Increased risk organ transplantation in the pediatric population.

IRD organs are classified by the Public Health Service to be at above-average risk for harboring human immunodeficiency virus, hepatitis C, and hepatitis B. Traditionally underutilized, there exists even greater reluctance for their use in pediatric patients. We performed a retrospective analysis via the United Network for Organ Sharing database of all pediatric renal and hepatic transplants performed from 2004 to 2008 in the United States. Primary outcomes were patient and graft survival. Proportional hazards regression was performed to control for potentially confounding factors. Waitlist time, organ acceptance rates, and infectious transmissions were analyzed. There were 1830 SRD renal, 92 IRD renal, 1695 SRD hepatic, and 59 IRD hepatic transplants. There were no statistically significant differences in allograft or patient survival in either group. Acceptance rates of IRD organs were lower for kidney (1.5% IRD vs 4.82% SRD) and liver (1.99% IRD vs 4.51% SRD). One transmission of a bloodborne pathogen involving a pediatric recipient out of 7797 unique transplants was reported from 2008 to 2015. IRD organs appear to have equivalent outcomes. Increasing their utilization may improve access to transplant while decreasing wait times and circumventing waitlist morbidity and mortality.

Endovascular Treatment of Venous Outflow and Portal Venous Complications After Liver Transplantation.

Liver transplantation continues to rapidly evolve, and in 2020, 8906 orthotopic liver transplants were performed in the United States. As a technically complex surgery with multiple vascular anastomoses, stenosis and thrombosis of the venous anastomoses are among the recognized vascular complications. While rare, venous complications may be challenging to manage and can threaten the graft and the patient. In the last 20 years, endovascular approaches have been increasingly utilized to treat post-transplant venous complications. Herein, the evaluation and interventional treatment of post-transplant venous outflow complications, portal vein stenosis, portal vein thrombosis, and recurrent portal hypertension with transjugular intrahepatic portosystemic shunt (TIPS) are reviewed.

Patient Selection for Kidney Transplant.

The incidence of end-stage renal disease has continued to increase. Similarly, the number of patients living with a functioning renal allograft has also increased. Transplantation has improved with advances in surgical techniques, immunosuppression, and better control of comorbid conditions. Transplantation is transformative and offers the greatest potential for restoring a healthy, productive, and durable life to appropriately selected patients. This article describes factors to address in selection of renal transplant candidates and discusses commonly encountered perioperative events. Paramount to selecting appropriate candidates is the collaboration between a multidisciplinary team focused on a systematic process guided by protocols and common practices.

Improving the performance of virtual crossmatch results by correlating with nationally-performed physical crossmatches: Obtaining additional value from proficiency testing activities.

PURPOSE: When donor specific HLA antibodies (DSA) are identified, the predictive value of whether a certain strength of reactivity (mean fluorescence intensity, MFI) leads to a positive crossmatch is uncertain. To determine this, we compared the DSA MFI results we generated locally for nationally distributed proficiency samples against the percentage of other laboratories reporting a positive crossmatch. METHOD: DSA MFI from single antigen beads reported by our laboratory for nationally-distributed proficiency testing survey samples was compared against the aggregate percentage of participating laboratories reporting the crossmatch positive using direct, antiglobulin-enhanced microcytotoxic (CDC-AHG), or flow cytometric methods from 2011 to 2015. RESULTS: 180 surveys were analyzed. Positive CDC-AHG and flow cytometric crossmatches were associated with MFI greater than 8554 and 2748 respectively for HLA class I, and 6919 and 3707 respectively for class II. Institutional MFI less than 3000 had high positive predictive values (0.98, 0.85, 0.81) for negative direct, AHG, and flow crossmatches, while MFI greater than 8000 had high negative predictive values for a positive direct, AHG, and flow crossmatches (1.00, 1.00, 0.97). CONCLUSION: Review of locally-generated MFI results as part of participating in proficiency testing allow for predictability of crossmatch results against other laboratories, providing a replicable model for other participating centers.

Resection of noncolorectal nonneuroendocrine liver metastases: a comparative analysis.

