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Ciliated hepatic foregut cyst (CHFC) is a rare foregut developmental malformation usually diagnosed in adulthood; however, rare cases have been reported in the pediatric population. CHFC can transform into a squamous cell carcinoma resulting in death despite surgical resection of the isolated malignancy. We report the presentation, evaluation, and surgical management of a symptomatic 17-year-old girl found to have a 6.5 x 4.5 cm CHFC and suggest that all patients with suspected CHFC undergo prompt evaluation and complete cyst excision.

New antimalarial drugs are urgently needed to combat emerging multidrug resistant strains of malaria parasites. This Highlight focuses on plant-derived natural products that are of interest as potential leads towards new antimalarial drugs including synthetic analogues of natural compounds, with the exception of artemisinin derivatives, which are not included due to limited space. Since effective antimalarial treatment is often unavailable or unaffordable to many of those who need it, there is increasing interest in the development of locally produced herbal medicines; recent progress in this area will also be reviewed in this Highlight.

Background: Recent studies demonstrate that obesity does not affect survival after kidney transplantation. However, overweight and obesity impair health-related quality of life (HRQOL) in patients with chronic illnesses. We wished to examine the effects of pre-transplant overweight and obesity on post-transplant physical HRQOL in kidney transplant recipients., Study Design: Patient-reported HRQOL data were systematically collected in kidney transplant recipients receiving post-transplant follow-up at Vanderbilt Transplant Center. Patients who received kidney transplants between 1998 and 2008, had at least 1 post-transplant physical component summary (PCS) measurement, and did not receive other solid organ transplants were included in this retrospective cohort study. Pre-transplant body mass index was stratified as normal, overweight, obese class I, and obese class II/extremely obese. HRQOL was measured primarily with the PCS scale of the Medical Outcomes Study Short Form 36 Health Survey. Multivariate linear and logistic regression models were used to test the effects of body mass index and demographic and clinical covariates on post-transplant HRQOL., Results: The study cohort included 464 adults (mean body mass index 27.5 +/- 5.1; range 18.5 to 47.4). After controlling for gender (p = 0.148), pre-transplant dialysis (p = 0.003), previous kidney transplantation (p = 0.255), donor type (p = 0.455), steroid avoidance immunosuppression (p = 0.070), and follow-up time (p = 0.352), there was no effect of pre-transplant overweight or obesity on post-transplant PCS (all p > or = 0.112). Kidney transplant recipients who did not require dialysis pre-transplant and those who were managed with steroid avoidance after transplantation were more likely to achieve post-transplant PCS scores at or above the general population average (both p < or = 0.011)., Conclusions: Pre-transplant overweight and obesity do not affect physical quality of life after kidney transplantation., (Copyright 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Ancient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions.

Medicinal plants used to treat infectious diseases in Bunda district, Tanzania, were screened for activity against Plasmodium falciparum and Human Immunodeficiency Virus Type 1 (HIV-1, IIIB strain) and Type 2 (HIV-2, ROD strain). Antiplasmodial activity was observed for the 80 % MeOH extract of Ormocarpum kirkii (root; MIC = 31.25 microg/mL), Combretum adenogonium (leaves), Euphorbia tirucalli (root), Harrisonia abyssinica (root), Rhynchosia sublobata (root), Sesbania sesban (root), Tithonia diversifolia (leaves), and Vernonia cinerascens (leaves; MIC value of 62.5 microg/mL). With regard to HIV, 80 % MeOH extracts of Barleria eranthemoides (root), Combretum adenogonium (leaves and stem bark), Elaeodedron schlechteranum (stem bark and root bark), Lannea schweinfurthii (stem bark), Terminalia mollis (stem bark and root bark), Acacia tortilis (stem bark), Ficus cycamorus (stem bark) and Indigofera colutea (shoot), as well as H2O extracts from Barleria eranthemoides (root), Combretum adenogonium (leaves and stem bark), and Terminalia mollis (stem bark and root bark) exhibited IC50 values below 10 microg/mL against HIV-1 (IIIB strain). The highest anti-HIV-1 activity value was obtained for the B. eranthemoides 80 % MeOH root extract (IC50 value 2.1 microg/mL). Only a few extracts were active against HIV-2, such as the 80 % MeOH extract from Lannea schweinfurthii (stem bark) and Elaeodedron schlechteranum (root bark), showing IC50 values < 10 microg/mL., (Georg Thieme Verlag KG Stuttgart . New York.)

Background: Hepatic injury remains an important cause of exsanguination after major trauma. Recent studies have noted a dramatic reduction in mortality amongst severely injured patients when trauma exsanguinations protocols (TEP) are employed. We hypothesised that utilisation of our institution's TEP at the initiation of hospital resuscitation would improve survival in patients with significant hepatic trauma., Patients and Methods: All patients who (1) sustained intra-abdominal haemorrhage with Grades III-V hepatic injury and (2) underwent immediate operative intervention between February 2004 and January 2008 were included in the study. TEP was instituted in February 2006, and all subsequent patients who met inclusion criteria and were treated with TEP constituted the study group. Patients who met inclusion criteria, were treated before introduction of TEP, and received at least 10 units packed red blood cells in the first 24h constituted pre-TEP comparison group. Univariate and multivariate analyses evaluated the effects of TEP on the study population., Results: Seventy-five patients were included in the study: 39 in the pre-TEP cohort (31% 30-day survival) and 36 in the TEP cohort (53% 30-day survival). There were no differences in demographics, extent of hepatic injury, or operative approach between the patient groups (all p > or = 0.27). Injury Severity Scores were significantly higher in the TEP group (41+/-18 vs. 28+/-15, p<0.01). TEP patients received more plasma and platelets during operative intervention and significantly less crystalloid (all p<0.01). Occurrence of cardiac dysfunction and abdominal compartment syndrome was significantly lower in TEP patients who survived 24-h post-injury (both p < or = 0.04). After adjusting for the significant negative effects of Grade V injury and involvement of major hepatic vasculature (both p < or = 0.02), TEP significantly improved 30-day survival: OR=0.22, 95% CI: 0.06-0.81, p=0.02., Conclusions: TEP allows for an effective use of plasma and platelets during intra-operative management of severe hepatic injury. Utilisation of TEP is associated with significant reductions of cardiac dysfunction and development of abdominal compartment syndrome, as well as, significant improvement in 30-day survival.

