Dysregulated miRNAs modulate tumor microenvironment associated signaling networks in pancreatic ductal adenocarcinoma.

The desmoplastic and complex tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) has presented tremendous challenges for developing effective therapeutic strategies. Strategies targeting tumor stroma, albeit with great potential, have met with limited success due to the lack of knowledge on the molecular dynamics within the tumor microenvironment (TME). In pursuit of a better understanding of the influence of miRNAs on TME reprogramming and to explore circulating miRNAs as diagnostic and prognostic biomarkers for PDAC, using RNA-seq, miRNA-seq, and single-cell RNA-seq (scRNA-seq), we investigated the dysregulated signaling pathways in PDAC TME modulated by miRNAs from plasma and tumor tissue. Our bulk RNA-seq in PDAC tumor tissue identified 1445 significantly differentially expressed genes with extracellular matrix and structure organization as the top enriched pathways. Our miRNA-seq identified 322 and 49 abnormally expressed miRNAs in PDAC patient plasma and tumor tissue, respectively. We found many of the TME signaling pathways were targeted by those dysregulated miRNAs in PDAC plasma. Combined with scRNA-seq from patient PDAC tumor, our results revealed that these dysregulated miRNAs were closely associated with extracellular matrix (ECM) remodeling, cell-ECM communication, epithelial-mesenchymal transition, as well as immunosuppression orchestrated by different cellular components of TME. The findings of this study could assist the development of miRNA-based stromal targeting biomarkers or therapy for PDAC patients.

Combined coronary artery bypass graft and liver/kidney transplantation in a liver failure patient with acute on chronic kidney failure and antiphospholipid syndrome.

Coexisting coronary artery disease (CAD), end-stage liver disease (ESLD), renal failure, and hypercoagulable state poses a formidable clinical challenge. Here, we discuss the first known case of a patient with antiphospholipid syndrome (APLS), ESLD complicated by hepatorenal syndrome (HRS), and severe CAD who successfully underwent combined coronary artery bypass grafting (CABG) and simultaneous liver/kidney (SLK) transplant.

Utility of Framingham Score for Optimizing Preoperative Evaluation Among Patients Undergoing Liver Transplant Evaluation.

BACKGROUND: Cardiac testing of candidates for liver transplant (LT) requires balancing risks and benefits of cardiac procedures. The goal of this study was to evaluate the utility of the Framingham score (FS) for optimizing preoperative risk stratification for coronary artery disease (CAD). METHODS: In this single-center retrospective study of 615 adults undergoing LT evaluation from 2016 to 2019, data of preoperative evaluation, post-LT 1-year mortality, and post-LT cardiac events were reviewed. Patients >30 years of age with normal echocardiogram underwent FS calculation. Elevated FS (≥35%) patients were triaged to undergo angiogram for CAD evaluation; FS <35% patients underwent stress testing as initial CAD evaluation. RESULTS: Of 615 patients referred for LT, 481 underwent cardiac testing. Ninety-five were excluded from the FS pathway because of age, abnormal baseline echocardiogram, or known CAD. Of the remaining 386 patients in the FS pathway, 342 had a low FS and 44 had a high FS. In patients with low FS, 90% underwent stress testing as initial test; 16% underwent invasive testing at some time. In those with elevated FS, 59% underwent invasive testing as initial test. Listing rate and posttransplant outcomes were similar between patients with low and high FS. CONCLUSION: We demonstrated the feasibility of a simple algorithmic evaluation process using FS for optimizing pre-LT risk stratification for CAD. Although exceptions to the protocol occur, the proposed protocol allows for a streamlined approach by prioritizing testing based on cardiac risk. This approach may maximize diagnostic yield while limiting invasive procedures.

Predictors of Systolic Heart Failure and Mortality Following Orthotopic Liver Transplantation: a Single-Center Cohort.

