Metal free oxidative coupling of aryl formamides with alcohols for the synthesis of carbamates.

A direct transformation of N-aryl formamides to the corresponding carbamates via the formation of isocyanate intermediates is achieved in good yields using hypervalent iodine as an oxidant.

Repeat liver resection after a hepatic or extended hepatic trisectionectomy for colorectal liver metastasis.

OBJECTIVE: A right and left hepatic trisectionectomy and an extended trisectionectomy are the largest liver resections performed for malignancy. This report analyses a series of 23 patients who had at least one repeat resection after a hepatic trisectionectomy for colorectal liver metastasis (CRLM). METHODS: A retrospective analysis of a single-centre prospective liver resection database from May 1996 to April 2009 was used for patient identification. Full notes, radiology and patient reviews were analysed for a variety of factors with respect to survival. RESULTS: Twenty-three patients underwent up to 3 repeat hepatic resections after 20 right and 3 left hepatic trisectionectomies. In 18 patients the initial surgery was an extended trisectionectomy. Overall 1-, 3- and 5-year survival rates after a repeat resection were 100%, 46% and 32%, respectively. No factors predictive for survival were identified. CONCLUSION: A repeat resection after a hepatic trisectionectomy for CRLM can offer extended survival and should be considered where appropriate.

Subtotal hepatectomy and whole graft auxiliary transplantation for acetaminophen-associated acute liver failure.

BACKGROUND: An acetominophen overdose (AOD) is the leading cause of acute liver failure (ALF) in the UK and USA. For patients who meet the King's College Hospital criteria, (mortality risk > 85%), an emergency orthotopic liver transplantation (OLT) is conventionally performed with subsequent life-long immunosuppression. A new technique was developed in 1998 for AOD-induced ALF where a subtotal hepatectomy (right hepatic trisectionectomy) and whole graft auxiliary liver transplant (WGALT) was performed with complete withdrawal of immunosupression during the first year post-operatively. RESULTS: During 1998-2010, 68 patients were listed for an emergency transplantation for AOD ALF at our institution: 28 died waiting, 16 underwent OLT and 24 a subtotal hepatectomy with WGALT. Eight OLT (50%) and 16 WGALT remain alive (67%); actuarial survival at 5 years OLT 50%, WGALT 63%, P = 0.37. All patients who had successful WGALT are off immunosuppression. Poor prognostic factors in the WGALT group included higher donor age (40.4 versus 53.9, P = 0.043), requirements for a blood transfusion (4.3 versus 7.6, P = 0.0043) and recipient weight (63.1 versus 54 kg, P = 0.036). CONCLUSION: Although OLT remains standard practice for AOD-induced ALF, life-long immunosuppression is required. A favourable survival rate using a subtotal hepatectomy and WGALT has been demonstrated, and importantly, all successful patients have undergone complete immunosuppression withdrawal. This technique is advocated for patients who have acetominophen hepatotoxicity requiring liver transplantation.

Pre-liver transplant biopsy in hepatocellular carcinoma: a potential criterion for exclusion from transplantation?

BACKGROUND: In cirrhotic patients with hepatocellular carcinoma (HCC), poor differentiation in pre-liver transplantation (LT) biopsy of the largest tumour is used as a criterion for exclusion from LT in some centres. The potential role of pre-LT biopsy at one centre was explored. METHODS: A prospective database of patients undergoing orthotopic LT for radiologically diagnosed HCC at St James's University Hospital, Leeds during 2006-2011 was analysed. RESULTS: A total of 60 predominantly male (85.0%) patients with viral hepatitis were identified. There were discrepancies between radiological and histopathological findings with respect to the number of tumours identified (in 27 patients, 45.0%) and their size (in 63 tumours, 64.3%). In four (6.7%) patients, the largest lesion, which would theoretically have been targeted for biopsy, was not the largest in the explant. Nine (31.0%) patients with multifocal HCC had tumours of differing grades. In two (6.9%) patients, the largest tumour was well differentiated, but smaller tumours in the explant were poorly differentiated. In one patient, the largest lesion was benign and smaller invasive tumours were confirmed histologically. CONCLUSIONS: The need to optimize selection for LT in HCC remains. In the present series, the largest tumour was not always representative of overall tumour burden or biological aggression and its potential use to exclude patients from LT is questionable.

