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Neuroendocrine tumors (NET) are a heterogeneous group of cancers, with indolent behavior. The most common primary origin is the gastro-intestinal tract but can also appear in the lungs, kidneys, adrenals, ovaries and other organs. In general, NET is usually discovered in the metastatic phase (40%-80%). The liver is the most common organ involved when metastases occur (40%-93%), followed by bone (12%-20%) and lung (8%-10%).A number of different therapeutic options are available for the treatment of hepatic metastases including surgical resection, transplantation, ablation, trans-arterial chemoembolization, chemotherapy and somatostatin analogues. Recently, molecular targeted therapies have been used, usually in combination with other treatment options, to improve outcomes in patients with metastases. This article emphasizes on the role of surgery in the treatment of liver metastases from NET.

Numerous signaling pathways, such as Ras/Raf/MAPK, have been implicated in hepatic carcinogenesis. There are at least 35 combination therapy studies for advanced stage hepatocellular carcinoma (HCC) ongoing, and numerous reagents are being tested targeting novel signaling cascades. The management of HCC has changed substantially in recent times, and the successful development of sorafenib has prompted further expansion on molecular targeted therapies to potentially inhibit different pathways in hepatocarcinogenesis.

Activation of the Wnt/β-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the β-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the β-catenin pathway, could inhibit β-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using β-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed β-catenin, including the constitutively active form of β-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of β-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC.

Background/aim: The aim of this study is to find synergistic effect using FH535 and sorafenib by targeting the RAS/RAF/MAPK and WNT/β-catenin pathways., Materials and Methods: 3H-Thymidine incorporation assays were performed to address Huh7 and liver cancer stem cell (LCSC) inhibition using FH535 and sorafenib, alone and in combination. Calcusyn analysis was used to calculate the combination index (CI). A western blot assay was performed to check for potential targets., Results: FH535 and sorafenib caused inhibition of Huh7 and LCSC. Combination therapy was significantly better than monotherapy in inhibition of HuH7. Combination with sorafenib and FH535 was found to be synergistic in inhibition of LCSC with a CI of less than 1. The western blot assay demonstrated enhanced cleaved poly (ADP-ribose) polymerase (PARP) and inhibition of cyclin D1, B-cell lymphoma 2 (Bcl2), survivin and cellular myelocytomatosis oncogene (c-MYC)., Conclusion: FH535 and sorafenib combination produced synergistic effect on inhibition of HCC and LCSC. Our study demonstrated that FH535 can induce apoptosis in these two different hepatocellular carcinoma (HCC) cell lines.

Background: Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells)., Materials and Methods: Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways., Results: Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM (P < 0.001; n = 12) and 67% by PKI-587 at 0.1 μM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12)., Conclusions: LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine peri-operative mortality and long-term outcomes in patients undergoing liver transplantation in the US using the United Network for Organ Sharing (UNOS) database., Methods: This study is a retrospective review of liver transplantations (LT) recorded in the UNOS database performed between 1988 and 2010. In total, 107 411 LT were performed in the US, 357 (0.3%) were for adult polycystic liver disease (PLD). A random group of 9416 adult patients transplanted for other diagnoses was created for comparison (10% of the adult non-PLD database)., Results: Two hundred and seventy-one patients in the adult PLD group were females (75.9%), the mean age was 52.3 ± 8.2 [standard deviation (SD)] years. The median length of transplantation hospital stay was 11 days (interquartile range 8-21). Patients from the PLD group versus the comparison group (9416 patients) consisted of more females, lower Model for End-Stage Liver Disease (MELD) scores (17 versus 21 points), more multi-organ transplants (41% versus 4 %), chronic renal failure (creatinine 2.7 versus 1.5) and fewer patients with chronic hepatitis C (1.4% versus 32%). Peri-operative mortality (≤30 days) was 9% in the PLD versus 6% in the comparison group; however, at 1 year PLD survival was similar (85% versus 85%) to other diagnoses and better at 3 (81% versus 77%) and 5 years (77% versus 71%, overall Log Rank P = 0.006). A similar PLD survival advantage was observed in isolated initial transplants (P = 0.019)., Conclusion: In spite of early technical challenges and mortality, transplantation should be considered an option for selected patients with PLD as excellent long-term outcomes can be achieved., (© 2012 International Hepato-Pancreato-Biliary Association.)