Aim: This paper is a report of a study investigating the effects of clinical factors (side effects of immunosuppressive medications, transplant-related hospitalizations, donor type, duration of dialysis before transplantation and time post-transplant) on cognitive appraisal of health, perceived self-efficacy, perceived social support, coping and health-related quality of life after renal transplantation., Background: Some clinical factors such as hospitalizations, side effects of medications, donor type and dialysis, which influence the health-related quality of life of renal transplant recipients, have been investigated. However, the effects of these clinical factors on psychosocial variables after renal transplantation have not been well documented. Method. Using a descriptive cross-sectional design, a convenience sample of 160 renal transplant recipients was recruited (N = 55 < 1 year post-transplant; N = 105 1-3 years post-transplant) from May, 2005 to January, 2006. Standardized instruments were used to measure the key constructs. Multivariate analysis of variance was used to examine the effects of clinical factors on the psychosocial outcome measures., Results: Participants reporting more (>17) immunosuppressive medication-associated side effects appraised their health more negatively, used more disengagement coping, had lower degrees of perceived self-efficacy, and reported lower physical and mental health-related quality of life than those with fewer symptoms (

This paper reports 35 medicinal plants belonging to 25 families used in the treatment of malaria by the people inhabiting the forests located near to Bhubaneswar, the capital city of Orissa, a south-eastern state in India. The methods adopted for the preparation of plant parts are discussed along with their family and local name(s). The majority of the herbal preparations were made in the form of juices or by using water as the medium in the form of decoctions or infusions. Various plant parts, such as leaves, flowers, fruits, barks, stems, roots, and in some cases the whole plants are used to prepare these remedies each of which contains a single species.

Cryptolepine is the major alkaloid of the West African shrub, Cryptolepis sanguinolenta. Cryptolepine has been shown to inhibit nitric oxide production, and DNA binding of Nuclear Factor-kappa B following inflammatory stimuli in vitro. In order to validate the anti-inflammatory property of this compound in vivo, we investigated its effects on a number of animal models of inflammation. Cryptolepine (10-40 mg/kg i.p.) produced significant dose-dependent inhibition of the carrageenan-induced rat paw oedema, and carrageenan-induced pleurisy in rats. These effects were compared with those of the non-steroidal anti-inflammatory drug indomethacin (10 mg/kg). At doses of 10-40 mg/kg i.p., cryptolepine inhibited lipopolysaccharide (LPS)-induced microvascular permeability in mice in a dose-related fashion. Oral administration of up to 40 mg/kg of the compound for four consecutive days did not induce gastric lesion formation in rats. Analgesic activity was also exhibited by cryptolepine through a dose-related (10-40 mg/kg i.p.) inhibition of writhing induced by i.p. administration of acetic acid in mice. The results of this study reveal that cryptolepine possesses in vivo anti-inflammatory activity., ((c) 2009 John Wiley & Sons, Ltd.)

The plant derived indoloquinoline alkaloid cryptolepine was investigated for its cytotoxic properties in 12 human tumour cell lines and in primary cultures of tumour cells from patients. The fluorometric microculture cytotoxicity assay was used to assess cytotoxicity and DNA micro-array analysis to evaluate gene expression. Cryptolepine mean IC(50) in the cell line panel was 0.9 microM compared with 1.0 and 2.8 microM in haematological and solid tumour malignancies, respectively. Among patient solid tumour samples, those from breast cancer were the most sensitive and essentially as sensitive as haematological malignancies. Cryptolepine activity showed highest correlations to topoisomerase II and microtubule targeting drugs. In the cell lines cryptolepine activity was essentially unaffected by established mechanisms of drug resistance. A number of genes were identified as associated with cryptolepine activity. In conclusion, cryptolepine shows interesting in vitro cytotoxic properties and its further evaluation as an anti-cancer drug seems warranted.

Background: Ventilator-associated pneumonia (VAP) causes significant morbidity and mortality in critically ill surgical patients. Recent studies suggest that the success of preventive measures is dependent on compliance with ventilator bundle parameters., Hypothesis: Implementation of an electronic dashboard will improve compliance with the bundle parameters and reduce rates of VAP in our surgical intensive care unit (SICU)., Design: Time series analysis of VAP rates between January 2005 and July 2008, with dashboard implementation in July 2007., Setting: Multidisciplinary SICU at a tertiary-care referral center with a stable case mix during the study period., Patients: Patients admitted to the SICU between January 2005 and July 2008., Main Outcome Measures: Infection control data were used to establish rates of VAP and total ventilator days. For the time series analysis, VAP rates were calculated as quarterly VAP events per 1000 ventilator days. Ventilator bundle compliance was analyzed after dashboard implementation. Differences between expected and observed VAP rates based on time series analysis were used to estimate the effect of intervention., Results: Average compliance with the ventilator bundle improved from 39% in August 2007 to 89% in July 2008 (P < .001). Rates of VAP decreased from a mean (SD) of 15.2 (7.0) to 9.3 (4.9) events per 1000 ventilator days after introduction of the dashboard (P = .01). Quarterly VAP rates were significantly reduced in the November 2007 through January 2008 and February through April 2008 periods (P < .05). For the August through October 2007 and May through July 2008 quarters, the observed rate reduction was not statistically significant., Conclusions: Implementation of an electronic dashboard improved compliance with ventilator bundle measures and is associated with reduced rates of VAP in our SICU.

c-IAP1 (cellular inhibitor of apoptosis 1) has recently emerged as a negative regulator of the non-canonical NF-kappaB (nuclear factor kappaB) signalling cascade. Whereas synthetic IAP inhibitors have been shown to trigger the autoubiquitination and degradation of c-IAP1, less is known about the physiological mechanisms by which c-IAP1 stability is regulated. In the present paper, we describe two distinct cellular processes that lead to the targeted loss of c-IAP1. Recruitment of a TRAF2 (tumour necrosis factor receptor-associated factor 2)-c-IAP1 complex to the cytoplasmic domain of the Hodgkin's/anaplastic large-cell lymphoma-associated receptor, CD30, leads to the targeting and degradation of the TRAF2-c-IAP1 heterodimer through a mechanism requiring the RING (really interesting new gene) domain of TRAF2, but not c-IAP1. In contrast, the induced autoubiquitination of c-IAP1 by IAP antagonists causes the selective loss of c-IAP1, but not TRAF2, thereby releasing TRAF2. Thus c-IAP1 can be targeted for degradation by two distinct processes, revealing the critical importance of this molecule as a regulator of numerous intracellular signalling cascades.

Iatrogenic porta hepatis transection is a rare but devastating surgical complication. There are no systematic studies examining the best treatment strategy in patients with this injury. We report two cases of transection of all three portal structures, one during an open right adrenalectomy and another during a laparoscopic cholecystectomy, both of which were transferred to our tertiary care center hours postinjury. Diagnostic imaging and exploration revealed nonsalvageable livers, and both patients underwent total hepatectomies and portocaval shunting. Donor livers were available 12 to 20 hours after United Network for Organ Sharing Status 1 listing and both patients survived their postoperative course with 2- and 6-year follow up to date. Two-stage total hepatectomy with portocaval shunting followed by liver transplantation should be considered for patients presenting with porta hepatis transection.

The alkaloid cryptolepine (1) and eight synthetic analogues (2-8) were assessed for in vitro activities against Trypanosoma brucei. Four of the analogues were found to be highly potent with IC50 values of less than 3 nM and three of these were assessed against T. brucei brucei infection in rats. The most effective compound was 2, 7-dibromocryptolepine (7); a single oral dose of 20 mg/kg suppressed parasitaemia and increased the mean survival time to 13.6 days compared with 8.4 days for untreated controls. In addition, four huperzine derivatives (9-12) were shown to have in vitro antitrypanosomal activities with IC50 values ranging from 303-377 nM.