Role of quantification of hepatic steatosis and future remnant volume in predicting hepatic dysfunction and complications after liver resection for colorectal metastases: a pilot study.

OBJECTIVES: Accurate prediction of safe remnant liver volume to minimize complications following liver resection remains challenging. The aim of this study was to assess whether quantification of steatosis improved the predictive value of preoperative volumetric analysis. METHODS: Thirty patients undergoing planned right or extended right hemi-hepatectomy for colorectal metastases were recruited prospectively. Magnetic resonance imaging was used to assess the level of hepatic steatosis and future remnant liver volume. These data were correlated with data on postoperative hepatic insufficiency, complications and hospital stay. Correlations of remnant percentage, remnant mass to patient mass and remnant mass to body surface area with and without steatosis measurements were assessed. RESULTS: In 10 of the 30 patients the planned liver resection was altered. Moderate-severe postoperative hepatic dysfunction was seen in 17 patients. Complications arose in 14 patients. The median level of steatosis was 3.8% (range: 1.2-17.6%), but was higher in patients (n= 10) who received preoperative chemotherapy (P= 0.124), in whom the median level was 4.8% (range: 1.5-17.6%). The strongest correlation was that of remnant liver mass to patient mass (r= 0.77, P < 0.001). However, the addition of steatosis quantification did not improve this correlation (r= 0.76, P < 0.001). CONCLUSIONS: This is the first study to combine volumetric with steatosis quantifications. No significant benefit was seen in this small pilot. However, these techniques may be useful in operative planning, particularly in patients receiving preoperative chemotherapy.

Inferior vena cava resection with hepatectomy: challenging but justified.

OBJECTIVE: The aim of this study was to evaluate the clinical outcome of hepatectomy combined with inferior vena cava (IVC) resection and reconstruction for treatment of invasive liver tumours. METHODS: From February 1995 to September 2010, 2146 patients underwent liver resections in our hospital's hepatopancreatobiliary unit. Of these, 35 (1.6%) patients underwent hepatectomy with IVC resection. These patients were included in this study. Data were analysed from a prospectively collected database. RESULTS: Resections were carried out for colorectal liver metastasis (CRLM) (n= 21), hepatocellular carcinoma (n= 6), cholangiocarcinoma (n= 3) and other conditions (n= 5). Resections were carried out with total vascular occlusion in 34 patients and without in one patient. In situ hypothermic perfusion was performed in 13 patients; the ante situm technique was used in three patients, and ex vivo resection was used in six patients. There were four early deaths from multiple organ failure. Postoperative complications occurred in 14 patients, three of whom required re-operation. Median overall survival was 29 months and cumulative 5-year survival was 37.7%. Rates of 1-, 2- and 5-year survival were 75.9%, 58.7% and 19.6%, respectively, in CRLM patients. CONCLUSIONS: Aggressive surgical management of liver tumours with IVC involvement offers the only hope for cure in selected patients. Resection by specialist teams affords acceptable perioperative morbidity and mortality rates.

Evolution of the surgical management of perihilar cholangiocarcinoma in a Western centre demonstrates improved survival with endoscopic biliary drainage and reduced use of blood transfusion.