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver accounting for 7% of all cancers worldwide. Most cases of HCC develop within an established background of chronic liver disease. For that reason, liver resection is only possible in selected patients. Liver transplantation has become the treatment of choice in patients with HCC, end-stage liver disease, and significant portal hypertension. Shortage of organ donors has resulted in overall increase of waiting list time with increased risk of dropout due to tumor progression. Neoadjuvant therapies have emerged as an alternative to control tumor growth in patients while waiting. The aim of this study is to review the literature on the role of bridging therapy and downstaging prior to liver transplantation in patients with HCC. We are also presenting our single-center experience of 96 patients undergoing transplantation for HCC with and without bridging therapy.

Background: Deregulated Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PKI-587 and sorafenib as single agents or in combination on HCC (Huh7 cell line) proliferation., Materials and Methods: (3)H-thymidine incorporation and MTT assay were used to assess Huh7 cell proliferation. Phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways was detected by Western blot., Results: We found that PKI-587 is a more potent PI3K/mTOR inhibitor than PI-103. Combination of PKI-587 and sorafenib was a more effective inhibitor of Huh7 proliferation than the combination of PI-103 and sorafenib. Combination of PKI-587 and sorafenib synergistically inhibited epidermal growth factor (EGF)-stimulated Huh7 proliferation compared with monodrug therapy. EGF increased phosphorylation of Ras/Raf downstream signaling proteins MEK and ERK; EGF-stimulated activation was inhibited by sorafenib. However, sorafenib, as a single agent, increased AKT (Ser473) phosphorylation. EGF-stimulated AKT (ser473) activation was inhibited by PKI-587. PKI-587 is a potent inhibitor of AKT (Ser473), mTOR (Ser2448), and S6K (Thr389) phosphorylation; in contrast, rapamycin stimulated mTOR complex 2 substrate AKT(Ser473) phosphorylation although it inhibited mTOR complex 1 substrate S6K phosphorylation. PKI-587, as a single agent, stimulated MEK and ERK phosphorylation. However, when PKI-587 and sorafenib were used in combination, they inhibited all the tested kinases in the Ras/Raf /MAPK and PI3K/AKT/mTOR pathways., Conclusion: The combination of PKI-587 and sorafenib has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Deregulated RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PI-103 (a small molecule inhibitor of PI3K and mTOR) and sorafenib as single agents and in combination on HCC tumorigenesis in an in vivo xenograft model., Materials and Methods: In vitro study: Huh7 proliferation was assayed by 3H-thymidine incorporation and by thiazolyl blue tetrazolium bromide (MTT) assay. Western blots were used to detect phosphorylation of the key enzymes in the two pathways. In vivo study: Human HCC cell line Huh7 was inoculated into nude mice s.c. and the mice were treated with sorafenib (20 mg/kg/day) and PI-103 (5 mg/kg, every 4 days). Tumor size was measured every other day. Tumors were isolated for western blot and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay detection of apoptosis and signaling pathway enzymes., Results: Our in vitro study found that combination of sorafenib and PI-103 additively inhibited Huh7 proliferation as compared to single-agent treatment. Sorafenib and PI-103 as single agents differentially inhibited or activated key enzymes (MEK, ERK, AKT, mTOR, and S6K) in PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways. Combination of sorafenib and PI-103 inhibited all the key enzymes in the two pathways. Our in vivo study demonstrated significant differences between control group, mono-drug groups and drug-combination group (p<0.05). Combination of Sorafenib and PI-103 more efficiently inhibited tumorigenesis as compared to mono-drug treatments (p<0.032)., Conclusion: The combination of PI-103 and sorafenib has the advantage over mono-drug therapy on inhibition of HCC cell proliferation and tumorigenesis by inhibiting both PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways.