OBJECTIVES: The purpose of this study was to identify risk factors that may predict heart failure with reduced ejection fraction (HFrEF) following orthotopic liver transplantation (OLT) and associated mortality. BACKGROUND: HFrEF following OLT is a poorly understood phenomenon, reported in 3% to 7% of transplanted patients. METHODS: This is a retrospective analysis of 176 consecutive patients who underwent OLT from 2010 to 2017. Multivariate logistic regression was used to identify associations between cardiovascular risk factors and perioperative variables with post-OLT HFrEF, defined as reduction in left ventricular ejection fraction of at least 10% and left ventricular ejection fraction less than or equal to 40% with acute heart failure symptoms. Multivariate cox proportional hazards regression (with inverse probability weighting by propensity scores) was used to evaluate effects of HFrEF on 1-year mortality. RESULTS: Of the176 patients, 14% developed HFrEF with a median of 5 days. History of heart failure (OR 10.99, 2.15-56.09; P = .04) and intraoperative transfusion of greater than 11 units of packed red blood cells (OR 3.377, 1.025-11.13; P = .045) were associated with increased incidence of HFrEF. Pre-transplant hemoglobin greater than 8.5 g/dL (OR 0.252, CI 0.0954- 0.665; P = .05) was protective against HFrEF. Thirty-three percent of HFrEF group died within 1 year (HR 7.36, 2.57-21.12; P < .001). CONCLUSIONS: The incidence of acute HFrEF post-OLT is 14% and is associated with a 7-fold increase in 1-year mortality. Cirrhotic cardiomyopathy and stress-induced cardiomyopathy maybe the underlying mechanisms. Our study identified risk factors associated with post-OLT HFrEF and should provide additional guidance for risk stratification of patients undergoing OLT.

Should donors who have used marijuana be considered candidates for living kidney donation?

BACKGROUND: The use of marijuana in the USA has been steadily increasing over the last 10 years. This study is the first to investigate the effect of marijuana use by live kidney donors upon outcomes in both donors and recipients. METHODS: Living kidney donor transplants performed between January 2000 and May 2016 in a single academic institution were retrospectively reviewed. Donor and recipient groups were each divided into two groups by donor marijuana usage. Outcomes in donor and recipient groups were compared using t-test, Chi-square and mixed linear analysis (P < 0.05 considered significant). RESULTS: This was 294 living renal donor medical records were reviewed including 31 marijuana-using donors (MUD) and 263 non-MUDs (NMUD). It was 230 living kidney recipient records were reviewed including 27 marijuana kidney recipients (MKRs) and 203 non-MKRs (NMKR). There was no difference in donor or recipient perioperative characteristics or postoperative outcomes based upon donor marijuana use (P > 0.05 for all comparisons). There was no difference in renal function between NMUD and MUD groups and no long-term difference in kidney allograft function between NMKR and MKR groups. CONCLUSIONS: Considering individuals with a history of marijuana use for living kidney donation could increase the donor pool and yield acceptable outcomes.

How a Donor Nephrectomy Population Can Help Give Perspective to the Effects of Renal Parenchymal Preservation During Partial Nephrectomy.