Objectives: To determine whether patients with a complete or near-complete response to neoadjuvant radiation therapy (XRT) have improved survival compared with those with less of a response and to compare survival between patients with disease downstaged after neoadjuvant XRT and patients with stage I disease undergoing resection alone., Design, Setting, and Patients: Retrospective cohort of 10,971 patients (3760 patients with neoadjuvant XRT; 7211 with stage I disease with resection alone) from the Surveillance, Epidemiology, and End Results registry using data from January 1, 1994, through December 31, 2003., Main Outcome Measures: Overall survival and disease-specific survival (DSS) of patients undergoing resection for nonmetastatic rectal adenocarcinoma receiving neoadjuvant XRT and patients with stage I disease undergoing surgical resection alone., Results: The 5-year DSS and overall survival were 94% and 82%, respectively, for responders to neoadjuvant XRT, 78% and 60%, respectively, for nonresponders, and 97% and 79%, respectively, for patients with stage I disease undergoing resection alone. Responders had improved DSS (P < .001) and overall survival (P < .001) compared with nonresponders by Cox regression. Patients with stage I disease undergoing resection alone had improved DSS (P = .01) but not overall survival (P = .89) compared with XRT responders., Conclusions: Patients with rectal adenocarcinoma downstaged after neoadjuvant XRT have improved survival compared with nonresponders. While DSS is excellent for responders to neoadjuvant XRT, it did not equal the DSS of patients with stage I disease undergoing resection alone.

Deregulated expression of members of the IAP (inhibitor of apoptosis) family has been identified in a wide variety of neoplastic cells, and synthetic IAP antagonists represent a promising novel class of chemotherapeutic agents. Early work focused on the ability of these compounds to block the caspase-inhibitory function of XIAP (X-linked IAP). However, recent studies have shown that IAP antagonists, although primarily designed to target XIAP, trigger ubiquitin-mediated degradation of two related proteins, c-IAP (cellular IAP) 1 and c-IAP2, and through this process potentiates the death of tumour cells via autocrine cellular-signalling pathways. In this context, the relative contribution of XIAP as a target of this class of compounds is unclear. In the present study, we examine the involvement of XIAP using a recently described synthetic IAP antagonist, AEG40730, and through comparison of a human XIAP-depleted tumour cell line with its isogenic wild-type control line. Treatment with nanomolar concentrations of AEG40730 resulted in the loss of both XIAP and c-IAP1 proteins, albeit with different kinetics. Although XIAP-deficient HCT116 cells retained some sensitivity to external apoptotic stimuli, the results suggest that IAP antagonists, such as AEG40730, exert their apoptosis-enhancing effects through XIAP in addition to the c-IAPs. These results indicate that IAP antagonists can target multiple IAPs to augment distinct pro-apoptotic signalling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies.

Objective: To determine whether a correlation exists between the Model for End-Stage Liver Disease (MELD) score and health-related quality of life (HRQOL) after liver transplant (LT)., Design: Prospective cohort., Setting: University hospital., Patients: Adult LT recipients (N = 209)., Main Outcome Measures: Postoperative HRQOL over a 1-year period after LT as measured via multiple regression-based path analysis testing the effects of the MELD score, preoperative variables, and postoperative variables on scores on the physical component summary and mental component summary scales of the 36-Item Short Form Health Survey and on composite physical and mental HRQOL scores derived from multiple scales., Results: The MELD score (beta = .16), cholestatic cirrhosis (beta = .12), autoimmune/metabolic disease (beta = .18), neoplasm (beta = .23), time after LT (beta = .16), and the Karnofsky score (beta = .49) had significant effects on the physical component summary scale score. Autoimmune/metabolic disease (beta = .16) and the Karnofsky score (beta = .25) had significant effects on the mental component summary scale score. The MELD score (beta = .15), high school education (beta = .15), college education (beta = .17), autoimmune/metabolic disease (beta = .15), neoplasm (beta = .23), time after LT (beta = .11), and the Karnofsky score (beta = .51) had significant effects on the composite physical HRQOL score. Autoimmune/metabolic disease (beta = .23), neoplasm (beta = .15), and the Karnofsky score (beta = .42) had significant effects on the composite mental HRQOL score., Conclusions: An increasing MELD score, when computed without any diagnosis-based exception points, was associated with improved physical HRQOL in the first year after LT. The MELD score did not affect mental HRQOL.

Expression and signaling of CD30, a tumor necrosis factor receptor family member, is up-regulated in numerous lymphoid-derived neoplasias, most notably anaplastic large-cell lymphoma (ALCL) and Hodgkin's lymphoma. To gain insight into the mechanism of CD30 signaling, we used an affinity purification strategy that led to the identification of the aryl hydrocarbon receptor nuclear translocator (ARNT) as a CD30-interacting protein that modulated the activity of the RelB subunit of the transcription factor nuclear factor kappaB (NF-kappaB). ALCL cells that were deficient in ARNT exhibited defects in RelB recruitment to NF-kappaB-responsive promoters, whereas RelA recruitment to the same sites was potentiated, resulting in the augmented expression of these NF-kappaB-responsive genes. These findings indicate that ARNT functions in concert with RelB in a CD30-induced negative feedback mechanism.

Health utility instruments assess patients' valuation of specific health states, which can be converted to quality-adjusted life years for cost-utility analysis. Data from the EQ-5D, a generic health-related quality of life questionnaire from EuroQoL, can be reported as 5 health status scores or as a single health preference weight (HPW). US population-based HPWs were published by Shaw and colleagues in 2005 (Med Care 2005;43:203-220). Our aim was to test the validity of US EQ-5D HPWs and health status scores in liver transplant patients. EQ-5D scores were converted to HPWs with Shaw et al.'s model. Data were stratified by measurement period: pretransplant period, early posttransplant period (< or =12 months), intermediate posttransplant period (13-36 months), and late posttransplant period (>36 months). EQ-5D scores were compared to specific, hypothesized Short Form 36 Health Survey, Center for Epidemiologic Studies Depression Scale, and Beck Anxiety Inventory scores that were identified a priori on the basis of construct similarity. Criterion-related and construct validity were tested with nonparametric methods. Two hundred eighty-five adults participated (113 in the pretransplant period, 60 in the early posttransplant period, 47 in the intermediate posttransplant period, and 65 in the late posttransplant period), and follow-up averaged 36 +/- 36 months. Eighty-one percent of the hypothesized relationships between EQ-5D and gold-standard scales were strong (r > or = |0.5|, P < 0.001), and the remainder were moderate (r > |0.3|, P < 0.001). Differences between pretransplant and posttransplant EQ-5D HPWs were statistically significant. In conclusion, EQ-5D dimensions and the health utility index generated from Shaw's US population preference weights demonstrated criterion-related and construct validity in liver transplant patients. It is a valid instrument for cost-utility analysis in this setting., (Copyright 2008 AASLD.)

