The OPTN Deceased Donor Potential Study: Implications for Policy and Practice.

The Organ Procurement and Transplantation Network (OPTN) Deceased Donor Potential Study, funded by the Health Resources and Services Administration, characterized the current pool of potential deceased donors and estimated changes through 2020. The goal was to inform policy development and suggest practice changes designed to increase the number of donors and organ transplants. Donor estimates used filtering methodologies applied to datasets from the OPTN, the National Center for Health Statistics, and the Agency for Healthcare Research and Quality and used these estimates with the number of actual donors to estimate the potential donor pool through 2020. Projected growth of the donor pool was 0.5% per year through 2020. Potential donor estimates suggested unrealized donor potential across all demographic groups, with the most significant unrealized potential (70%) in the 50-75-year-old age group and potential Donation after Circulatory Death (DCD) donors. Actual transplants that may be realized from potential donors in these categories are constrained by confounding medical comorbidities not identified in administrative databases and by limiting utilization practices for organs from DCD donors. Policy, regulatory, and practice changes encouraging organ procurement and transplantation of a broader population of potential donors may be required to increase transplant numbers in the United States.

Photodynamic therapy provides local control of cholangiocarcinoma in patients awaiting liver transplantation.

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)-directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP-directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol-driven neoadjuvant chemoradiation and ERCP-directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP-directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention-to-treat disease-free survival was 75% at mean follow-up of 28.1 months. In summary, ERCP-directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.

Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.

Regional variability in symptom-based MELD exceptions: a response to organ shortage?

MELD (model for end-stage liver disease) exception awards affect the liver allocation process. Award rates of specific nonhepatocellular carcinoma exceptions, termed symptom-based exceptions (SBE), differ across UNOS regions. We aimed to characterize the regional variability in SBE awards and examine predictive factors for receiving a SBE in the MELD era. The OPTN liver transplant and waiting list dataset was analyzed for waiting list registrants during the MELD allocation on February 27, 2002, until November 22, 2006. Competing risks proportional hazards regression analysis was used to examine predictors for receiving a SBE in 39 169 registrants. The hazard ratios for receiving a SBE differed significantly across regions when adjusted for multiple variables including age, gender, ethnicity, physiologic MELD score, blood group, functional status, etiology of liver disease, insurer and education level. Utilization of SBE is highly significantly variable across UNOS regions, and does not correlate with organ availability as estimated by the regional mean physiologic MELD score at transplantation. Patients with Medicaid as their primary payer have a lower likelihood of receiving a SBE award, while patients with cryptogenic/NASH cirrhosis or cholestatic liver disease have a higher likelihood of receiving a SBE. Reasons for these regional and demographic disparities deserve further investigation.

Virologic and clinical outcomes of hepatitis B virus infection in HIV-HBV coinfected transplant recipients.

Liver transplantation (LT) is the treatment of choice for end-stage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV-hepatitis B virus (HBV) coinfected patients transplanted between 2001-2007; outcomes including survival and HBV clinical recurrence were determined. Twenty-two coinfected patients underwent LT; 45% had detectable HBV DNA pre-LT and 72% were receiving anti-HBV drugs with efficacy against lamivudine-resistant HBV. Post-LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow-up 3.5 years. Low-level HBV viremia (median 108 IU/mL, range 9-789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow-up of 4.0 years, patient and graft survival were similar: 100% versus 85% in HBV mono- versus coinfected patients (p = 0.08, log rank test). LT is effective for HIV-HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low-level HBV DNA is detectable in approximately 50% of recipients.

Database comparison of the adult-to-adult living donor liver transplantation cohort study (A2ALL) and the SRTR U.S. Transplant Registry.