Background:   Postoperative infections are frequent complications after liver resection and have significant impact on length of stay, morbidity and mortality. Surgical site infection (SSI) is the most common nosocomial infection in surgical patients, accounting for 38% of all such infections., Objectives:   This study aimed to identify predictors of SSI and organ space SSI after liver resection., Methods:   Data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for patients who underwent liver resection in 2005, 2006 or 2007 in any of 173 hospitals throughout the USA were analysed. All patients who underwent a segmental resection, left hepatectomy, right hepatectomy or trisectionectomy were included., Results:   The ACS-NSQIP database contained 2332 patients who underwent hepatectomy during 2005-2007. Rates of SSI varied significantly across primary procedures, ranging from 9.7% in segmental resection patients to 18.3% in trisectionectomy patients. A preoperative open wound, hypernatraemia, hypoalbuminaemia, elevated serum bilirubin, dialysis and longer operative time were independent predictors for SSI and for organ space SSI., Conclusions:   These findings may contribute towards the identification of patients at risk for SSI and the development of strategies to reduce the incidence of SSI and subsequent costs after liver resection., (© 2011 International Hepato-Pancreato-Biliary Association.)

Objective: To determine outcomes in patients undergoing liver transplantation (LT) for metastatic neuroendocrine tumors (NETs)., Design: Retrospective analysis., Setting: University of Kentucky Medical Center., Patients: Patients undergoing LT performed for NET metastases from October 1, 1988, through January 31, 2008, were analyzed using the United Network for Organ Sharing database. Main Outcome Measure  Patient survival., Results: During the study period, 87 280 LTs were performed. One hundred fifty LTs were performed for metastatic NETs. Among those 150 patients undergoing LT, 51 patients (34.0%) had carcinoid, 6 had insulinoma (4.0%), 3 had glucagonoma (2.0%), 11 had gastrinoma (7.3%), and 9 had vasoactive intestinal peptide-secreting tumors (6.0%); an additional 70 (46.7%) had an unspecified NET. The mean (SE) age of the patients was 45.1 (12.5) years. The mean (SE) cold ischemic time was 8.9 (4.1) hours. One hundred forty-four patients were adults and 6 were children. Thirteen patients received another organ at the time of LT. During the same period, 4693 patients underwent transplantation for hepatocellular carcinoma. Overall, 1-, 3-, and 5-year survival rates for patients with NETs undergoing isolated LT were 81%, 65%, and 49%, respectively. No difference in survival was observed in patients with carcinoid vs noncarcinoid tumors (P = .84). No significant difference was observed in patient survival between those with metastatic NETs and those with hepatocellular carcinoma. Patients waiting for LT longer than 2 months had improved survival (P = .005)., Conclusions: Patients with liver metastases from NETs who were undergoing LT had long-term survival similar to that of patients with hepatocellular carcinoma. Longer wait times were associated with better outcomes in our series. Waiting for disease to stabilize before considering patients with liver metastases from NETs for transplantation may be appropriate. Excellent results can be obtained in highly selected patients.

Background: Aberrant Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study reports how sorafenib (a multi-kinase inhibitor) and PI-103 (a dual PI3K/mTOR inhibitor) alone and in combination inhibit the proliferation of the HCC cell line, Huh7., Materials and Methods: Huh7 proliferation was assayed by 3H-thymidine incorporation and by MTT assay. Western blot was used to detect phosphorylation of the key enzymes in the Ras/Raf and PI3K pathways., Results: Sorafenib and PI-103, as single agents inhibited Huh7 proliferation and epidermal growth factor (EGF)-stimulated Huh7 proliferation in a dose-dependent fashion; the combination of sorafenib and PI-103 produced synergistic effects. EGF increased phosphorylation of MEK and ERK, key Ras/Raf downstream signaling proteins; this activation was inhibited by sorafenib. However, sorafenib as a single agent increased AKT(Ser473) and mTOR phosphorylation. EGF-stimulated activation of PI3K/AKT/mTOR pathway components was inhibited by PI-103. PI-103 is a potent inhibitor of AKT(Ser473) phosphorylation; in contrast, rapamycin stimulated AKT(Ser473) phosphorylation. It was found that PI-103, as a single agent, stimulated MEK and ERK phosphorylation. However, the combination of sorafenib and PI-103 caused inhibition of all the tested kinases in the Ras/Raf and PI3K pathways., Conclusion: The combination of sorafenib and PI-103 can significantly inhibit EGF-stimulated Huh7 proliferation by blocking both Ras/Raf/MAPK and PI3K/AKT/mTOR pathways.