Introduction: Volume of renal parenchymal loss is known to affect postoperative renal function after partial nephrectomy (PN). We utilize a novel comparison using donor nephrectomy (DN) patients to demonstrate the primary effect parenchymal volume loss plays on postoperative renal function following PN. Materials and Methods: Records of 250 living donor (DN) and 118 PN patients were retrospectively reviewed. Baseline characteristics and preoperative estimated glomerular filtration rate (eGFR)s were recorded. Percent changes in eGFR and incidences of surgically induced chronic kidney disease (CKD-S) in short, intermediate, and long-term postoperative periods were compared. Univariate and multivariate analyses of prognostic factors for development of CKD-S were performed. The PN group was further divided into subgroups with different lengths of warm ischemia time (WIT) and compared with DN patients. Results: At baseline, DN patients were younger, less likely to be male, had lower body mass index, lower American Society of Anesthesiologists, and higher preoperative eGFR (all p < 0.001). At hospital discharge, intermediate follow-up, and latest follow-up, renal function changes in DN and PN groups were -40.5% vs. -3.6%, -34.1% vs. -5.5%, and -33.2% vs. -4.4%, respectively (all p < 0.001). More DN than PN patients developed CKD-S (p < 0.001). DN was a significant risk factor for the development of chronic kidney disease on univariate and multivariate analyses (p < 0.001). On subgroup analysis, both subgroups with WIT 1 to 30 minutes and 31 to 60 minutes had less renal function decline at all time points compared with DN (p < 0.001). Conclusions: Volume of renal parenchyma retained is the dominant driver of postoperative renal function after nephrectomy, compared with all other factors. Surgeons should minimize parenchymal loss during PN to optimize postoperative renal function.

Transplantation of hepatitis C virus (HCV) antibody positive, nucleic acid test negative donor kidneys to HCV negative patients frequently results in seroconversion but not HCV viremia.

Anecdotal reports have suggested that transplantation of hepatitis C virus (HCV) antibody positive (Ab+)/nucleic acid test negative (NAT-) donor kidneys into HCV negative recipients is not associated with HCV transmission. We reviewed our center's outcomes of 32 HCV negative patients who received kidney allografts from 25 donors who were HCV Ab+/NAT-. The mean recipient age was 56.9 ± 12.1 years and the mean donor age was 41.5 ± 14 years, with a median Kidney Donor Profile Index (KDPI) of 68%. Twelve donors (48%) met Public Health Service (PHS) increased risk status. All patients received antithymocyte globulin induction followed by tacrolimus, mycophenolate mofetil, and steroid maintenance immunosuppression. With a mean follow-up posttransplant of 10 ± 2.7 months, 1- and 3- month serum creatinine levels were 1.7 ± 0.8 and 1.3 ± 0.4, respectively, and patient and graft survival rates were 100% and 97%, respectively. Fourteen patients (44%) seroconverted and became HCV Ab+ posttransplant. However, all 32 patients were HCV RNA negative at 1- and 3- months posttransplant, and 27 and 8 patients tested at 6- and 12-months posttransplant, respectively, remain HCV RNA negative. In conclusion, transplantation of HCV Ab+/NAT- kidneys to HCV negative recipients frequently causes HCV Ab seroconversion but not HCV viremia.

Post-Transplant Diabetes Mellitus After Kidney Transplant in Hispanics and Caucasians Treated with Tacrolimus-Based Immunosuppression.

BACKGROUND Development of post-transplant diabetes mellitus after kidney transplant (PTDM) significantly increases kidney graft loss and mortality. Several risk factors for PTDM have been reported, including Hispanic ethnicity and the use of calcineurin inhibitors and corticosteroids. The incidence and impact of PTDM in the Hispanic kidney transplant population is unknown. MATERIAL AND METHODS We retrospectively reviewed the medical records of 155 Hispanic and 124 Caucasian patients, who were not diabetics and underwent kidney transplant between January 2006 and December 2011. We analyzed their clinical outcomes at 12 months post-transplant, including the incidence of PTDM, acute rejection rates, and patient and graft survival. RESULTS Hispanics who developed PTDM (n=22) were more than 10 years older and had higher body mass index (BMI) than Hispanics without PTDM (p<0.001 and p=0.001, respectively). Caucasians with PTDM (n=13) were non-significantly older (2.5 years) and had higher BMI than Caucasians without PTDM (p=0.526, p=0.043, respectively). The incidence of PTDM was not significantly different between Hispanics and Caucasians treated with tacrolimus-based immunosuppression (14.2% and 10.5%, respectively). CONCLUSIONS PTDM did not cause significant difference in short-term outcomes after kidney transplant in Hispanics or Caucasians. Larger multicenter prospective and long-term clinical trials are needed to validate these findings.