BACKGROUND: Perihilar cholangiocarcinoma (PHCCA) remains a surgical challenge for which few large Western series have been reported. The aims of this study were to investigate the results of surgical resection for PHCCA and assess how practice has evolved over the past 15 years. METHODS: A prospectively maintained database was interrogated to identify all resections. Clinicopathological data were analysed for impact on survival. Subsequently, data for resections carried out during the periods 1994-1998, 1999-2003 and 2004-2008 were compared. RESULTS: Eighty-three patients underwent resection. Trisectionectomy was required in 67% of resections. Overall survival was 70%, 36% and 20% at 1, 3 and 5 years, respectively. Size of tumour, margin (R0) status, lymph node status, distant metastasis, tumour grade, portal vein resection, microscopic direct vascular invasion, T-stage and blood transfusion requirement significantly affected outcome on univariate analysis. Distant metastasis (P = 0.040), percutaneous biliary drainage (P = 0.015) and blood transfusion requirement (P = 0.026) were significant factors on multivariate analysis. Survival outcomes improved and blood transfusion requirement was significantly reduced in the most recent time period. DISCUSSION: Blood transfusion requirement and preoperative percutaneous biliary drainage were identified as independent indicators of a poor prognosis following resection of PHCCA. Longterm survival can be achieved following the aggressive surgical resection of this tumour, but the emergence of a clear learning curve in our analyses indicates that these patients should be managed in high-volume centres in order to achieve improved outcomes.

An effective assessment of cluster tendency through sampling based multi-viewpoints visual method.

Social networks are the rich sources to people for sharing the knowledge on health-related issues. Nowadays, Twitter is one of the great significant social platforms to the people for a discussion on topics. Analyzing the clusters for the tweets concerning terms is a complex process due to the sparsity problem. Topic models are useful or avoiding this problem with derivations of topic clusters. Finding pre-cluster tendency is the major problem in many clustering methods. Existing methods, such as visual access tendency (VAT), cosine-based VAT (cVAT), multi viewpoints-based cosine similarity VAT (MVS-VAT) majorly used to access the prior information about clusters tendency problem. Solution of cluster tendency indicates the tractable number of clusters. The MVS-VAT enables the cluster tendency for the tweet documents effectively than other visual methods. However, it takes a higher number of viewpoints, thus requiring more computational time for the clustering of tweets data. Therefore, sampling-based visual methods are proposed to overcome the computational problem. Several standard health keywords are used for the extraction of health tweets to illustrate the effectiveness of proposed work in the experimental study.

Correlation between postoperative infective complications and long-term outcomes after hepatic resection for colorectal liver metastasis.

BACKGROUND: The impact of postoperative morbidity, and in particular infective complications on long-term outcomes, following hepatic resection for colorectal liver metastasis (CRLM) is not widely published. OBJECTIVE: To evaluate the effect of postoperative complications on disease recurrence and overall survival in patients undergoing hepatic resection for CRLM. METHODS: All patients undergoing hepatic resection for CRLM from January 1993 and March 2007 were identified, and postoperative complications analyzed. Patients who died of postoperative complications within 30 days of surgery were excluded form the study. Postoperative complications were graded using a validated system of classification. Complications were further classified into infective and noninfective complication groups and the primary end points of the study were disease free survival (DFS) and overall survival (OS) at 5 years. RESULT: A total of 705 patients underwent hepatic resection in the study period. Median follow-up was 38 months. Operative morbidity and mortality were 28% and 3.6%, respectively. The total number of patients was 197 (28%) with complications, and 508 (72%) without complications. The 5 year DFS and OS for those with and without complications were: 13% versus 26% (P < 0.001) and 24% versus 37% (P < 0.001), respectively. Multivariate analysis showed inflammatory response to tumor score, blood transfusion, tumor number >8, and postoperative sepsis to be independent factors associated with DFS, and inflammatory response to tumor, tumor number >8, and postoperative sepsis to be independent predictors for OS. Intra-abdominal and respiratory infection but not wound infections were associated with poorer long-term outcomes. CONCLUSIONS: Postoperative complications influence long-term outcomes in hepatic resection for CRLM. Specifically, postoperative sepsis is an independent predictor of disease free and overall survival. Thorough preoperative optimization, meticulous surgical technique and careful management in the postoperative period may reduce the incidence of these complications and influence long-term outcomes.