BACKGROUND: Although established for metastatic colorectal (CR) and neuroendocrine (NE) malignancies, the role of partial hepatectomy in management of metastases from other primaries (NCRNE) is not well-defined. STUDY DESIGN: The objective of this retrospective study is to compare outcomes after partial hepatectomy for NCRNE, NE, and CR metastases and to identify factors associated with longterm survival for patients with NCRNE diseases. Tumor characteristics, treatments, and outcomes of 360 consecutive patients undergoing resection of NCRNE (n = 82), CR (n = 245), and NE (n = 33) hepatic metastases from 1995 to 2005 were analyzed. NCRNE tumors included breast (n = 20), sarcomas (n = 19), genitourinary (n = 18), melanoma (n = 11), and other (n = 14) cancers. The start date for follow-up and survival analyses was the date of partial hepatectomy. RESULTS: For patients with NCRNE, CR, and NE tumors, there were no marked differences in postoperative mortality (4%, 4%, and 9%) or complication (30%, 42%, and 42%) rates. Median overall survival was longest for NE patients (not yet reached) versus NCRNE and CR (both 44 months) patients (p < 0.05, log-rank test). NCRNE patients had shorter disease-free survival than CR counterparts (13 versus 16 months), p < 0.05 (log-rank test). After median followup of 59 months for NCRNE patients, actuarial 5-year overall and disease-free survival was 37% and 16%, respectively, with 15 5-year survivors. Multivariable analysis suggests that interval from discovery of liver metastases to resection > 6 months (p = 0.08) and administration of chemoradiotherapy after resection (p = 0.06) might be associated with improved overall survival. CONCLUSIONS: In selected patients, resection of NCRNE liver metastases can be done safely with survival similar to CR metastases. Delay of liver resection for at least 6 months and treatment with chemoradiotherapy after resection might be associated with improved longterm survival after partial hepatectomy.

Temporal trends in early clinical outcomes and health care resource utilization for liver transplantation in the United States.

INTRODUCTION: Procedures such as liver transplantation, which entail large costs while benefiting only a small percentage of the population, are being increasingly scrutinized by third-party payors. The purpose of our study was to conduct a longitudinal analysis of the early clinical outcomes and health care resource utilization for liver transplantation in the United States. METHODS: The Nationwide Inpatient Sample database was used to conduct a longitudinal analysis of the clinical outcome and resource utilization data for liver transplantation procedures in adult recipients performed in the United States over three time periods (Period I: 1988-1993; Period II: 1994-1998: Period III: 1999-2003). RESULTS: Compared to Period I, adult liver transplant recipients were more likely to be male, older, and non-White in Period III. Recipients were more likely to have at least one major comorbidity preoperatively than in Period I. The in-hospital mortality rate after liver transplantation decreased significantly from Period I to Period III, but the major intraoperative and postoperative complication rates increased over the same time period. Mean length of hospital stay decreased over the 15-year period, but the percentage of patients with a non-routine discharge status increased. CONCLUSION: Our findings indicate that the rate of postoperative complications and non-routine discharges after liver transplantation is increasing. However, these negative changes in the cost-outcomes relationship for liver transplantation are balanced by improving postoperative survival rates and reductions in the length of hospital stay.

Half-life analysis of pancreas and kidney transplants.

Although graft and patient survival data are available for pancreas and kidney transplants, they are rarely reported in terms of half-life. Our aim was to determine whether a more relevant measure of outcome is patient and allograft half-life. Using the data from the Organ Procurement and Transplantation Network Registry on kidney and pancreas transplants from January 1988 to December 1996, patient and graft half-life and 95% confidence intervals were calculated and demographic variables compared. No significant differences were found between demographic variables. Kidneys transplanted in diabetics as a simultaneous kidney-pancreas (SPK) fared better than diabetics receiving a kidney alone (9.6 vs. 6.3 years). Pancreatic graft survival in an SPK pair was better than pancreas after kidney transplant or pancreas transplant alone (11.2 vs. 2.5 years). Because kidney and pancreatic grafts have a longer half-life when transplanted with their mate grafts, we should consider the relative benefits of SPKs over pancreas after kidney transplant or pancreas transplant alone to limit the loss of precious resources.