Randomized Clinical Trial Comparing Proton Beam Radiation Therapy with Transarterial Chemoembolization for Hepatocellular Carcinoma: Results of an Interim Analysis.

PURPOSE: To describe results of a planned interim analysis of a prospective, randomized clinical trial developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Eligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria. Patients were randomly assigned to transarterial chemoembolization (TACE) or to proton beam radiation therapy. Patients randomized to TACE received at least 1 TACE with additional TACE for persistent disease. Proton beam radiation therapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractions over 3 weeks. The primary endpoint was progression-free survival, with secondary endpoints of overall survival, local tumor control, and treatment-related toxicities as represented by posttreatment days of hospitalization. RESULTS: At the time of this analysis 69 subjects were available for analysis. Of these, 36 were randomized to TACE and 33 to proton. Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days, respectively (P<.001). Ten TACE and 12 proton patients underwent liver transplantation after treatment. Viable tumor identified in the explanted livers after TACE/proton averaged 2.4 and 0.9 cm, respectively. Pathologic complete response after TACE/proton was 10%/25% (P=.38). The 2-year overall survival for all patients was 59%, with no difference between treatment groups. Median survival time was 30 months (95% confidence interval 20.7-39.3 months). There was a trend toward improved 2-year local tumor control (88% vs 45%, P=.06) and progression-free survival (48% vs 31%, P=.06) favoring the proton beam treatment group. CONCLUSIONS: This interim analysis indicates similar overall survival rates for proton beam radiation therapy and TACE. There is a trend toward improved local tumor control and progression-free survival with proton beam. There are significantly fewer hospitalization days after proton treatment, which may indicate reduced toxicity with proton beam therapy.

Diffuse hepatic epithelioid hemangioendothelioma developed in a patient with hepatitis C cirrhosis.

Hepatic epithelioid hemangioendothelioma (HEHE) is an infrequent vascular tumor of endothelial origin that primarily occurs in women in the mid-fifth decade of life without underlying chronic liver disease or cirrhosis. Liver transplant should be the first-line of therapy in patients with large or diffuse unresectable tumors even in the presence of metastatic disease due to the favorable long-term outcome. We report the case of a 48-year-old female who complained of abdominal pain and weight loss. She has a history of cirrhosis secondary to chronic hepatitis C (HCV) and was treated with interferon and ribavirin with sustained virological response. Her work-up revealed multiple confluent infiltrating bilobar liver masses diagnosed as HEHE. She underwent a successful liver transplant without evidence of recurrent HCV infection. She developed cervical spine (C4-C6) HEHE metastases 4 years after transplant. She underwent surgical resection and local radiotherapy after resection with good clinical response. To the best of our knowledge, this is the first report of HEHE that developed in a patient with HCV cirrhosis successfully treated with antiviral therapy before transplant and liver transplant with good allograft function without evidence of recurrent liver tumor or HCV infection but developed metastases to the cervical spine 4 years after transplant.

Comparison of outcomes of hand-assisted laparoscopic to open donor nephrectomy for pediatric recipients.

The purpose of this study is to compare the outcome of pediatric recipients of kidneys procured using a hand-assisted laparoscopic (HALDN group) to an open technique (ODN group). Twenty-eight patients ≤18 yr old (HALDN group) were compared with 17 patients (ODN group). The serum creatinine for HALDN and ODN groups at discharge were 0.93 ± 0.48 and 0.94 ± 0.54 mg/dL (p = 0.917), respectively. The serum creatinine for HALDN and ODN groups at six and 12 months was 1.01 ± 0.44 and 1.11 ± 0.55, and 1.04 ± 0.52 and 1.14 ± 0.46 mg/dL (p = 0.516, p = 0.554), respectively. The eGFR for HALDN and ODN groups at discharge was 108.66 ± 37.23 and 106.1 ± 50.55 mL/min/1.73 m(2) (p = 0.845), respectively. The eGFR for HALDN and ODN groups at six and 12 months was 97.77 ± 28.25 and 81.73 ± 27.46, and 94.56 ± 28.3 and 85.74 ± 30.1 mL/min/1.73 m2 (p = 0.085, p = 0.344), respectively. The patient and graft survival for both groups were 100% at 12 months post-transplant. In conclusion, the short-term outcome of recipients of kidneys procured via HALDN is comparable to that of kidneys procured via ODN in pediatric patients.