Metabonomics: a useful tool for the future surgeon.

BACKGROUND: In the past decade or so, a range of technologies have emerged that have shown promise in increasing our understanding of disease processes and progression. These advances are referred to as the "omics" technologies; genomics, transcriptomics, and proteomics. More recently, another "omics" approach has come to the fore: metabonomics, and this technology has the potential for significant clinical impact. Metabonomics refers to the analysis of the metabolome, that is, the metabolic profile of a system. The advantage of studying the metabolome is that the end points of biological events are elucidated. RESULTS: Although still in its infancy, the metabonomics approach has shown immense promise in areas as diverse as toxicology studies to the discovery of biomarkers of disease. It has also been applied to studies of both renal and hepatic transplants. Metabolome analysis may be conducted on a variety of biological fluids and tissue types and may utilize a number of different technology platforms, mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy being the most popular. In this review, we cover the background to the evolution of metabonomics and its applications with particular emphasis on clinical applications. CONCLUSIONS: We conclude with the suggestion that metabonomics offers a platform for further biomarker development, drug development, and in the field of medicine.

Do smaller adults wait longer for liver transplantation? A comparison of the UK and the USA data.

BACKGROUND: The number of patients on the UK and the USA liver transplant list is increasing. As size match is an important factor in the UK organ allocation, we studied the effect of recipient size on liver transplantation in the UK and the USA. METHODS: The UK Transplant and United Network for Organ Sharing databases were used to assess difference in access to transplantation between smaller adult patients and their larger counterparts over three time periods. Subsequently, proportions of split, NHBD and living-donor transplants were analyzed. RESULTS: There were 1576 UK and 29,150 USA patients in our analysis. The UK small patients have been significantly disadvantaged in access to transplantation particularly in early years and in adult only transplant units. This contrasts to the USA where smaller patients have never been disadvantaged and transplantation rates are steadily increasing. Split-liver transplants are being carried out in increasing numbers in the UK but not the USA. CONCLUSIONS: Small adults are still less likely to be transplanted at six months in adult only units in the UK. The lack of size matched organs for smaller adults and the overall decrease in rates of transplantation in the UK may be remedied by careful consideration of allocation policy and increased use of innovative techniques.

Synthesis and biological evaluation of novel benzyl-substituted flavones as free radical (DPPH) scavengers and α-glucosidase inhibitors.

Pharmacologically motivated natural product investigations have yielded a large variety of structurally unique lead compounds with interesting biomedical properties, but the natural roles of these molecules often remain unknown. In the present investigation, a series of benzyl substituted-flavone derivatives have been synthesized from the lead compounds and were screened against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory properties. The resulting activity profiles of these flavone derivatives were compared for degree of similarity to the profile of 1-3. Most of the synthesized derivatives displayed potent activities when compared to the parent compounds. Maximum potencies for DPPH free radical scavenging activity were observed only in compounds containing the 4-hydroxyl substitution and 3-methoxyl group on the phenyl ring. While the 2- and 4-hydroxyl group substitutions on the phenyl ring seem to be crucial for the intestinal α-glucosidase inhibitory activity.

CD105 is a prognostic marker and valid endothelial target for microbubble platforms in cholangiocarcinoma.