Data submitted by transplant programs to the Organ Procurement and Transplantation Network (OPTN) are used by the Scientific Registry of Transplant Recipients (SRTR) for policy development, performance evaluation and research. This study compared OPTN/SRTR data with data extracted from medical records by research coordinators from the nine-center A2ALL study. A2ALL data were collected independently of OPTN data submission (48 data elements among 785 liver transplant candidates/recipients; 12 data elements among 386 donors). At least 90% agreement occurred between OPTN/SRTR and A2ALL for 11/29 baseline recipient elements, 4/19 recipient transplant or follow-up elements and 6/12 donor elements. For the remaining recipient and donor elements, >10% of values were missing in OPTN/SRTR but present in A2ALL, confirming that missing data were largely avoidable. Other than variables required for allocation, the percentage missing varied widely by center. These findings support an expanded focus on data quality control by OPTN/SRTR for a broader variable set than those used for allocation. Center-specific monitoring of missing values could substantially improve the data.

Liver and intestine transplantation in the United States 1998-2007.

Liver transplantation numbers in the United States remained constant from 2004 to 2007, while the number of waiting list candidates has trended down. In 2007, the waiting list was at its smallest since 1999, with adults > or =50 years representing the majority of candidates. Noncholestatic cirrhosis was most commonly diagnosed. Most age groups had decreased waiting list death rates; however, children <1 year had the highest death rate. Use of liver allografts from donation after cardiac death (DCD) donors increased in 2007. Model for end-stage liver disease (MELD)/pediatric model for end-stage liver disease (PELD) scores have changed very little since 2002, with MELD/PELD <15 accounting for 75% of the waiting list. Over the same period, the number of transplants for MELD/PELD <15 decreased from 16.4% to 9.8%. Hepatocellular carcinoma exceptions increased slightly. The intestine transplantation waiting list decreased from 2006, with the majority of candidates being children <5 years old. Death rates improved, but remain unacceptably high. Policy changes have been implemented to improve allocation and recovery of intestine grafts to positively impact mortality. In addition to evaluating trends in liver and intestine transplantation, we review in depth, issues related to organ acceptance rates, DCD, living donor transplantation and MELD/PELD exceptions.

Fully covered self-expandable metallic stents in the management of complex biliary leaks: preliminary data - a case series.

Techniques for management of bile leaks include biliary sphincterotomy and stenting. Partially covered self-expandable metallic stents have been used in complex bile leaks, but they are associated with migration and hyperplasia. A fully covered self-expandable metallic stent (CSEMS) with anchoring fins might be effective in treating bile leaks without these complications. The aim of this study was to investigate the safety and efficacy of temporary placement of a CSEMS for resolving complex bile leaks. Thirteen patients with complex bile leaks underwent endoscopic retrograde cholangiopancreatography (ERCP) with temporary placement of a CSEMS following cholecystectomy (n = 8) or liver transplantation (n = 5). All patients had resolution of their bile leaks. Two patients developed a stricture below the confluence. Three patients died from unrelated causes. Two deaths occurred prior to CSEMS removal. Ten of 11 patients had evidence of biliary debris at the time of CSEMS removal. Overall, temporary placement of CSEMS is efficacious atresolving bile leaks. CSEMS are less prone to migration, but are associated with ulcerations, de novo choledocholithiasis, and strictures.

Liver and intestine transplantation in the United States, 1997-2006.

Liver transplantation in 2006 generally resembled previous years, with fewer candidates waiting for deceased donor liver transplants (DDLT), continuing a trend initiated with the implementation of the model for end-stage liver disease (MELD). Candidate age distribution continued to skew toward older ages with fewer children listed in 2006 than in any prior year. Total transplants increased due to more DDLT with slightly fewer living donor liver transplants (LDLT). Waiting list deaths and time to transplant continued to improve. In 2006, there also were fewer DDLT for patients with MELD <15, fewer pediatric Status 1A/B transplants and more transplants from donation after cardiac death (DCD) donors. Adjusted patient and graft survival rates were similar for LDLT and DDLT. This article also contains in-depth analyses of transplantation for hepatocellular carcinoma (HCC). Recipients with HCC had lower adjusted 3-year posttransplant survival than recipients without HCC. HCC recipients who received pretransplant ablative treatments had superior adjusted 3-year posttransplant survival compared to HCC recipients who did not. Intestinal transplantation continued to slowly increase with the largest number of candidates on the waiting list since 1997. Survival rates have increased over time. Small children waiting for intestine grafts continue to have the highest waiting list mortality.