Background/aims: In cirrhotic patients, ascites may increase weight and adversely impact liver transplant candidacy., Methodology: In this study we used linear and volume measurements from abdominal CT imaging to estimate dry weight of transplant candidates using multivariable linear regressions. We reviewed 200 scans. For males there were 81, 26, and 41 scans with no/small, moderate, and large ascites, respectively, and 41, 6, and 5 scans of females with no/small/moderate, and large ascites respectively., Results: In males without ascites, subxiphoid subcutaneous fat volume had the strongest correlation with weight (r = 0.826); the best prediction utilized four variables including height, subcutaneous subxiphoid fat volume, and intraabdominal and subcutaneous umbilicus fat volumes (r = 0.923, r2 = 0.852, SEE = 15.15, p < 0.001). In females, subcutaneous fat volume above the umbilicus had the best correlation (r = 0.815); incorporating height and anterior subxiphoid fat thickness increased predictive accuracy (r = 0.892, r2 = 0.796, SEE = 15.37, p < 0.001). These regressions consistently under-predicted scale weight in patients with moderate and large ascites (5.92 +/- 25.50 pounds and 11.21 +/- 19.34 pounds in males, and 2.29 +/- 23.76 and 8.37 +/- 11.44 in females)., Conclusions: Equations to estimate patient weight regardless of ascites may offer a more accurate representation of size than scale weight in transplant candidates with ascites.

Background: To determine factors associated with outcomes and microvascular invasion (MVI) in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC)., Methods: Between July 1996 and August 2008 at the Universities of Kentucky or Tennessee, LT recipients were retrospectively analysed., Results: One hundred and one patients had HCC in the explanted liver; one patient was excluded because of fibrolamellar histology. Seventy-nine (79%) were male and 81 (81%) were older than 50. HCC was incidental in 32 patients (32%). Median follow-up was 31 months. Ten patients (10%) developed recurrence, which was associated with poor survival (P= 0.006). Overall 1-, 3-, and 5-year survival rates were 87%, 69% and 62%, respectively. Excluding patients with lymph node metastasis (LNM) or MVI yielded 91%, 81% and 75% survival at the same time points. MVI was independently associated with recurrence (OR 28.40, 95% CI 1.77-456.48, P= 0.018) and decreased survival (OR 4.70, 95% CI 1.24-17.80, P= 0.023), and LNM with decreased survival (OR 6.05, 95% CI 1.23-29.71, P= 0.027). Tumour size (OR 4.1, 95% CI 1.2-13.5, P= 0.013) and alpha-fetoprotein (AFP) > 100 (OR 5.0, 95% CI 1.4-18.1, P= 0.006) were associated with MVI., Conclusions: MVI greatly increases the risk of recurrence and death after LT for HCC, and is strongly associated with tumour size and AFP > 100.