Redox-mediated upregulation of hepatocyte iNOS transcription requires coactivator PC4.

BACKGROUND: Redox-mediated upregulation of transcription of hepatocyte inducible nitric oxide synthase (iNOS) requires hepatocyte nuclear factor IV-alpha (HNF-4alpha). In this setting, PC4 is often isolated with HNF-4alpha in DNA-protein pull-down studies. Transcriptional coactivator PC4 facilitates activator-dependent transcription via interactions with basal transcriptional machinery that are independent of PC4-DNA binding. We hypothesized that PC4 is a necessary component of HNF-4alpha-regulated redox-sensitive hepatocyte iNOS transcription. METHODS: Murine CCL9.1 hepatocytes were stimulated with interleukin-1beta (IL-1beta; 1000 U/mL) in the presence and absence of peroxide (H(2)O(2); 50 nmol/L). Antisense and sense oligonucleotides to HNF-4alpha and PC4 were added selectively. Coimmunoprecipitation (Co-IP) studies determined the association between HNF-4alpha and PC4. Transient transfection was performed with the use of a luciferase reporter construct containing the murine iNOS promoter (1.8 kb). Chromatin immunoprecipitation assays determined in vivo binding of PC4 and HNF-4alpha to the iNOS promoter region. RESULTS: Ablation of either HNF-4alpha or PC4 blunted the peroxide-mediated increase in the activation of the iNOS promoter. In IL-1beta+H(2)O(2) only, co-IP studies demonstrated the presence of an HNF-4alpha-PC4 protein complex, and chromatin immunoprecipitation assays demonstrated that this complex binds to the genomic iNOS promoter. CONCLUSIONS: Redox-mediated upregulation of hepatocyte iNOS transcription requires an HNF-4alpha-PC4 transcriptional complex.

Acute kidney transplant failure following transurethral bladder polyp fulguration.

Ureteral obstruction and anastomotic leak represent the most common urologic complications of kidney transplantation. Delay in diagnosis or treatment can lead to allograft loss. Obstruction of the ureter occurs in 2% of kidney transplant recipients. Although the majority of cases are immediate technical complications of the operation, subsequent manipulation of the genitourinary system can result in iatrogenic ureteral injury. We report the case of a long-term kidney transplant recipient who developed obstructive uropathy and acute renal failure requiring dialysis after undergoing cystoscopy and bladder polyp fulguration. The etiology was inadvertent thermal injury of the ureteroneocystostomy incurred during the procedure. After attempted percutaneous management, definitive open repair resulted in a return of allograft function to baseline.

Osteopontin increases CD44 expression and cell adhesion in RAW 264.7 murine leukemia cells.

BACKGROUND: Osteopontin (OPN) is an inducible cell attachment protein which binds alphavbeta3-integrin and CD44 receptors to promote tumor metastasis. We hypothesized that OPN alters expression of its CD44 receptor to promote neoplastic cell migration. METHODS: RAW264.7 cells were stimulated with OPN (0-10 nM) for 0-12 hours to determine the time- and concentration-dependence of CD44 protein and mRNA expression. In selected instances, a competitive ligand for the alphavbeta3-integrin, GRGDSP (50 nM), or an inhibitor of protein synthesis, anisomycin (10 microg/ml), was added. Cell adhesion to hyaluronan was assayed with the crystal violet assay. RESULTS: OPN upregulates plasma membrane total CD44 protein in a concentration-(ANOVA P = 0.001) and time-dependent (ANOVA P = 0.001) fashion. CD44v6 is not altered. Cell adhesion to hyaluronate increases in parallel with CD44 expression. Steady state mRNA levels for CD44 are not altered by OPN. 5 nM OPN increases CD44 protein half-life from 105 +/- 11 minutes to 278 +/- 15 minutes. (P < 0.03) Blockade of either alphavbeta3-integrin ablates the OPN-dependent increase in CD44. CONCLUSIONS: These data indicate that OPN increases plasma membrane CD44 expression and cell adhesion by binding to its alphavbeta3-integrin receptor. We conclude that OPN may promote tumor metastatic behavior by CD44 expression.