We have used the budding yeast Saccharomyces cerevisiae to identify genes that may confer sensitivity in vivo to the antimalarial and cytotoxic agent cryptolepine. Five S. cerevisiae strains, with different genetic backgrounds in cell permeability and DNA damage repair mechanisms, were exposed to several concentrations of cryptolepine. Cryptolepine showed a relatively mild toxicity for wild-type strains, which was augmented by either increasing cell permeability (Deltaerg6 or ISE2 strains) or disrupting DNA damage repair (Deltarad52 strains). These results are compatible with the ability of cryptolepine to intercalate into DNA and thus promote DNA lesions. The effects of low concentrations of cryptolepine (20% and 40% inhibitory concentrations [IC(20) and IC(40)]) were analyzed by comparing the gene expression profiles of treated and untreated Deltaerg6 yeast cells. Significant changes in expression levels were observed for 349 genes (117 upregulated and 232 downregulated). General stress-related genes constituted the only recognizable functional cluster whose expression was increased upon cryptolepine treatment, making up about 20% of upregulated genes. In contrast, analysis of the characteristics of downregulated genes revealed a specific effect of cryptolepine on genes related to iron transport or acid phosphatases, as well as a significant proportion of genes related to cell wall components. The effects of cryptolepine on the transcription of iron transport-related genes were consistent with a loss of function of the iron sensor Aft1p, indicating a possible disruption of iron metabolism in S. cerevisiae. Since the interference of cryptolepine with iron metabolism is considered one of its putative antimalarial targets, this finding supports the utility of S. cerevisiae in drug-developing schemes.

Although numerous studies have implicated the IAPs (inhibitor of apoptosis proteins) in the control of apoptotic cell death, analyses of murine Iap-targeted cells have not revealed significant differences in their susceptibility to apoptosis. In the present study, we show that, under defined conditions, murine cells lacking XIAP (X-linked inhibitor of apoptosis) and c-IAP (cellular IAP) 2, but not c-IAP1, exhibit heightened apoptotic sensitivity to both intrinsic and extrinsic apoptotic stimuli.

Despite decades of intense research, malaria remains a deadly disease worldwide and new antimalarials are urgently needed due to increasing drug resistance of Plasmodium falciparum to existing drugs. This article reports the evaluation of four Indian Diospyros species viz., Diospyros melanoxylon, D. peregrina, D. sylvatica, D. tomentosa for antiplasmodial activities against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. Six of eight methanolic extracts were found to have significant activity, (IC(50) = 16.5-92.9 microg ml(-1)), against strain 3D7 and five of these showed similar activities against strain K1 (IC(50) = 20.5-121.6 microg ml(-1)). Diospyros sylvatica was found to be the most active species (IC(50) = 16.5-29.4 microg ml(-1)) and is worthy of further investigation.

Background: The purpose of this study was to define donation patterns and lost donor opportunities in severe traumatic brain injury (TBI) patients., Methods: The trauma registry was queried for all deaths after severe TBI in 2004; this was cross matched with the regional organ procurement organization database and subjected to post hoc statistical analysis., Results: One hundred thirty-five patients met criteria for inclusion. Forty percent had isolated TBI. Forty-two patients (31%) were eligible for deceased donation. Seventeen eligible patients (40%) did not convert to donation, 15 from family declining. Twenty-five eligible patients (60%) donated 85 organs (yield 3.4 organs/donor). Yield was similar in both isolated TBI (3.2) and patients with head injuries (3.5). Ineligible patients had higher admission Glasgow Coma Scale scores, lower head Abbreviated Injury Scale scores, and were more likely to develop cardiovascular or pulmonary dysfunction (p < 0.05). Of the 25 donors, 48% did not donate hearts and 84% did not donate lungs, despite the absence of chest trauma in the majority of patients., Conclusion: Less than one-third of severe TBI patients were identified as eligible organ donors and only 40% actually donated. Half of all donors fail to donate hearts and over 80% fail to donate lungs. Within this population, opportunities may exist to improve both donor conversion and organ yield.

Background: The purpose of this study was to develop a prognostic system applicable to patients with hepatic metastasis from colorectal cancer in whom extrahepatic disease was excluded by preoperative PET with [(18)F]fluoro-2-deoxy-D-glucose (FDG-PET). Data from two institutions were analyzed separately and together to improve general applicability of results., Study Design: Data were analyzed for 285 consecutive patients undergoing liver resection for colorectal metastases from 1995 to 2005 at 2 institutions routinely using preoperative FDG-PET with. Fifteen clinicopathologic variables of the primary and secondary tumors were examined to identify factors predictive of survival., Results: Outcomes were correlated with poorly differentiated tumor grade in both data sets. Because patients with poorly differentiated tumors comprised a small proportion (16%) of the population, patients with well-differentiated or moderately differentiated tumors were analyzed independently. In this subgroup, positive lymph node status in the primary colorectal tumor resection specimen was the only characteristic that predicted survival of patients in both institutions. Consequently, patients were sorted into three prognostic categories: poor tumor differentiation; well-differentiated or moderately differentiated tumors and node positive; and well-differentiated or moderately differentiated tumors and node negative. These groups had significantly different overall survival on Kaplan-Meier analysis (p=0.0014)., Conclusions: In patients with colorectal liver metastases staged with FDG-PET with overall survival can be predicted directly from data in the pathology report of the colorectal primary tumor. This study also indicates the need for new molecular tumor markers of prognosis to complement clinicopathologic markers if the goal of prediction of outcomes in individual patients is to be reached.

Two new prenylated flavanones, 2 S-3'-(2-hydroxy-3-methylbut-3-enyl)licoflavone-4'-methyl ether ( 3) and 2 S-3'-(2-hydroxy-3-methylbut-3-enyl)abyssinone II ( 4), and four known flavanones ( 1, 2, 5, 6) were isolated from the stem bark of Erythrina addisoniae. The structures were elucidated on the basis of their spectroscopic and physicochemical data. None of the compounds showed antioxidative properties. 4'-Methylabyssinone V ( 1) and abyssinoflavanone VII ( 6) showed moderate cytotoxic activity (IC 50 = 5 and 3.5 micromol/L, respectively), but apoptosis (caspase-3/7-activation, nuclear fragmentation) was selectively induced by abyssinoflavanone VII ( 6).