Background: Protein Kinase C (PKC) is a family of enzymes that plays a key role in cell signaling pathways leading to cellular activation and proliferation. Conventional PKC (cPKC) is dependent on calcium for activation. We have proposed that cyclosporin A (CsA), despite being a calcineurin inhibitor, will activate PKC in B cells, thus promoting Epstein-Barr virus (EBV)-induced transformation. Here we show that CsA promoted atypical PKC isoform PKC-zeta in B cells., Materials and Methods: Western-blot was used to assay PKC-zeta protein level in EBV-B cells. Confocal microscopy was used to assay PKC-zeta translocation from cytosol to cell membrane, a known process of PKC activation., Results: CsA (500 ng/mL) time dependently increased PKC-zeta from control of 7055 units to 7145, 10,805, 10,914, and 12,705 units, respectively, after 15 min, 1 h, 12 h, and 24 h of incubation in EBV-transformed human B-cell line (LCL). CsA increased PKC-zeta expression was inhibited 50% by Vit.E (40 microM) indicating that this effect may be due to oxidative stress induced by CsA. Indeed, after oxidant H(2)O(2) (0.1 mM) treatment, PKC-zeta protein level in LCL cells increased 124%, 257%, 349%, and 359% after 15 min, 1 h, 12 h, and 24 h of culture compared with control. Addition of Vit.E (40 microM) in H(2)O(2) (0.1 mM) treatment and then with Vit.E in the culture decreased PKC-zeta level in LCL cells 26%, 20%, 41%, and 60% after 15 min, 1 h, 12 h, and 24 h of culture. In confocal microscopy in Jurkat T cell line, phorbol 12-myristate 13-acetate (PMA) activated cPKC isoform PKCalpha after 30 min treatment and activated PKC-zeta after 60 min treatment. CsA inhibited PMA activation of PKC-alpha, but not PKC-zeta. CsA alone did not activate PKC-alpha or PKC-zeta in Jurkat T cells. In LCL and in EBV-infected human B-cells, PMA stimulated PKC-alpha activation after 30 min treatment and stimulated PKC-zeta activation after 60 min treatment. CsA inhibited PMA activation of PKC-alpha, but not PKC-zeta. In addition, CsA activated PKC-zeta in the EBV-transformed and EBV-infected human B cells., Conclusion: These experiments show that CsA-induced oxidative stress caused PKC-zeta up-regulation in LCL cells, and show the differential effect of CsA in the PKC signaling pathways in T cells versus B cells. CsA-induced PKC-zeta activation may be an important signaling step in EBV-induced post-transplant lymphoproliferative disorders.

Objective: To investigate independent contributions of obesity, diabetes, and smoking to resource utilization in patients following liver resection., Summary Background Data: Despite being highly resource-intensive, liver resections are performed with increasing frequency. This study evaluates how potentially modifiable factors affect measures of resource utilization after hepatectomy., Methods: The American College of Surgeons' National Surgical Quality Improvement Program (ACS NSQIP) public-use database was queried for patients undergoing liver resection. Resource variables were operative time (OT), intraoperative transfusion, length of stay (LOS), ventilator support at 48 hours, and reoperation. Bivariable and multivariable linear and logistic regressions were performed., Results: There were 1029 patients identified. Most resections involved less than a hemiliver (599 patients, 58.2%). Mean BMI was 28.0 +/- 6.0. Mean OT was 253 +/- 122 minutes (range, 27 to 794) but varied by procedure (P < 0.001). Mean LOS was 8.7 +/- 10.7 days (range, 0 to 202). Morbid obesity added 48 minutes to OT (P = 0.018), 1.1 units to transfusions (P = 0.049), 2.2 days to LOS (P < 0.001), and accounted for delayed ventilator weaning (odds ratio, 4.5; P = 0.022). Underweight patients had shorter OT, but stayed 3.3 days longer than normal weight patients (P < 0.001). Insulin-treated patients with diabetes had longer OT (P < 0.001), increased transfusions (P < 0.001), and delayed ventilator weaning (odds ratio, 6.7; P < 0.001), while orally-treated patients with diabetes showed opposite trends. Smokers stayed 1.9 days longer (P < 0.001), with increased risk of prolonged ventilation (odds ratio, 3.3; P = 0.002) and reoperation (odds ratio, 2.3; P = 0.015)., Conclusion: Obesity, diabetes, and smoking are each associated with important components of healthcare expenditure. Education and prevention programs are needed to limit their impact on overall resource utilization.