PURPOSE: The current treatment outcomes in cholangiocarcinoma are poor with cure afforded only by surgical extirpation. The efficacy of targeting the tumoural endothelial marker CD105 in cholangiocarcinoma, as a basis for potential microbubble-based treatment, is unknown and was explored here. METHODS: Tissue expression of CD105 was quantified using immunohistochemistry in 54 perihilar cholangiocarcinoma samples from patients who underwent resection in a single centre over a ten-year period, and analysed against clinicopathological data. In vitro flow assays using microbubbles functionalised with CD105 antibody were conducted to ascertain specificity of binding to murine SVR endothelial cells. Finally, CD105-microbubbles were intravenously administered to 10 Balb/c nude mice bearing heterotopic subcutaneous human extrahepatic cholangiocarcinoma (TFK-1 and EGI-1) xenografts after which in vivo binding was assessed following contrast-enhanced destruction replenishment ultrasound application. RESULTS: Though not significantly associated with any examined clinicopathological variable, we found that higher CD105 expression was independently associated with poorer patient survival (median 12 vs 31 months; p = 0.002). In vitro studies revealed significant binding of CD105-microbubbles to SVR endothelial cells in comparison to isotype control (p = 0.01), as well as in vivo to TFK-1 (p = 0.02) and EGI-1 (p = 0.04) mouse xenograft vasculature. CONCLUSION: Our results indicate that CD105 is a biomarker eminently suitable for cholangiocarcinoma targeting using functionalised microbubbles.

Surgical technique and systemic inflammation influences long-term disease-free survival following hepatic resection for colorectal metastasis.

BACKGROUND: To date, there is limited data available on prognostic factors that influence long-term disease-free survival following hepatic resection for colorectal liver metastasis (CRLM). The aim of the study was to identify prognostic factors that were associated with long-term disease-free survival (>5 years) following resection for CRLM. METHODS: Patients undergoing resection for CRLM from January 1993 to March 2007 were identified from the hepatobiliary database. Data analyzed included demographics, laboratory results, operative findings and histopathological data. RESULTS: Seven hundred five curative primary hepatic resections were performed, of which 434 patients developed disease recurrence within 5 years and 67 patients were disease-free more than 5 years. There was a significant association between systemic inflammatory response (raised neutrophil to lymphocyte ratio and/or C-reactive protein), blood transfusion, >2 tumors, bilobar disease and resection margin involvement with developing recurrence during the follow-up period. On multivariate analysis, three independent predictors for recurrent disease within the 5-year follow-up were identified: pre-operative inflammatory response; blood transfusion requirement; and status of resection margin. CONCLUSION: Absence of a systemic inflammatory response and surgical technique to minimize transfusion requirements and obtain a R0 resection margin, are associated with long-term disease-free survival.

Neutrophil Gelatinase-associated Lipocalin as a Theragnostic Marker in Perihilar Cholangiocarcinoma.

BACKGROUND/AIM: Platforms using valid molecular targets can provide concurrent diagnostic and treatment (theragnostic) options in perihilar cholangiocarcinoma (PHC). Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker in the biliary secretome of PHC. Its potential as a theragnostic target and its prognostic significance in this cancer was, therefore, explored. MATERIALS AND METHODS: In-vitro studies were used to determine NGAL localization in several cholangiocarcinoma cell lines. Tissue expression of NGAL was quantified in PHC resection cases from 2000-2010 by immunohistochemistry. RESULTS: NGAL was expressed in the majority of tested cell lines and localized to their membranes. Tissues from 54 patients underwent NGAL immunohistochemistry. Median tumoral NGAL expression was significantly higher than that in matched liver controls (p<0.001). Higher NGAL tumor expression was associated with nodal metastasis (p=0.021), although no significant association with survival was observed. CONCLUSION: The expression and localization of NGAL in PHC make it a valid candidate biomarker for exploitation in theragnostic platforms.

Large hepatocellular carcinoma: time to stop preoperative biopsy.