Two kinetically-distinct components of UDP-glucuronic acid transport in rat liver endoplasmic reticulum.

Previous studies have documented the presence of protein-mediated transport of UDP-glucuronic acid (UDP-GlcUA) in rat liver endoplasmic reticulum (ER). Measurement of uptake at varying concentrations of high specific activity [beta-32P]UDP-GlcUA has revealed the presence of a two component UDP-GlcUA transporting system. Transport at low substrate concentrations occurred predominantly via a high affinity component (K(m) = 1.6 microM), whereas a low affinity component (K(m) = 38 microM) predominated at high substrate concentrations. The K(m) for the high affinity system is in agreement with that previously published, while the low affinity component is a new finding. The uptake of UDP-GlcUA was temperature-sensitive, time dependent, and saturable for both components. The high affinity transport was affected by trans-stimulation and cis-inhibition by UDP-N-acetylglucosamine (UDP-GlcNAc); however, the same concentrations of UDP-GlcNAc had less effect on the low affinity system. In order to further study the two transport components, various inhibitors of anion transport carriers were tested. The high affinity component was strongly inhibited by 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) and furosemide, while the low affinity system was less sensitive to these reagents. Dose-dependent inhibition by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) was found for both transport systems. Probenecid was found to be a weak inhibitor of both components of the UDP-GlcUA uptake. Finally, the major metabolite of 3'-azido-3'-deoxythymidine, 3'-azido-3'-deoxythymidine monophosphate (AZTMP), was able to inhibit the uptake of UDP-GlcUA by both components. The results indicate the presence of two carrier-mediated UDP-glucuronic acid transporting components in rat liver ER.

Polyethylene glycol conjugated insulin-like growth factor binding protein-1 (IGFBP-1) inhibits growth of breast cancer in athymic mice.

Insulin-like growth factor (IGF) binding protein-1 (BP-1) inhibits IGF-mediated proliferation of some breast cancer cell lines in vitro. Here we examined whether recombinant human wild-type IGFBP-1 (WT-BP-1) and IGFBP-1 conjugated with polyethylene glycol (PEG-BP-1) could inhibit breast cancer growth. Three breast cancer cell lines were used: MCF-7, MDA-MB-231 and MDA-MB-435A (ascites model). The cells were grown in agar with or without the BP-1 conjugates to investigate their effect on colony formation. Both WT-BP-1 and PEG-BP-1 inhibited anchorage-independent growth (AIG) of MCF-7 and MDA-MB-435A cells. AIG of MDA-MB-231 cells was not inhibited by PEG-BP-1, whereas WT-BP-1 significantly stimulated colony number. We also tested both forms of BP-1 in xenograft tumour models. Two solid breast tumour models were studied using MCF-7 and MDA-MB-231 cell lines, and one ascites model using the MDA-MB-435A cell line. PEG-BP-1 inhibited malignant ascites formation in the MDA-MB-435A model. Conversely, PEG-BP-1 did not significantly inhibit MCF-7 xenograft growth. However, the MDA-MB-231 tumour growth curves were significantly different by a constant amount, suggesting that PEG-BP-1 treatment inhibited early tumour growth of this cell line. In contrast, WT-BP-1 was ineffective in the MDA-MB-231 tumours. These data show that anti-IGF strategies can be used to inhibit breast cancer cell growth. Since PEG-BP-1 inhibited the in vivo, but not in vitro, growth of MDA-MB-231, we speculate that PEG-BP-1 may block host IGF functions required for optimal tumorigenesis. Because PEG-BP-1 has a prolonged serum half-life compared to WT-BP-1, we conclude that improvements in BP-1 pharmacological properties enhanced its antitumour effects in vivo.

Morphine attenuates the effects of juvenile isolation in rats.