Surgical management of gastrointestinal posttransplant lymphoproliferative disorders in liver transplant recipients.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a well-established complication of immunosuppression. The involvement of the gastrointestinal (GI) tract occurs in 25% of all cases of PTLD. Fortunately, surgical intervention is seldom required. We report our experience of surgical treatment of complicated GI-PTLD after liver transplantation (LTx). METHODS: A retrospective analysis of 5677 adult patients who underwent LTx between 1983 and 2009 was conducted. RESULTS: Thirty-six patients presented with GI-PTLD. Sixteen patients presented with complications associated with GI-PTLD requiring emergency surgery. The average (SD) time from LTx to GI surgery was 7.9 (5.8) years (range, 4 months to 17 years). Indications for surgical intervention were small bowel obstruction (seven cases), perforation (six cases), and GI bleeding (three cases). Most GI-PTLD occurred in the small bowel or right colon (81%). In addition to the surgery, treatment of PTLD consisted of reduction of immunosuppression, use of rituximab (n=10), and systemic chemotherapy (n=7). Overall mortality was 69%, with most of the deaths occurring within 8 months after emergency laparotomy. GI bleeding and perforation were associated with higher mortality (>66%). Despite higher early mortality in the surgical group, no differences on long-term outcome were observed between patients with GI-PTLD who required surgery and those who did not (P=0.371). CONCLUSIONS: In summary, GI-PTLD requiring surgical intervention is an extremely rare condition with high early mortality. Most of the cases are monoclonal, present a late onset, and involve the lower GI tract. Intestinal obstruction is the main indication for surgical intervention and is associated with better prognosis.

Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression.

Administration of high-dose interleukin-2 (HDIL-2) has durable antitumor effects in 5% to 10% of patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multiorgan dysfunction characterized by a cytokine-induced systemic autophagic syndrome. Here, we hypothesized that the autophagy inhibitor chloroquine would enhance IL-2 immunotherapeutic efficacy and limit toxicity. In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion. These antitumor effects were significantly enhanced upon addition of chloroquine. The combination of IL-2 with chloroquine increased long-term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen. HDIL-2 alone increased serum levels of HMGB1, IFN-γ, IL-6, and IL-18 and also induced autophagy within the liver and translocation of HMGB1 from the nucleus to the cytosol in hepatocytes, effects that were inhibited by combined administration with chloroquine. In tumor cells, chloroquine increased autophagic vacuoles and LC3-II levels inhibited oxidative phosphorylation and ATP production and promoted apoptosis, which was associated with increased Annexin-V(+)/propidium iodide (PI)(-) cells, cleaved PARP, cleaved caspase-3, and cytochrome c release from mitochondria. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for patients with cancer.

Ethical management of conflict of interest: proposed standards for academic surgical societies.