BACKGROUND: In Western countries, hepatocellular carcinoma (HCC) often presents at a large size, which is seen as a contraindication to transplantation and often resection. Although diagnosis by imaging and alpha-fetoprotein is usually straightforward, nonspecialist units continue to use biopsy to prove the diagnosis before transfer for specialist surgical opinion. We have looked at the impact of this on our practice. STUDY DESIGN: We retrospectively analyzed all large HCCs resected in our unit during the last 12 years. Survival data were calculated according to size and univariate and multivariate analyses were carried out to determine impact of preoperative, operative, and histologic factors affecting outcomes. RESULTS: We identified 85 large HCCs (> 3 cm) and classified 42 as giant (> 10 cm). Overall survival at 1, 3, and 5 years was 76%, 54%, and 51%. Size did not influence survival, although more complex surgical techniques were required for giant tumors. Predictors of poorer disease-free survival were positive resection margin (p < 0.001), multiple tumors (p = 0.003), macroscopic vascular invasion (p = 0.015), and preoperative lesion biopsy (p = 0.027). CONCLUSIONS: Our data shows excellent outcomes after resection for large HCC. This supports the management of such patients in large-volume units that are fully equipped and experienced in the management of these patients. Preoperative biopsy should be avoided, as this unnecessary maneuver appears to have worsened our longterm results.

Total laparoscopic pancreaticoduodenectomy and reconstruction for a cholangiocarcinoma of the bile duct.

BACKGROUND: In this paper, we report on our experience with a totally laparoscopic pancreatico-duodenectomy performed for a cholangiocarcinoma of the lower third of the bile duct. METHODS: The patient was placed in the steep reverse Trendelenberg, Lloyd-Davis position. The procedure was performed with six laparoscopic ports, using similar steps to the open approach, with the use of an ultrasonic cutting and coagulating instrument for dissection and endoscopic linear stapling devices for the bile duct, intestinal, and gastroduodenal artery division. Reconstruction was done on a single loop by an intracorporeally sutured pancreaticojejunostomy, hepaticojejunostomy, and a stapled gastroenterostomy. The resection specimen was placed in a bag and retrieved through a 5-cm Pfannenstiel incision. RESULTS: Histology confirmed a T3 N1 R0 cholangiocarcinoma with the involvement of 1 of 17 lymph nodes. Twelve months following surgery, he remains well, having completed a course of adjuvant chemotherapy. CONCLUSIONS: Although the operation was technically demanding, it can be safely performed with a good oncologic result.

Radical operation for hilar cholangiocarcinoma in comparable Eastern and Western centers: Outcome analysis and prognostic factors.

BACKGROUND: Extensive resection for hilar cholangiocarcinoma is the most effective treatment, but high morbidity and poor prognosis remain concerns. Previous data have shown marked differences in outcomes between comparable Eastern and Western centers. We compared the outcomes of the management for hilar cholangiocarcinoma at one Japanese and one British institution with comparable experience. METHODS: Of 298 consecutive patients with hilar cholangiocarcinoma evaluated at Hirosaki University Hospital, Japan and St. James's University Hospital, Leeds, UK, 183 underwent radical resection. Clinicopathologic variables and postoperative outcomes were compared. RESULTS: Significant differences were not observed between the Hirosaki and Leeds cohorts in overall outcomes despite several differences in the patient characteristics. Although there was a difference in 90-day mortality (2.5% vs 13.6%, respectively), disease-specific 5-year survival rates were 32.8% and 31.9%, respectively (P = .767). Multivariate analysis identified trisectionectomy (odds ratio = 2.32; P = .010), combined pancreatoduodenectomy (odds ratio = 7.88; P = .010), and perioperative blood transfusion (odds ratio = 1.88; P = .045) were associated with postoperative major complications, while preoperative biliary drainage associated with postoperative major complications, while preoperative biliary drainage (risk ratio = 2.21; P = .018), perioperative blood transfusion (risk ratio = 1.58; P = .029), lymph node metastasis (risk ratio = 2.00; P = .002), moderate/poorly differentiated tumor (risk ratio = 1.72; P = .029), microvascular invasion (risk ratio = 1.63; P = .046), and R1 resection (risk ratio = 1.90; P = .005) were risk factors for poor survival. CONCLUSION: Disease-specific survival and prognostic factors were similar in both centers. Meticulous operative technique to avoid perioperative blood transfusion may improve long-term survival.