Cassia siamea L. (Fabaceae) was identified from the southwest Nigerian ethnobotany as a remedy for febrile illness. This led to the bioassay-guided fractionation of stem bark of the plant extract, using the parasite lactate dehydrogenase assay and multi-resistant strain of Plasmodium falciparum (K1) for assessing the in vitro antimalarial activity. Emodin and lupeol were isolated from the ethyl acetate fraction by a combination of chromatographic techniques. The structures of the compounds were determined by spectroscopy, co-spotting with authentic samples and comparison with literature data. Both compounds were found to be the active principles responsible for the antiplasmodial property with IC(50) values of 5 microg/mL, respectively.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase polycomb group (PcG) protein, which has been implicated in the process of cellular differentiation and cancer progression for both breast and prostate cancer. Although transcriptional repression by histone modification appears to contribute to the process of cellular differentiation, it is unclear what mediates the specificity of PcG proteins. Since EZH2 requires a binding partner for its histone methyltransferase activity, we surmised that evaluating interacting proteins might shed light on how the activity of EZH2 is regulated. Here we describe the identification of a novel binding partner of EZH2, the repressor of estrogen receptor activity (REA). REA functions as a transcriptional corepressor of the estrogen receptor and can potentiate the effect of anti-estrogens. REA expression levels have also previously been associated with the degree of differentiation of human breast cancers. We show here that EZH2 can also mediate the repression of estrogen-dependent transcription, and that moreover, the ability of both REA and EZH2 to repress estrogen-dependent transcription are mutually dependent. These data suggest that EZH2 may be recruited to specific target genes by its interaction with the estrogen receptor corepressor REA. The identification of a novel interaction between EZH2 and REA, two transcription factors that have been linked to breast cancer carcinogenesis, may lead to further insights into the process of deregulated gene expression in breast cancer.

A growing number of studies have revealed that the inhibitor of apoptosis (IAP) proteins play a variety of cellular roles in addition to suppression of apoptosis. A recent study in Molecular Cell demonstrates that one IAP member, c-IAP1, functions to potentiate the activity of Myc by triggering the ubiquitination and proteasomal degradation of the Myc inhibitory protein Mad1.

Aim: To test the effects of pre- and post-transplant clinical covariates on post-transplant health-related quality of life (HRQOL) score profiles in liver transplant recipients., Material and Methods: HRQOL was measured before and after transplantation using the SF-36 Health Survey. Clinical data [diagnosis, model of end-stage liver disease (MELD) score, post-transplant rejection and infection episodes], pre-transplant functional performance (FP), and demographics were collected. Multivariate models for the eight SF-36 scales and two summary components were developed using multiple regression. Discriminant analysis was used to test whether the score profiles differentiated among recipients with and without hepatitis C virus (HCV) infection., Results: 104 adults reported pre- and post-transplant HRQOL. Time post-transplant averaged 9+/-8 months (range 1-39). Scores on all SF-36 measures improved from pre- to post-transplant (p<0.001), and 7 of 10 models were significant (p<0.05). After controlling for pre-transplant HRQOL and time post-transplant, HCV infection had a negative effect on the role physical, bodily pain, and role emotional scales. History of a rejection episode had a negative effect on the bodily pain and vitality scales. MELD scores > or = 18 had a positive effect on the role physical scale. Pre-transplant FP and post-transplant infection episodes did not affect post-transplant HRQOL. HCV infection had a significant effect on the SF-36 score profile (canonical correlation=0.50; p<0.001)., Conclusions: Pre-transplant HCV infection, MELD score, and post-transplant rejection episodes have significant independent effects on HRQOL after liver transplantation. Their specific effects vary among the individual SF-36 scales, and HRQOL score profiles differ among HCV+ and HCV- recipients.

Previous research demonstrated that physical health-related quality of life (HRQOL) improves after liver transplantation, but improvements in mental HRQOL are less dramatic. The aim of this study was to test the effects of physical HRQOL, time post-transplant, and gender on pre- to post-transplant change in anxiety and depression. Longitudinal HRQOL data were prospectively collected at specific times before and after liver transplantation using the SF-36(R) Health Survey (SF-36), Center for Epidemiologic Studies Depression Scale (CES-D), and Beck Anxiety Inventory (BAI). Within-subject change scores were computed to represent the longest follow-up interval for each patient. Multiple regression was used to test the effects of baseline score, time post-transplant, gender, and SF-36 physical component summary scores (PCS) on change in BAI and CES-D scores. About 107 patients (74% male, age=54+/-8 years) were included in the analysis. Time post-transplant ranged 1 to 39 months (mean=9+/-8). Improvement in symptoms of anxiety and depression was greatest in those patients with the most severe pre-transplant symptoms. Significant improvement in symptoms of depression occurred after liver transplant, but the magnitude of improvement was smaller with time suggesting possible relapse of symptoms. Better post-transplant physical HRQOL was associated with a greater reduction in symptoms of anxiety and depression after liver transplantation. This demonstrates clear improvements in post-transplant mental HRQOL and the significant relationships between physical and mental HRQOL.

Introduction: Several methods for hepatic parenchymal division exist. The primary aim was to assess differences in postoperative bile leaks, operative blood loss, and margin status between three transection methods: crush/clamp (CC), stapler (SP), or dissecting sealer (DS)., Methods: A single institution, retrospective cohort study was performed on data collected over a three-year period in patients undergoing elective liver resection using the CC, SP, or DS. Patients were excluded if multiple methods of transection were used or for intraoperative death. The association of bile leak with transection type was assessed. A logistic regression model was tested to assess if blood loss was associated with the covariates of transection method, use of portal inflow occlusion, extent of liver resection, and other concurrent major operations., Results: Analyses included 141 patients. The stapler method was quicker than the other methods (p=0.01). The risk of postoperative bile leak was no different between CC, SP, and DS transection methods (p=0.23). There was no difference in mean blood loss or transfusions; however, hepatectomies performed with DS were associated with an increased risk of blood loss > or = 1000 mL compared to CC (p=0.04). There were no differences in mean surgical margin between the three methods., Conclusion: The risk of bile leaks was not different between the three methods. While mean blood loss was similar, hepatectomy performed with the DS was associated with an increased risk of having operative blood loss > or = 1000 mL compared to CC. Margins were equal by all methods. The stapler method was quicker.

Introduction: Tumor extent (T stage) and lymph node involvement (N stage) have a known combined negative effect on survival in patients with gallbladder adenocarcinoma, but the independent effects of these factors have been less well described. We investigated whether T stage and N stage independently predict survival after surgery for gallbladder adenocarcinoma., Methods: We queried the Surveillance, Epidemiology and End Results database for patients treated with surgical resection for gallbladder adenocarcinoma between 1988 and 2004. Cases were stratified by disease severity based on tumor extent and nodal involvement. Kaplan-Meier and Cox regression methods were used to test the effect of disease severity and to develop multivariate models of the effects of demographic and clinical covariates on survival. Univariate and multivariate models were tested in the entire cohort and in a subsample with pathologically confirmed lymph node status., Results: Four thousand and forty-eight patients who survived the immediate perioperative period comprised the full cohort. The subsample with pathologically confirmed lymph node status included 1298 patients. Age, gender, radiation treatment, tumor grade, tumor extent and lymph node status had statistically significant independent effects on survival in both models (all p<0.03). After accounting for T by N stage interactions, both tumor extent (1.21 < or = HR < or = 3.81, all p < or = 0.005) and lymph node involvement (1.80 < or = HR < or = 2.84, p<0.001) had independent effects on survival., Conclusions: Tumor extent and lymph node metastases are independent predictors of survival after surgical resection for gallbladder adenocarcinoma. Tumor penetration of the gallbladder wall and pathologically confirmed lymph node involvement each carry poor prognosis.