Temporal trends in liver transplant centre volume in the USA.

BACKGROUND: Although prior studies have suggested an inverse association between liver transplant centre volume and postoperative patient mortality, more recent analyses have failed to confirm this association. To date, all studies of the relationship between centre volume and outcomes in liver transplantation have been cross-sectional in design. OBJECTIVE: The objective of our study was to examine temporal trends in the volume-outcomes relationship for liver transplantation. METHODS: We used information obtained from the Scientific Registry of Transplant Recipients (SRTR) programme-specific data reports to examine the outcomes of adult liver transplant recipients stratified by annual centre volume. This relationship between centre volume and patient outcomes was assessed over three consecutive time periods from 2000 through 2007. RESULTS: The overall 25% increase in adult liver transplant volume in the USA from 2000 to 2007 appeared to be distributed fairly equally among existing transplant centres. In the earliest time period of our analysis, high-volume centres achieved superior risk-adjusted 1-year patient outcomes compared with low-volume centres. By the third and most recent time period of the analysis, this discrepancy between the outcomes of high- and low-volume centres was no longer statistically apparent. CONCLUSIONS: The relationship between centre volume and patient outcomes for liver transplantation in the USA has become less pronounced over time, suggesting that the use of procedure volume as a marker of liver transplant centre quality cannot be justified. The performance-based review process currently utilized in the USA may have contributed to this diminishing influence of centre volume on liver transplant recipient outcomes. This type of review process should be considered as a potential alternative to the volume-based referral initiatives that have been developed for other non-transplant, complex surgical procedures.

Regionalization of hepatic resections is associated with increasing disparities among some patient populations in use of high-volume providers.

BACKGROUND: The goal of our study was to determine the temporal trends in provider volume for liver resection procedures. STUDY DESIGN: The Nationwide Inpatient Sample database for 1988 through 2003 was used to determine temporal trends in hospital and surgeon volume of liver resection procedures. We also examined whether these trends in provider volume were associated with any changes in postoperative outcomes or in patients' access to high-volume providers. RESULTS: Regionalization of liver resection procedures to high-volume surgeons and hospitals has been occurring since 1988 and, in the most recent time period assessed, 25.8% of patients underwent hepatic resection by high-volume surgeons (> or = 17 procedures per year) and 29.9% of patients underwent resection in high-volume hospitals (> or = 45 procedures per year). Unadjusted mortality data suggest that these trends might be associated with a strengthening of the inverse relationship between hospital volume of hepatic resection and postoperative mortality and with an increasing disparity for some patient populations in use of high-volume hospitals. CONCLUSIONS: Regionalization of liver resections is occurring at both the level of the individual surgeon and the hospitals where these procedures are performed. These trends in provider volume might be associated with increasing discrepancies in outcomes and patient demographics among different volume categories of hospitals.

Relationship between provider volume and outcomes for orthotopic liver transplantation.

INTRODUCTION: Recent data suggests that the previously demonstrable relationship between hospital volume and outcomes for liver transplant procedures may no longer exist. Furthermore, to our knowledge, no study has been published examining whether individual surgeon volume is associated with outcomes in liver transplantation. MATERIALS AND METHODS: The Nationwide Inpatient Sample database was used to obtain early clinical outcome and resource utilization data for liver transplant procedures performed in the USA from 1988 through 2003. The relationship between surgeon and hospital volume and early clinical outcomes was analyzed with and without adjustment for certain confounding variables such as patient age and presence of co-morbid disease. RESULTS: The in-hospital mortality rate, major postoperative complication rate, and length of hospital stay after liver transplantation did not differ significantly based on hospital procedural volume. These outcome variables did, however, exhibit a statistically significant inverse relationship with individual surgeon volume of liver transplant procedures. A significant relationship between procedure volume and outcomes for liver transplantation cannot be demonstrated at the level of transplant center, but does appear to exist at the level of the individual transplant center. CONCLUSION: Minimal volume requirements for individual liver transplant surgeons may be justified, pending validation of this volume-outcomes relationship using a clinical data source.

