duplicated.

The hypusine biosynthetic steps represent novel targets for intervention in cell proliferation. Hypusine is a rare amino acid, formed posttranslationally in one cellular protein, eIF5A, and is essential for cell proliferation. Deoxyhypusine hydroxylase, the metalloenzyme catalyzing the final step in hypusine biosynthesis, and prolyl 4-hydroxylase, a non-heme iron enzyme critical for collagen processing, can be inhibited by small chelating molecules that target their essential metal atom. We examined the effects of 5 compounds (ciclopirox, deferiprone, deferoxamine, mimosine and 2,2′-dipyridyl) on these protein hydroxylases in HUVECs, on cell proliferation and on angiogenesis using 2 model assays: tube-like vessel formation on Matrigel and the chick aortic arch sprouting assay. These compounds inhibited cellular deoxyhypusine hydroxylase in a concentration-dependent manner, but their efficacy varied widely in the following order: ciclopirox deferoxamine2,2′-dipyridyldeferipronemimosine (IC50 5–200 μM). Inhibition of DNA synthesis, following the same order (IC50 10–450 μM), correlated with G1 arrest of the cell cycle. These compounds also inhibited proline hydroxylation and maturation of collagen in HUVECs and caused inhibition of angiogenesis in vitro. Of the compounds tested, ciclopirox was by far the most effective inhibitor of HUVEC proliferation and angiogenesis. The strong antiangiogenic activity of this readily available antifungal drug along with its antiproliferative effects suggests a new potential application for ciclopirox in the treatment of solid tumors. Published 2002 Wiley-Liss, Inc.

Introduction: We have previously shown that Epothilone B, a microtubule stabilizer, is a potent antiangiogenic in an intact human tumor-based angiogenesis assay. Clinical studies have demonstrated Epothilone B can be effective in patients resistant to the microtubule stabilizer paclitaxel. Methods: We hypothesized that equimolar doses of Epothilone B would be more potent than paclitaxel in our in vitro human tumor angiogenesis assay. To evaluate our hypothesis discarded portions of eleven fresh human tumors were obtained. Tumor fragments were embedded in fibrin-thrombin clots in 96 well plates. Drug-treated wells contained a control nutrient media supplemented with Epothilone B or paclitaxel at equimolar (10–6 to 10–10 M) concentrations. Wells were assessed over time and evaluated for onset of neovessel invasion (%I) and the degree of subsequent angiogenic development (angiogenic index, AI). Epothilone B (10–8 M) and paclitaxel (10–8 M) were compared at a statistical significance level of 5%. Results: At doses of 10–6 M, both Epothilone B and paclitaxel completely inhibited angiogenesis. Epothilone B was statistically superior to paclitaxel in its ability to block angiogenic initiation in 4 of 11 (36%) of the cases studied, and demonstrated a numerical advantage in 9 out of the 11 (82%) cases. Epothilone B was statistically superior to paclitaxel in prohibiting subsequent angiogenic proliferation in 5/11(45%) tumors, and showed a numerical advantage in 8/11 (73%) specimens. Conclusions: At equimolar, clinically relevant (10–8M) drug doses, Epothilone B exhibits statistical and numerical advantage over paclitaxel's ability to inhibit human tumor-derived angiogenesis.

Hepatic retransplantation is considered to carry a higher risk than primary transplantation. Survival might improve with more experience and better immunosuppression. We studied all 55 patients who were adults at the time of their first retransplantation and who underwent retransplantation between 1979 and May 2001. Patient survival at 1, 5 and 10 years was 73%, 63%, and 63%, respectively. Multivariate analysis of pre-transplant variables revealed prothrombin time, creatinine level, and indication for retransplantation, as independent predictive factors. Survival was highest in patients who had undergone retransplantation for hepatic artery thrombosis. Multivariate analysis, including pre-, per-, and post-operative variables, showed that era of transplantation, prothrombin time, blood loss, and intensive care unit (ICU) stay, were independent predictive factors. Survival at 1 and 5 years improved from 56% and 48%, respectively, before 1996 to 89% and 81%, respectively, after 1996. In conclusion, survival after hepatic retransplantation improved significantly through the years. Independent pre-transplant predictive factors were prothrombin time, creatinine level, and indication for retransplantation.

In the rat Walker 256 carcinosarcoma the cytotoxicity of the anticancer drug 5-fluorouracil (FU) is thought to be mediated by the 5-fluoronucleotide (FNuct) FUTP. which interferes with RNA metabolism [ 11. Total FNuct can be detected in vivo, as a composite peak, by "F n.m.r. and we have found in the Walker 256 carcinosarcoma that decreased concentrations of FNuct (mainly FUTP) formed in vivo accompanied decreased cytotoxicity [ 21. Sequential treatment of Walker tumours with methotrexate (MTX) followed by FU (MTX-FU) is known to produce increased cytotoxicity compared with either drug alone or to the reverse schedule (FU-MTX) [3]. This effect may be due to MTX increasing intracellular pyrimidine ribosylpyrophosphate (PRPP) and thus increasing anabolism of FU to FNuct [4]. The aim of this study was to use "F n.m.r. to determine whether MTX pretreatment increases FNuct formation in vivo and to correlate this with cytotoxicity.