The genus Erythrina (Leguminosae), consisting of over 100 different species, is distributed in tropical regions. In traditional medicine, Erythrina species are used to treat cancer, but little is known about the anticancer mechanisms. From the stem bark of Erythrina addisoniae Hutch. & Dalziel, six prenylated pterocarpans were isolated and analysed for pharmacological activity: While calopocarpin, cristacarpin, orientanol c, and isoneorautenol showed only a weak or moderate toxicity in H4IIE hepatoma cells (EC(50)-value> 25 microM), the toxicity of neorautenol and phaseollin was in the low micromolar range (EC(50)-value: 1 and 1.5 microM, respectively). We further focused on these two substances showing that both increased caspase 3/7 activity and nuclear fragmentation as markers for apoptotic cell death. Neorautenol (10 microM, 2h), but not phaseollin induced the formation of DNA strand breaks (comet assay). Both substances showed no effect on NF-kappaB signalling (SEAP assay: basal activity and stimulation with TNF-alpha), on the other hand both pterocarpans (10 microM, 2 h) decreased the activation of the ERK kinase (p44/p42), an mitogen activated protein kinase which is associated with cell proliferation. We conclude that the pterocarpans phaseollin and neorautenol may be responsible for the anticarcinogenic actions of the plant extract reported in the literature. Further analysis of these substances may lead to new pharmacons to be used in cancer therapy.

Objective: To examine the impact of the Model for End-stage Liver Disease (MELD) on waiting list mortality., Design: Interrupted time series with a nominal inception point of the intervention on February 27, 2002., Setting: United Network for Organ Sharing Standard Transplant Analysis and Research file data from March 1, 1999, to July 30, 2004., Participants: All adult candidates on the waiting list for liver transplantation in the United States during the study period., Intervention: Implementation of the MELD policy., Main Outcome Measures: Waiting list mortality, waiting time to transplantation, number of new registrants, and posttransplantation survival., Results: Although no preintervention trend was identified, the policy change was associated with an immediate effect of increasing waiting list mortality by 2.2 deaths per 1000 registrants per month (from approximately 11 to 13 deaths per 1000 registrants per month; 95% confidence interval [CI], 1.1 to 3.4; P = .001) followed by a postintervention decline in waiting list mortality over time (-0.09 death per 1000 registrants per month; 95% CI, -0.16 to -0.03; P <.001). An immediate effect of decreased waiting time was also noted (from approximately 294 to 250 days; -44.4 days; 95% CI, -77.1 to -11.7 days; P <.001), which reached a new, lower postintervention steady state. The intervention had no effect on the number of new registrants listed per month or on 3- and 6-month posttransplantation survival., Conclusion: After an initial increase in waiting list mortality, the implementation of the MELD-based allocation policy was associated with an overall decline in waiting list mortality and time to transplantation.

Adult polycystic liver disease (PCLD) is an autosomal dominant condition commonly associated with autosomal dominant polycystic kidney disease (ADPKD). However in the last decade, it has been recognized that there is a distinct form of autosomal dominant PCLD that arises without concomitant ADPKD. Early knowledge of the pathogenesis was gained from the study of hepatic cysts in patients with ADPKD. Bile duct overgrowth after embryogenesis results in cystic hepatic dilatations that are known as biliary microhamartomas or von Meyenburg complexes. Further dilatation arises from cellular proliferation and fluid secretion into these cysts. There is a variable, broad spectrum of manifestations of PCLD. Although PCLD is most often asymptomatic, massive hepatomegaly can lead to disabling symptoms of abdominal pain, early satiety, persistent nausea, dyspnea, ascites, biliary obstruction, and lower body edema. Complications of PCLD include cyst rupture and cyst infection. Also, there are associated medical problems, especially intracranial aneurysms and valvular heart disease, which clinicians need to be aware of and evaluate in patients with PCLD. In asymptomatic patients, no treatment is indicated for PCLD. In the symptomatic patient, surgical therapy is the mainstay of treatment tailored to the extent of disease for each patient. Management options include cyst aspiration and sclerosis, open or laparoscopic fenestration, liver resection with fenestration, and liver transplantation. The surgical literature discussing treatment of PCLD, including techniques, outcomes, and complication rates, are summarized in this review.

A series of 10 novel nitro-analogues of cryptolepine (1) has been synthesised and these compounds were evaluated for their in-vitro cytotoxic properties as well as their potential for reductive activation by the cytosolic reductase enzymes NQO1 and NQO2. Molecular modelling studies suggest that cryptolepine is able to fit into the active site of NQO2 and thus raising the possibility that nitro-analogues of 1 could act as bioreductive prodrugs and be selectively reduced by NQO1 and NQO2 to more toxic species in cancer cells in which these enzymes are over-expressed. Analogues were screened against the RT112 cell line (high in NQO2), in the presence and absence of the essential cofactor dihydronicotinamide riboside (NRH), whereby all analogues were shown to be cytotoxic (IC50<2microM) in the absence of NRH. With the addition of NRH, one analogue, 2-fluoro-7,9-dinitrocryptolepine (7), exhibited a 2.4-fold increase in cytotoxic activity. Several nitro-derivatives were also evaluated as substrates for purified human NQO1 and analogues that were found to be substrates were subsequently tested against the H460 (high NQO1) and BE (low NQO1) cell lines to detect in-vitro activation by NQO1. The analogue 8-chloro-9-nitrocryptolepine (9) was found to be the best substrate for NQO1 but it was not more toxic to H460 than to BE cells. Fluorescence laser confocal microscopy of 1 and several analogues showed that in contrast to 1 the analogues were not localised into the nucleus suggesting that their cytotoxic mode(s) of action are different. This study has identified novel substrates for both NQO1 and NQO2 and further work on nitrocryptolepine derivatives as a lead towards novel anticancer agents would be worthwhile.

Objective: To present an overview of methods for incorporating the measurement of health-related quality of life and patient satisfaction into a comprehensive outcomes assessment program in the organ transplantation setting. An introduction to basic psychometric concepts as they relate to survey instrument selection is presented, and the complementary nature of health status instruments and preference-based utility measures is discussed. The role of these concepts and measures in a transplant outcomes assessment and research program and the psychometric evidence for selected instruments are described., Data Sources: Descriptions of specific survey instruments were abstracted from published reports or manuals. Data describing the Vanderbilt Transplant Center Patient Satisfaction Inventory were derived from a single institution transplant outcomes research database., Study Selection and Data Extraction: Previously reported research was selected from the literature to provide brief examples of basic concepts, which are not intended to be a comprehensive review of these topics. Illustrative data from the Vanderbilt program were extracted from a longitudinal database., Data Synthesis: Data and published reports were synthesized for descriptive and illustrative purposes., Conclusions: This review describes various types of health-related quality of life and patient satisfaction outcomes assessment tools and measurement methods; introduces considerations relevant to survey instrument selection and development; and outlines the evolution of and psychometric support for a transplant center-wide outcomes assessment and research program.

Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues.

CD30 is a member of the tumor necrosis factor receptor superfamily whose expression is up-regulated on anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) cells. Many different outcomes of CD30 stimulation have been reported, including cell cycle arrest, apoptosis, and activation of the prosurvival transcription factor, NF-kappaB, although this last activity is much less well defined in ALCL cells. In order to better understand the signaling properties of CD30 in cancer, we established a system for the stimulation of CD30 with its physiological ligand. Using this system, CD30 was stimulated on ALCL and HL cells, and the subsequent CD30 signaling properties were characterized. We show that a fraction of ALCL cells rapidly underwent apoptosis following CD30 stimulation, whereas HL cells were unaffected. The surviving ALCL cells exhibited robust activation of both the canonical and alternative NF-kappaB pathways as measured by nuclear translocation of RelA, p50, RelB, and p52, and this culminated in the transactivation of classical NF-kappaB-responsive genes. With prolonged CD30 stimulation, ALCL cells underwent cell cycle arrest that correlated with expression of the cell cycle inhibitor p21(waf1). Furthermore, p21(waf1) expression and cell cycle arrest were found to depend predominantly on the canonical NF-kappaB pathway, since it was reversed by RNA interference-mediated suppression of RelA. In contrast, suppression of the p100/p52 NF-kappaB subunit had little effect on p21(waf1). These data reveal that in ALCL cells, in contrast to other cell types, CD30 stimulation elicits p21(waf1)-mediated arrest through the canonical but not the alternative NF-kappaB pathway.

Biliary complications following orthotopic liver transplantation have been reported in 10% to 30% of patients. Most surgeons perform an end-to-end choledochocholedochostomy with interrupted sutures for biliary reconstruction. The goal of this study was to compare biliary complications between interrupted suture (IS) and continuous suture (CS) techniques during liver transplantation in which an end-to-end choledochocholedochostomy over an internal biliary stent was performed. A retrospective cohort study of 100 consecutive liver transplants occurring between December 2003 and July 2005 was conducted. An end-to-end choledochocholedochostomy over an internal biliary stent was performed during liver transplantation. Data were analyzed using Kaplan-Meier methods, t tests, and chi-square tests of proportions. IS and CS techniques were used in 59 and 41 patients, respectively, for biliary reconstruction during liver transplantation. Mean follow-up time for the CS group was 17 +/- 8 months and 15 +/- 7 months for the IS group (P = .21). The overall biliary complication rate was 15%. There was no difference in the proportion of leaks (CS = 7.3%, IS = 8.5%; P = .83) or strictures (CS = 9.8%, IS = 5.1%; P = .37) between groups. Kaplan-Meier event rates show no difference in leaks (P = .79), strictures (P = .41), graft survival (P = .52), and patient survival (P = .32) by anastomosis type. In conclusion, there was no difference in biliary complications, graft survival, or patient survival between the 2 groups. CS and IS techniques for biliary reconstruction during liver transplantation yield comparable outcomes., ((c) 2007 AASLD.)

The alkaloid cryptolepine is thought to mediate the anti-inflammatory effects of the climbing shrub, Cryptolepis sanguinoleta. The underlying mechanism of action, however, is largely unknown. In the present study, we show that the synthetic cryptolepine-hydrochloride (2.5-10microM) dose-dependently inhibits lipopolysaccharide (LPS)-induced nitric oxide production in the murine macrophage cell line RAW 264.7. We furthermore demonstrate a strong inhibition of nuclear factor (NF)-kappaB, a transcription factor primarily involved in inflammatory and immune responses, by cryptolepine (2.5-10microM) using a luciferase reporter gene assay in human HEK 293 cells. Examining the individual steps of NF-kappaB activation in the presence of cryptolepine we could exclude an inhibitory effect on degradation of IkappaB or nuclear translocation of NF-kappaB by the alkaloid. However, EMSA of nuclear extracts from LPS-activated RAW cells revealed reduced DNA binding activity of NF-kappaB by cryptolepine in vivo and in vitro. This indicates that cryptolepine may exhibit its anti-inflammatory action by blocking DNA binding of activated NF-kappaB and thus transcription of NF-kappaB-regulated proinflammatory proteins.

Introduction: Due to the scarcity of cadaveric livers, clinical judgment must be used to avoid futile transplants. However, the accuracy of human judgment for predicting outcomes following liver transplantation is unknown. The study aim was to assess expert clinicians' ability to predict graft survival and to compare their performance to published survival models., Materials and Methods: Pre-transplant case summaries were prepared based on 16 actual, randomly selected liver transplants. Clinicians specializing in the care of liver transplant patients were invited to assess the likelihood of 90-day graft survival for each case using (1) a 4-point Likert scale ranging from poor to excellent, and (2) a visual analog scale denoting the probability of survival. Four published models were also used to predict survival for the 16 cases. RESULTS. Completed instruments were received from 50 clinicians. Prognostic estimates on the two scales were highly correlated (median r=0.88). Individual clinicians' predictive ability was 0.61+/-0.13, by area under the receiver operating characteristic curve. The performance of published models was MELD 0.59, Desai 0.66, Ghobrial 0.61, and Thuluvath 0.45. For three cases, clinicians consistently overestimated the probability of survival (87+/-10%, 89+/-9%, 86+/-9%); these patients had early graft failures caused by postoperative complications. DISCUSSION. Clinicians varied in their ability to predict survival for a set of pre-transplant scenarios, but performed similarly to published models. When clinicians overestimated the chance of transplant success, either sepsis or hepatic artery thrombosis was involved; such events may be hard to predict before surgery.

Liver transplantation (LT) for hepatocellular carcinoma is effective for selected patients. LT for other malignancies like cholangiocarcinoma (CCA), hepatoblastoma (HB), hepatic epithelioid hemangioepithelioma (HEHE), angiosarcoma (AS), and neuroendocrine tumors (NET) is being defined. For CCA, series that did not emphasize highly selected early stage disease and neoadjuvant or adjuvant chemoradiation had an average 5-year survival of 10%. However, emphasizing neoadjuvant radiation and chemosensitization in operatively confirmed stage I or II hilar CCA has led to improved 5-year survival, up to 82%. LT is indicated under strict research protocols at selected centers, for patients with early stage CCA and anatomically unresectable (Bismuth type IV) lesions. HB is typically sensitive to cisplatin-based chemotherapy. LT plays a role as primary surgical therapy for those individuals in whom tumors remain unresectable after chemotherapy or as rescue therapy for those who are incompletely resected, recur after resection, or develop hepatic insufficiency after chemotherapy and/or resection. Long-term survival is reported at 58-88%. HEHE is a multifocal tumor that lies somewhere between benign hemangiomas and malignant AS. The extensive multifocal nature makes resection difficult and LT an attractive option. Series on LT for HEHE report overall survival of 71-78% at 5 years. However, AS is an aggressive tumor and LT is contraindicated. For NET, resection of the primary tumor and all gross metastatic disease is reported to provide 5-year survival of 70-85%. LT has been employed for some patients for unresectable tumors or for palliation of medically uncontrollable symptoms with 5-year survival reported between 36% and 80%.