Extended hepatic resection for gallbladder cancer.

BACKGROUND: Although radical cholecystectomy is the standard of care for gallbladder cancers that invade perimuscular connective tissue or perforate visceral peritoneum, the role of extended right hepatectomy in achieving negative resection margins is not clear. METHODS: Clinicopathologic, perioperative, and long-term outcome data were reviewed from patients who underwent hepatic resection for gallbladder cancer. RESULTS: From 1995 to 2005, 22 consecutive patients underwent hepatic resection for gallbladder cancer, and 11 underwent extended hepatectomy. Negative resection margins were achieved in all patients. There were no significant differences in postoperative morbidity, mortality, and long-term survival after extended and minor hepatectomy. T3 tumors negatively predicted overall and recurrence-free survival. COMMENTS: Extended hepatectomy achieves negative resection margins for patients with gallbladder cancer and is associated with acceptable morbidity and long-term survival.

Predictive indices of morbidity and mortality after liver resection.

OBJECTIVE: To determine if use of Model for End-Stage Liver Disease (MELD) scores to elective resections accurately predicts short-term morbidity or mortality. SUMMARY BACKGROUND DATA: MELD scores have been validated in the setting of end-stage liver disease for patients awaiting transplantation or undergoing transvenous intrahepatic portosystemic shunt procedures. Its use in predicting outcomes after elective hepatic resection has not been evaluated. METHODS: Records of 587 patients who underwent elective hepatic resection and were included in the National Surgical Quality Improvement Program Database were reviewed. MELD score, CTP score, Charlson Index of Comorbidity, American Society of Anesthesiology classification, and age were evaluated for their ability to predict short-term morbidity and mortality. Morbidity was defined as the development of one or more of the following complications: pulmonary edema or embolism, myocardial infarction, stroke, renal failure or insufficiency, pneumonia, deep venous thrombosis, bleeding, deep wound infection, reoperation, or hyperbilirubinemia. The analysis was repeated with patients divided according to their procedure and their primary diagnosis. Parametric or nonparametric analyses were performed as appropriate. Also, a new index was developed by dividing the patients into a development and a validation cohort, to predict morbidity and mortality in patients undergoing elective hepatic resection. ROC curves were also constructed for each of the primary indices. RESULTS: CTP and ASA scores were superior in predicting outcome. Also, patients undergoing resection of primary malignancies had a higher rate of mortality but no difference in morbidity. CONCLUSION: MELD scores should not be used to predict outcomes in the setting of elective hepatic resection.

Nitric oxide-dependent osteopontin expression induces metastatic behavior in HepG2 cells.

Our objective was to delineate the role of nitric oxide (NO) in osteopontin (OPN)-associated metastatic properties in HepG2 cells. OPN is the major phosphoprotein secreted by malignant cells in patients with advanced metastatic cancer, is frequently overexpressed in human tumors, and has been implicated as a key mediator of tumor cell metastasis. OPN is significantly overexpressed in hepatocellular cancer (HCC) and correlates with capsular infiltration and behavior. In addition, significantly increased inducible nitric oxide synthase (iNOS) and NO expression are found in HCC. In archived human samples of normal, cirrhotic, and HCC livers, we demonstrate that iNOS and OPN protein are strongly coexpressed in hepatoma cells. In the setting of cirrhosis, hepatocytes express iNOS, but not OPN. Further in vitro studies performed with HepG2 hepatocellular cancer cells demonstrate that exogenous NO transcriptionally upregulates OPN expression. Enhanced expression of OPN in this setting is associated with increased in vitro cell adhesion and invasion. These data suggest that NO enhances HCC expression of OPN and, as a result, conveys a metastatic phenotype.

Osteopontin silencing by small interfering RNA suppresses in vitro and in vivo CT26 murine colon adenocarcinoma metastasis.