Curcumin is a multi-functional and pharmacologically safe natural agent. Used as a food additive for centuries, it also has anti-inflammatory, anti-virus and anti-tumor properties. We previously found that it is a potent inhibitor of cyclosporin A (CsA)-resistant T-cell co-stimulation pathway. It inhibits mitogen-stimulated lymphocyte proliferation, NFkappaB activation and IL-2 signaling. In spite of its safety and efficacy, the in vivo bioavailability of curcumin is poor, and this may be a major obstacle to its utility as a therapeutic agent. Liposomes are known to be excellent carriers for drug delivery. In this in vitro study, we report the effects of different liposome formulations on curcumin stability in phosphate buffered saline (PBS), human blood, plasma and culture medium RPMI-1640+10% FBS (pH 7.4, 37 degrees C). Liposomal curcumin had higher stability than free curcumin in PBS. Liposomal and free curcumin had similar stability in human blood, plasma and RPMI-1640+10% FBS. We looked at the toxicity of non-drug-containing liposomes on (3)H-thymidine incorporation by concanavalin A (Con A)-stimulated human lymphocytes, splenocytes and Epstein-Barr virus (EBV)-transformed human B-cell lymphoblastoid cell line (LCL). We found that dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) were toxic to the tested cells. However, addition of cholesterol to the lipids at DMPC:DMPG:cholesterol=7:1:8 (molar ratio) almost completely eliminated the lipid toxicity to these cells. Liposomal curcumin had similar or even stronger inhibitory effects on Con A-stimulated human lymphocyte, splenocyte and LCL proliferation. We conclude that liposomal curcumin may be useful for intravenous administration to improve the bioavailability and efficacy, facilitating in vivo studies that could ultimately lead to clinical application of curcumin.

Background: Alcoholic liver disease (ALD) is a common indication for transplantation worldwide. This study identifies factors predicting posttransplant recidivism., Methods: Clinical and laboratory data were reviewed. Uni- and multivariate analyses for survival and relapse to alcohol and illicit drugs were performed., Result: Between July 1995 and November 2007, 387 patients underwent liver transplantation at our institution. Of these, 147 patients (38%) were found to have ALD. Five patients (3.4%) were excluded because of perioperative mortality. Overall survival was 96.2%, 89.6%, and 84.4% at 1, 3, and 5 years, respectively, with a median follow-up of 41.2 months. Twenty-seven patients (19%) returned to alcohol after transplantation. By univariate analysis, depression was the only significant factor affecting survival (P=0.01), whereas posttransplant relapse to alcohol trended toward significance (P=0.059). Multivariate analysis showed both factors to be independently associated with poor survival (P=0.008 and 0.017, respectively). Factors associated with relapse included less than 12 months of abstinence before transplant (P=0.019) and participation in rehabilitation (P=0.026). Multivariate analysis showed pretransplant abstinence less than 12 months as the only independent factor (P=0.037) associated with alcohol relapse after transplantation. Twenty-five patients (17.2%) had documented drug use after transplantation. Drug abuse before transplantation was the only independent predictor of drug abuse after transplantation (P=0.017)., Conclusions: Excellent results can be obtained in patients undergoing liver transplantation for ALD, though depression and recidivism adversely impact survival. In our series, abstinence less than 12 months was associated with relapse to alcohol. Similarly, those with prior drug abuse are more likely to continue drug use after transplantation.

To determine current immunosuppression regimens and strategies for acute cellular rejection in hepatitis C virus (HCV) patients after liver transplantation (LT), questionnaires were sent to 264 LT programs worldwide. Surveys from 81 programs were reviewed. In 27 centers (33.8%) the immunosuppression protocol used in HCV differed from non-HCV patients. Tacrolimus-based immunosuppression is utilized in 70 centers (86.42%). Triple therapy using tacrolimus, mycophenolate mofetil and steroids is the most common regimen (41%). Six programs (7.4%) use steroid-free protocols. In nine centers (11%) steroids are discontinued within a week, 56% within 3 months, and 98% within the first year. At 75% of centers, mild rejection is treated by increasing baseline immunosuppression. Moderate rejection is treated by increasing baseline immunosuppression in 38% of centers, steroid bolus in 44%, and either in 16%. For severe rejection, 46% of centers give bolus steroid, and 16% administer antibodies. Among respondents, non-US programs use significantly more cyclosporine than US programs (35.6% vs. 2.8%, P<0.001). Duration of steroid therapy is significantly shorter in US programs than non-US (10.8 vs. 29.4 weeks, P<0.001). There is no consensus regarding the best immunosuppressive regimen and rejection treatments in HCV patients after LT. Our results reveal the most prevalent management practices in this difficult group of patients.