Hepatocellular carcinoma (HCC) is one of the most common tumors globally, with varying prevalence based on endemic risk factors. In high-risk populations, including those with hepatitis B or C or with cirrhosis, serum alpha-fetoprotein (AFP) and screening ultrasound have improved detection of resectable HCC. Treatment options, including surgical resection, for patients with HCC must be selected based on the number and size of hepatic tumors, underlying hepatic function, patient condition, and available resources. An approach, which has been summarized shows the corresponding treatment choices under given clinical circumstances. For cirrhotic patients with less than three tumor nodules of a size less than 3 cm or a solitary HCC less than 5 cm, liver transplantation offers long-term survival similar to that observed in patients transplanted for nonmalignant disease. Ablative treatment using either chemical or thermal techniques provides locally effective tumor destruction. Transcatheter arterial chemoembolization (TACE) is commonly used for palliation of unresectable tumors as well as an adjunct to surgical resection, treatment of tumors before transplant, and in conjunction with other ablative therapies in a multimodality approach. Regional approaches to chemotherapy have produced more encouraging results than systemic chemotherapy, although both remain ineffective for long-term tumor control. Several newer treatment modalities are under investigation, including gene therapy, tagged antibodies, isolated perfusion, and novel radiotherapy techniques.

The purpose of this study was to assess regional variability in access to pediatric liver transplantation. The study population included all pediatric patients (age less than 18 years) listed for liver transplantation in the United Network for Organ Sharing (UNOS) database between 1988 and 2004. The effect of region on waiting list survival, the proportion of patients transplanted, and the proportion of patients remaining on the list was determined using Kaplan-Meier and Cox proportional hazard methods. The proportion of technical variant grafts used was compared between regions using chi-square analysis. Kaplan-Meier analyses showed significant effects of region on survival on the waiting list, transplantation, and remaining on the list (all log-rank P < 0.001). Cox proportional hazard models demonstrated that region, urgency status, and listing period exerted independent effects on survival on the waiting list, transplantation, and remaining on the list (all model P < 0.01). Regional variation existed with regard to donor type (P < 0.001). Similar to adults, pediatric survival on the waiting list, the proportion of patients transplanted, and the proportion of patients remaining on the waiting list vary considerably within the 11 U.S. regions. Organ procurement organization specific effects and regional differences in utilization of deceased donor split and living donor organs may contribute to this variability.

Background: Graft-versus-host disease (GVHD) is a rare complication following liver transplantation and carries a poor prognosis with mortality approaching 90-95%. Diagnosis of GVHD is often delayed due to early symptoms mimicking more common, entities such as drug reactions and viral syndromes. To date, definitive diagnosis has been difficult and has relied on a constellation of clinical and histopathologic variables. We present the use of short tandem repeat DNA "fingerprinting" technology as a method of early, definitive diagnosis of GVHD in patients after liver transplantation., Methods: A patient status-postorthotopic cadaveric-liver transplant, with an uncomplicated immediate posttransplant course, presented 4 weeks after transplant with fever, diarrhea, and maculopapular rash on her palms, soles, and back. The patient's condition worsened despite empiric treatment for an infectious etiology. Skin and rectal biopsies were suspicious for GVHD., Results: DNA was isolated from the skin and rectal biopsies as well as from a donor lymph node. PCR amplification was done for nine highly polymorphic short tandem repeats for each specimen and a unique DNA "fingerprint" was obtained from each. DNA from skin and rectum demonstrated mixed chimerism with both donor and recipient alleles detected. Thorough analysis confirmed GVHD., Conclusion: Short tandem repeats for DNA fingerprinting represents an efficient and reproducible method for the definitive diagnosis of GVHD after liver transplantation. Rapid detection of GVHD using this technology, coupled with early initiation of therapy, may lead to improved survival for patients with GVHD after solid organ transplant.

Background: Orthotopic liver transplantation (OLT) is the only treatment option for unresectable hepatoblastoma (HB) and hepatocellular carcinoma (HCC) in children. Aggregated outcomes of OLT for these hepatic malignancies have not been evaluated in the United Network for Organ Sharing national database., Purpose: The purpose of this study was to evaluate graft and patient survival in pediatric OLT recipients with HB and HCC., Methods: Data from the United Network for Organ Sharing Standard Transplant and Research Files were analyzed and included pediatric (<18 years) OLT recipients with HB or HCC from 1987 to 2004. The effects of diagnosis on pretransplant variables were evaluated using analysis of variance methods or chi2 tests, as appropriate. Actuarial survival and effect of diagnosis on survival were determined using Kaplan-Meier methods and log-rank tests., Results: Since 1987, 152 OLTs have been performed in 135 pediatric patients for HB and 43 OLTs in 41 pediatric patients for HCC. Respective 1-, 5-, and 10-year patient survival after OLT was 79%, 69%, and 66% for HB and 86%, 63%, and 58% for HCC (P = .73). The primary cause of death for both groups was metastatic or recurrent disease, accounting for 54% of deaths in the HB group and 86% in the HCC group (P = .338). Patients with hepatoblastoma were younger (mean age, 2.9 +/- 2.5 vs 10.4 +/- 4.8 years for the HCC group; P < .001) and more likely to receive a living donor organ (16% vs 4%, P = .03). A greater proportion of the patients with HB had previous abdominal surgery than patients with HCC (63% HB vs 37% HCC, P = .04). Pretransplant medical condition and transplant era were associated with graft and patient survival on univariate and multivariate analysis (all P < .05)., Conclusions: Orthotopic liver transplantation remains a viable option for pediatric patients with unresectable primary hepatic malignancies and results in good long-term survival. Pretransplant medical condition is an important predictor of outcome. Thus, in conjunction with better chemotherapy regimens, earlier evaluation for OLT in patients with unresectable HB and HCC may result in yet further improved long-term survival.

CPOE systems hold the promise of both reducing medical errors and improving compliance with evidence-based guidelines. Evidence-based order sets have been used to make evidence-based guidelines actionable at the point of care. Investigators have conducted research into factors effecting order set use, but little has been documented regarding order set compliance. Under the direction of the Chief Medical Officer, Vanderbilt University Medical Center undertook a major effort to ensure order sets in the Vanderbilt CPOE system are evidence-based. The Vanderbilt EvidenceWeb was developed in order to monitor use and progress, and to provide feedback to clinical teams based on their requests for data. Monitoring tools and feedback to clinical groups regarding order set use and compliance have proved to be key components in improving delivery of evidence-based care.