Hepatic metastasis is a primary cause for failure of locoregional therapy in colorectal cancer. Increased expression of osteopontin (OPN), a ligand for alpha(v)beta3 integrin and CD44 receptors, is associated with metastasis in several types of cancer. However, the mechanism by which OPN mediates metastasis in colorectal cancer remains unknown. We hypothesized that OPN mediates invasion of colon cancer cells through basement membrane and migration through extracellular matrix (ECM). In this study, we used CT26 murine colon adenocarcinoma cells syngeneic to BALB/c mice to generate cell lines (pS-OPN) in which OPN expression was suppressed through small interfering RNA (siRNA) plasmids. CT26 wild-type cells (WT) and CT26 cells stably expressing murine-mismatch siRNA (pS-MM) served as controls. Western blotting quantified OPN protein levels and our most downregulated clone, pS-OPN-A4, demonstrated a mean 3.0-fold decrease in OPN protein expression versus WT. In vitro cell motility and invasiveness were decreased in pS-OPN-A4 by 3.6-fold (P = 0.004 versus WT) and 4.1-fold (P = 0.01 versus WT), but proliferation was similar amongst cell lines. We demonstrated that OPN suppression significantly correlates with MMP-2 downregulation. In vivo hepatic metastasis was assessed by quantifying liver weights and surface tumor nodules in 33 BALB/c mice (11/group) subjected to intrasplenic injection of tumor cells. pS-OPN-A4 resulted in a 50.4% decrease in mean liver weight compared with WT (3.79 +/- 1.49 g versus 1.88 +/- 1.34 g, P = 0.009). Only 18% of pS-OPN-A4 livers had >20 metastatic surface nodules compared with 89% for WT and 75% for pS-MM-V6. This study demonstrates that RNA interference stably reduces CT26 tumor expression of OPN and significantly attenuates CT26 colon cancer metastasis by diminishing tumor cell motility and invasiveness.

Gastrointestinal hemorrhage due to complicated gastroduodenal ulcer disease in liver transplant patients taking sirolimus.

Sirolimus is emerging as a popular immunosuppressive agent for patients undergoing solid organ and pancreatic cell transplantation. Here, we report the clinical courses of three patients receiving sirolimus who developed aggressive gastroduodenal ulcer disease. One patient died from massive gastrointestinal bleeding, and ulcers in the other two patients healed only after discontinuation of sirolimus. We propose that the mechanism underlying this severe ulcer diathesis, and poor ulcer healing, was linked to the well-known inhibitory effects of sirolimus on wound healing. We propose that sirolimus should be used carefully (or even withheld) in patients with known or previous ulcer disease, and further that it should be used prudently and/or in conjunction with aggressive prophylaxis therapy in those at risk for ulcer disease.

Tolerance and the "Holy Grail" of transplantation.

Advances in transplantation biology have greatly improved patient outcomes following transplant surgery. However, generalized immunosuppression remains the Achilles heel of modern transplantation surgery with its associated infectious and neoplastic morbidities. Tolerance remains the ultimate goal for the entire field. Although recent advances in transplant immunology suggest that tolerance may be achievable in the near future, the complex and redundant nature of the human immune system may not allow us to circumvent such a basic function as the recognition of nonself. In this paper, advances in transplant immunology are reviewed and their potential relevance to achieving the "Holy Grail" of transplantation are discussed.

Emergencies after liver transplantation.

Liver transplantation has become the procedure of choice for a wide variety of patients with end-stage liver disease. Perioperative morbidity and mortality have decreased dramatically over the past two decades, and superior graft and patient survival rates are now routine. Despite these advances, however, there remain several potentially lethal possibilities that may complicate the immediate postoperative period. Failure of the graft to regain any useful metabolic activity is known as primary nonfunction, and almost uniformly requires retransplantation for any hope of survival. Lesser degrees of immediate dysfunction require experienced clinical judgment as to the probability of sustaining long-term patient viability. Another potentially catastrophic development is thrombosis of the grafted hepatic artery. This is sometimes successfully managed by surgical reconstruction. It may develop immediately, or present insidiously much later. Thrombosis of the portal vein, while not usually fatal, can significantly complicate the immediate course, carrying with it a significant risk of sepsis. Close monitoring of patients in the period following liver transplantation is crucial, as prompt diagnosis and early intervention directly affects the patient's chances of survival.