The incidence of post-transplant lymphoproliferative disorder (PTLD) has increased since cyclosporin A (CsA) became the mainstay of transplant immunosuppression. We have previously shown that, in addition to its potent immunosuppressive property, CsA-induced oxidative stress plays an important role in Epstein-Barr virus (EBV)-related PTLD. Using lipid hydroperoxide and malondialdehyde as markers of lipid oxidation, and protein carbonyls as markers of protein oxidation, we further investigated the in vitro effect of CsA on human B cells and EBV-infected human B cells. We found that CsA at 500 ng/ml, a relatively safe and effective blood concentration in organ transplant recipients, induced the highest lipid hydroperoxide and malondialdehyde after 10 min of treatment in time- and concentration-related kinetic studies. We also found that treatment with CsA at 500 ng/ml for 10 min increased the EBV-infected B cell protein carbonyl formation as assayed by immunoblot method. CsA-induced lipid and protein oxidation could be inhibited by vitamin E, N-acetyl cysteine, and pyrollidine dithiocarbamate. CsA significantly promoted the EBV-B cell transformation as assayed by colony counting, cell counting, and (3)H-thymidine incorporation. Our recent study provides further evidence to support the hypothesis that CsA exerts direct oxidative stress in EBV-infected as well as non-EBV-infected human B cells. A greater understanding of these cellular and molecular mechanisms may benefit the clinical practice and prevention of PTLD.

Background: Carcinoid tumors are characteristically low grade malignant neoplasms with neuroendocrine differentiation that arise in various body sites, most commonly the lung and gastrointestinal tract, but less frequently the kidneys, breasts, ovaries, testes, prostate and other locations. We report a case of a carcinoid of renal origin with synchronous single liver metastases on radiological studies., Case Presentation: A 45 year-old patient who presented with abdominal pain was found on CT scan to have lesions in the right ovary, right kidney, and left hepatic lobe. CA-125, CEA, and CA 19-9 were within normal limits, as were preoperative liver function tests and renal function. Biopsy of the liver mass demonstrated metastatic neuroendocrine tumor. At laparotomy, the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, radical right nephrectomy with lymphadenectomy, and left hepatectomy. Pathology evaluation reported a right ovarian borderline serous tumor, well-differentiated neuroendocrine carcinoma of the kidney (carcinoid) with 2 positive retroperitoneal lymph nodes, and a single liver metastasis. Immunohistochemistry revealed that this lesion was positive for synaptophysin and CD56, but negative for chromogranin as well as CD10, CD7, and CD20, consistent with a well-differentiated neuroendocrine tumor. She is doing well one year after her initial surgery, with no evidence of tumor recurrence., Conclusion: Early surgical intervention, together with careful surveillance and follow-up, can achieve successful long-term outcomes in patients with this rare malignancy.

The end-to-end "interposition" technique and end-to-side "piggyback" technique are standard approaches to in situ anastomosis during orthotopic liver transplantation. We demonstrate that anastomosis of liver allograft to a Dacron vena cava graft can be a feasible solution if traditional anastomoses cannot be used. A 55-year-old man with end-stage liver failure from alcoholic cirrhosis underwent orthotopic liver transplantation; however, an intraoperative complication during recipient hepatectomy rendered the native vena cava unsalvageable. In addition, the donor vena cava was too short to bridge the caval defect for interposition. We therefore used Dacron for an in situ graft to span the gap, with subsequent anastomosis of the allograft to the prosthetic graft in piggyback fashion. The patient did well postoperatively; his only major complication was late anastomotic stenosis, which was treated successfully with balloon dilatation. Unfortunately the patient became recidivous and expired ten months posttransplant, despite indications of satisfactory allograft function.

Background: Patients with acute massive pulmonary embolus have a high mortality even with treatment. For patients in whom thrombolytic intervention is contraindicated, surgical pulmonary embolectomy is a viable option., Case Report: We present a patient who, four months after kidney transplantation, developed acute massive PE with cardiac arrest. He underwent surgical pulmonary embolectomy and was discharged two weeks later, with preservation of renal allograft function and long-term survival., Conclusions: While the mortality risk of surgical embolectomy is high, survival has been greatly improved by the use of cardiopulmonary bypass. Early diagnosis and initiation of aggressive treatment is vital to achieving successful outcomes in patients who would otherwise be unsalvageable.