The acute effects of juvenile isolation on sucrose intake and its long-term consequences on adult social behavior were investigated. Additionally, the role of the endogenous opioid systems was studied. Juvenile rats were housed in one of three conditions: in groups or in isolation with (partial isolation, PI) or without 30 min of daily social contact from 22 to 35 days-of-age. During this period the rats were treated daily with saline or morphine. Juvenile isolated rats showed an increased sucrose intake as compared to non-isolated controls, with PI-rats somewhere in-between, suggesting a negative correlation between the amount of social contact and sucrose consumption. Morphine treatment during the isolation period enhanced the sucrose intake in non-isolated rats, whereas it decreased sucrose consumption in (partial) isolated rats. With regard to the long-term effects, (partial) isolated rats decreased social activity as compared to non-isolated controls which was reversed by morphine treatment during the isolation period. In non-isolated rats, morphine treatment caused an opposite effect: it decreased social activity as compared to the saline treated controls. The data suggest that stimulation of endogenous opioid systems in the juvenile phase may have an important modulatory role in the expression of adult social behavior. The results are discussed in relation to a possible function of morphine as a substitute for the release of endogenous opioid peptides during social play.

Isolation during the play period in infancy decreases adult social interactions in rats.

The effects of 1 or 2 weeks of social isolation immediately after weaning on social activity in adulthood were investigated in rats. In addition, it was studied whether these effects were influenced by social experiences of the cagemate when rehoused after the isolation period. Isolation during weeks 4 and 5 of age caused a reduction of social activity as compared to non-isolated controls. Previous social experiences of the cagemate (isolated or non-isolated) did not affect this decreased social activity. Isolation during week 4 of age resulted in similar effects, but the reduced social activity was not present when the rats were rehoused with non-isolated rats. Isolation during week 5 of age did not influence social activity patterns in adulthood. These findings support the idea of a sensitive period in infancy for subsequent social behavior in rats. It is suggested that especially deprivation of acquiring play behavior underlies the social disturbances in adulthood.

Isolation changes the incentive value of sucrose and social behaviour in juvenile and adult rats.

The present study was undertaken to assess the motivational aspects of social behaviour in juvenile and adult rats using the conditioned place preference (CPP) test and anticipatory behaviour for social contact. In addition, the consequences of social isolation during different periods of age on the motivational properties of sucrose-drinking and adult social behaviour were studied. Social play and adult social contact could be used as incentives for place preference conditioning and for inducing conditioned hyperactivity (anticipation) in rats. Both social activities have motivational properties for individually housed rats, whereas group-housing dramatically reduced the motivational aspects of adult social contact. In contrast, sucrose-drinking appears to have motivational aspects independent of the housing condition. Adult social behaviour could not induce a CPP in juvenile isolated rats, suggesting that juvenile isolation during 4 5 weeks reduced the motivational aspects of adult social contact. It seems likely that no CPP was established as a result of the reduced level of social behaviour during the conditioning sessions. Additionally, juvenile isolation during 4-5 weeks appeared to also decrease the motivational properties of sucrose-drinking in maturity, because the intensity of anticipation in response to sucrose was significantly suppressed. Thus, the data suggest that juvenile isolation during 4-5 weeks decreases the motivational properties of both social contact and sucrose-drinking in later life.

Morphine treatment during juvenile isolation increases social activity and opioid peptides release in the adult rat.