BACKGROUND: A significant increase in industry support of professional medical associations coupled with data suggesting that gifts from industry have significant clinical influence have prompted calls from the Institute of Medicine and physician leaders to identify and manage conflicts of interest that stem from financial support of professional medical associations by industry. STUDY DESIGN: A joint task force of members appointed by the Association for Academic Surgery and the Society of University Surgeons was convened in July 2009. Recommendations were developed regarding management of all potential conflicts of interest that can arise within the context of an academic surgical society, with specific focus on relationships with industry. Task force members reached consensus around each recommendation and the guidelines were subsequently adopted by the Executive Councils of both societies. RESULTS: The committee identified 4 primary areas of need for transparent and definitive management of conflict of interest: 1) individual society activities, including general budget support, society endorsements, and journal affiliation; 2) individual personnel conflicts such as society leadership and standards for disclosure of conflict; 3) meeting activities including budgetary support, program committee associations, and abstract review process; and 4) foundation support and research and travel awards. The resulting guidelines aim to protect the societies and their membership from undue bias that may undermine the credibility and mission of these associations. CONCLUSIONS: Policy guidelines to mitigate conflict of interest are necessary to protect the integrity of the work of academic surgical societies and their fiduciary duty to members and patients. Guidelines created and adopted by the Association for Academic Surgery and Society of University Surgeons form an effective model for academic surgical societies and their members.

Posttransplant biliary complications in the pre- and post-model for end-stage liver disease era.

Biliary complications remain a cause of morbidity after liver transplantation. The aim of this study was to determine whether changes in clinical practice in the era of the Model for End-Stage Liver Disease (MELD) has affected biliary complications after liver transplantation. We retrospectively reviewed all deceased donor liver transplants at a single center. Patients were categorized as pre- or post-MELD (transplant before or after February 28, 2002). A total of 1798 recipients underwent deceased donor liver transplants. Biliary stricture was more common in the post-MELD era (15.4% versus 6.4%, P < 0.001). The strongest risk factors for stricture development were donor age (odds ratio [OR] = 1.01), presence of a prior bile leak (OR = 2.24), use of choledochocholedochostomy (OR = 2.22), and the post-MELD era (OR = 2.30). Bile leak was more common in the pre-MELD era (7.5% versus 4.9%, P = 0.02), with use of a T-tube as the strongest risk factor (OR = 3.38). Surgical factors did not influence the biliary complication rate. In conclusion, even when employing multivariate analysis to allow for factors that may influence biliary strictures, transplant in the post-MELD era was an independent predictor for stricture development. Further studies are warranted to determine the etiology of this increase.

Hepatitis C recurrence is not adversely affected by the use of donation after cardiac death liver allografts.

Many factors can worsen a recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). We sought to determine whether the use of donation after cardiac death (DCD) livers affects HCV recurrence. From January 2000 to June 2008, 37 HCV patients underwent LT with DCD allografts. The outcomes and severity of HCV recurrence were analyzed along with those for 74 matched control patients with HCV who received donation after brain death (DBD) livers. The 2 groups had similar donor and recipient characteristics, immunosuppression regimens, rates of acute cellular rejection (ACR), and HCV profiles. DCD patients had a higher incidence of primary nonfunction (19% versus 3%, P = 0.006) and significantly higher peak aspartate aminotransferase levels in comparison with DBD subjects, suggesting a greater degree of ischemia/reperfusion injury. Although the survival rates were not significantly different, DCD recipients had lower 1- and 5-year patient survival rates (83% and 69% versus 84% and 78%, respectively, P = 0.75) and graft survival rates (70% and 61% versus 82% and 74%, respectively, P = 0.24). Three hundred fourteen protocol and clinically indicated liver biopsy procedures were performed within 6 years after transplantation, and mixed modeling analysis showed that fibrosis progression rates were similar for the 2 groups (0.6 fibrosis units/year according to the Ishak modified staging system). The rates of severe HCV recurrence (retransplantation or death due to recurrent hepatitis C and/or the development of stage 4/6 fibrosis or worse within 2 years) were similar [3 DCD patients (8%) versus 11 DBD patients (15%), P = 0.38], and cytomegalovirus infection (hazard ratio = 7.9, P = 0.002, 95% confidence interval = 2.1-28.9) and ACR (hazard ratio = 6.2, P = 0.002, 95% confidence interval = 2.0-19.7) were the only independent risk factors for severe recurrence. In summary, although there was a trend of poorer overall outcomes in DCD patients, the use of DCD livers did not appear to adversely affect HCV recurrence after LT.