Hypothesis: Patient outcome and the development of major intra-abdominal postoperative complications following removal of cavernous hemangiomas of the liver are affected by methods of resection., Design: Case-control study., Setting: Hepatobiliary surgery and liver transplantation unit in a tertiary care referral medical center., Patients: Between December 1, 1987, and December 1, 1997, 28 patients underwent the surgical removal of cavernous hemangioma either by hepatic resection or enucleation. Indications for the operation were pain, enlarging tumors, uncertain diagnosis, or rupture., Main Outcome Measures: The technique of tumor removal, hospital course, and the development of intra-abdominal complications. Independent factors influencing the development of complications were ascertained by multivariate analysis., Results: Twenty-four female and 4 male patients (age, 47.5+/-12.4 [mean +/- SD] years) underwent either enucleation (n = 23) or liver resection (n = 5). Lesions ranged from 2 to 16 cm in their postresection diameter. No surgical (30-day) mortality was observed. Four major intra-abdominal complications were found: 1 episode of intraoperative bleeding requiring abdominal packing and 3 intra-abdominal fluid collections requiring percutaneous drainage. Enucleation was the only independent factor found by univariate and multivariate analyses to be associated with a reduction in the number of intra-abdominal complications (P = .04)., Conclusions: Cavernous hemangiomas of the liver can be removed safely by either hepatic resection or enucleation. Enucleation is associated with fewer intra-abdominal complications and should be the technique of choice when tumor location and technical factors favor enucleation.

Hypothesis: The distal splenorenal shunt (DSRS) continues to play an important role in the management of recurrent variceal bleeding with minimal negative impact on subsequent orthotopic liver transplantation (OLT)., Design: Case-control study., Setting: Hepatobiliary surgery and liver transplantation unit in a tertiary referral medical center., Patients: From August 1, 1985, through October 31, 1997, a single team of surgeons performed 81 DSRS procedures for recurrent variceal hemorrhage. Eleven patients undergoing OLT subsequent to DSRS were compared with a group of 274 patients undergoing OLT without any previous shunt during the same period., Main Outcome Measures: Operative time, use of blood products, length of hospital stay, perioperative complications, and survival rates., Results: Operative (30-day) mortality for DSRS was 6% (n = 5). From follow-up information available for 74 patients, the 1- and 5-year survival rates were 86.4% (n = 64) and 74.3% (n = 55), respectively. Recurrent variceal bleeding and hepatic encephalopathy occurred in 5 (6.8%) and 11 patients (14.9%), respectively, after DSRS. In 9 patients, DSRS was used as salvage for failed transjugular intrahepatic portosystemic shunt., Conclusions: Distal splenorenal shunt is a safe, durable, and effective treatment for controlling recurrent variceal hemorrhage in patients with acceptable operative risk and good liver function. It does not compromise future liver transplantation and can considerably delay the time until transplantation is required. Given the early occlusion rate and need for constant surveillance, transjugular intrahepatic portosystemic shunting should be reserved for patients with Child C classification cirrhosis with chronic hemorrhage or intractable ascites or as an emergency procedure for patients with uncontrollable bleeding using endoscopic therapy.

We describe our technique to perform laparoscopic jejunostomies with an 18-mm trocar. This procedure facilitates the exteriorization of the proximal bowel and construction of the jejunostomy. We describe our laparoscopic technique in nine patients with severe neurologic conditions (two in the postoperative period of a cerebral aneurysm in a coma, three patients with severe head injury, and four patients with cerebrovascular strokes). The operative time ranged from 20 to 75 min (average, 44.38 min). Nutrition was initiated 24 h after the placement of the jejunostomy. Tolerance of the enteral nutrition was excellent in all cases. One major complication occurred, minor leakage around the feeding tube 3 weeks after the jejunostomy was constructed. The jejunostomy was removed without further consequences. Laparoscopy is an effective technique for the creation of feeding jejunostomies. We believe that this minimally invasive approach is an alternative for patients requiring long-term postpyloric enteral feeding.