The consequences of juvenile isolation and morphine treatment on general activity, social activity and endogenous opioid release during a social interaction test were investigated in the adult rat. Rats were either isolated or socially housed during weeks 4 and 5 of age and treated daily during this isolation period subcutaneously with either saline or morphine. Directly after a social interaction test at 10 weeks of age, rats were injected with [3H]-diprenorphine and subsequently prepared for in vivo autoradiography. The autoradiographic technique was used to visualise neuroanatomical changes in opioid receptor occupancy, probably reflecting changes in opioid peptide release, as a result of social activity. Juvenile isolation increased general activity during the social interaction test, an effect which was accompanied by a reduction of opioid receptor occupancy in many brain areas, suggesting an increased opioid peptide release as a consequence of socially-induced general activity. Morphine treatment in isolated rats caused an increase in adult social activity and enhanced opioid peptide release in some cortical regions and the ventral tegmental area as compared to saline treated rats. Both social activity and opioid receptor occupancy were unaffected by morphine treatment in non-isolated rats. The present study underscores the role of opioid systems in adult social behaviors as a consequence of juvenile isolation. The results suggest a relationship between social activity and opioid peptide release during social contact. Increased social activity seems to be accompanied by elevated opioid peptide release in distinct brain areas after morphine treatment during juvenile isolation.

Emotional and footshock stimuli induce differential long-lasting behavioural effects in rats; involvement of opioids.

Rats were exposed to either a footshock stimulus (FS) or emotional stimulus (ES, forced perception of another rat receiving footshocks) during a daily 10-min session for 5 consecutive days. The consequences of FS and ES on their behavioural responsiveness were assessed at different post-stress intervals using a small open-field. FS induced a decrease in ambulation, rearing and sniffing and an increased immobility in the small open field. These effects were present in rats tested immediately after the last session and remained present for at least 15 days. In contrast, ES induced a transient decrease in ambulation and rearing immediately after the last session, but in the period from half an hour until at least 15 days after the stimulus experience, an increase in ambulation, rearing and sniffing was observed. Exposure to one footshock per session for 5 consecutive days or to 10 footshocks in a single session also resulted in a long-lasting reduction in ambulation and sniffing and an increase in immobility. The former regime did not influence the behavioural response of ES rats, but the latter resulted in an increase in ambulation, rearing and sniffing in ES rats. Naloxone (1 mg/kg s.c.) pretreatment antagonized the increased behavioural activity of the ES rats whereas the activity of control and FS animals was not affected, suggesting an involvement of endogenous opioid systems in the behavioural responses observed in ES rats. It is suggested that the behavioural responses of the ES and FS animals are regulated by different mechanisms.

Endogenous opioids and reward.

The discovery of endogenous opioids has markedly influenced the research on the biology of addiction and reward brain processes. Evidence has been presented that these brain substances modulate brain stimulation reward, self-administration of different drugs of abuse, sexual behaviour and social behaviour. There appears to be two different domains in which endogenous opioids, present in separate and distinct brain regions, are involved. One is related to the modulation of incentive motivational processes and the other to the performance of certain behaviours. It is concluded that endogenous opioids may play a role in the vulnerability to certain diseases, such as addiction and autism, but also when the disease is present, such as alcoholism.

Zollinger-Ellison syndrome.

As clinical experience with patients with ZES has grown, increasing recognition has been made of the broad spectrum of symptoms associated with gastrinomas. Diarrhea and acid-induced esophageal injury have taken their place alongside chronic peptic ulcer disease as indications for screening for gastrinoma. Diagnostic testing should begin with fasting serum gastrin levels and should include intravenous secretin infusion if fasting serum levels of gastrin are nondiagnostic and the patient is not found to be hypochlorhydric. Tumor localization is critical to aid in the identification of patients with potentially curable localized disease. Preoperative evaluation utilizing CT scanning with intravenous contrast should be done early and should be supplemented by other imaging modalities as necessary. Exploratory laparotomy, including a thorough examination of the duodenum and perhaps intraoperative ultrasound, should be performed in all patients with sporadic gastrinoma who lack evidence of extensive metastatic disease on preoperative evaluation. By utilizing this approach, it is likely that at least 20% of patients with ZES can be cured. With the availability of the highly effective H(+)-K(+)-ATPase inhibitor omeprazole, excellent control of symptoms related to gastric acid hypersecretion can be expected. Patients with unresectable gastrinoma may thus avoid potentially morbid antisecretory surgery and be managed with a fairly simple medical regimen. Further developments in the chemotherapeutic management of these patients with unresectable disease should be forthcoming in the future.