Individual and environmental correlates and predictors of early adherence and outcomes after liver transplantation.

CONTEXT: Little is known about patients' contribution to health outcomes after liver transplantation. Yet, in other transplant recipients, nonadherent behavior is directly related to the leading causes of morbidity and mortality in liver transplant recipients. OBJECTIVE: To examine patient and environmental factors in relation to all aspects of adherence to the posttransplantation regimen and health outcomes in the first 6 months after transplantation. DESIGN: A descriptive analysis of individual and environmental factors in relation to adherence and health outcomes at 6 months after liver transplantation. PARTICIPANTS, SETTING: One hundred fifty-two adult liver transplant recipients at the University of Pittsburgh Medical Center. MAIN OUTCOME MEASURES: Adherence to medication taking, appointment keeping, lifestyle changes, mood, quality of life, and clinical markers of liver function. RESULTS: Nonadherence was prevalent (47% with appointments, 73% with medication); relapse to drug/alcohol use occurred among a few recipients (5.6%), all with a history of substance abuse before transplantation. Patterns of coping, decision making, attitude, and social support were correlated with adherence, clinical markers, and psychological function (r = 0.22-0.45). Avoidant coping, affective dysregulation, and caregiver support emerged as robust predictors of negative clinical and mental health outcomes (beta = .224-.363). CONCLUSION: This information about liver transplant recipients is important for researchers and clinicians. Researchers can develop guidelines by using stable but modifiable characteristics of patients to identify transplant candidates at risk of nonadherence. Such guidelines would enable clinicians to prepare patients better to manage the posttransplant regimen.

Monitoring the operationally tolerant liver allograft recipient.

PURPOSE OF REVIEW: A fundamental goal in transplantation is the establishment of allograft function without ongoing immunosuppression. Robust allograft tolerance has been established in experimental transplantation models, whereas clinical operational tolerance has been described most frequently following human liver transplantation. RECENT FINDINGS: Clinical assessment of tolerance has been limited to laboratory evaluation of organ function. Additional tools include graft monitoring through biopsy and blood sampling for biomarker analysis. Current biomarkers under assessment in recent years include dendritic cell subsets, regulatory T cells, antidonor antibodies, and gene polymorphisms. Emerging microarray analysis that is being prospectively validated will also be reviewed. A further tool in the characterization of the tolerant patient will be the accurate enrollment of such patients into a multicenter registry that will prospectively follow the natural history of the patient withdrawn from immunosuppression and help facilitate the entry of interested patients to mechanistic and immune monitoring trials. The International Solid Organ Transplant Tolerance Registry (www.transplant-tolerance.org) will be briefly described. SUMMARY: Effective biomarker characterization of the operationally tolerant liver allograft recipient would allow earlier, well tolerated, prospective drug withdrawal with the goal of extending the potential benefits of drug minimization to an increasing number of patients in a more predictable fashion.

Treatment of hepatic epithelioid hemangioendothelioma: a single-institution experience with 25 cases.

OBJECTIVE: To examine treatment of hepatic epithelioid hemangioendothelioma (EHE), a rare vascular tumor with a variable course. Treatment modalities at our institution include liver resection, transplantation, and catheter-based therapies. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURES: Retrospective review of 25 patients treated for hepatic EHE (1976-2007). We examined treatment modality, overall survival, complications, and clinicopathologic characteristics. RESULTS: Of the 25 patients treated for hepatic EHE, 17 underwent liver transplantation (LT); 4, transcatheter arterial chemoembolization (TACE); 2, resection; and 2, TACE followed by LT. Twelve patients (48%) were male. The median age at diagnosis was 38 years (range, 9 months to 72 years). Mean overall survival was 167 (95% confidence interval [CI], 123-212) months, with 172 (124-220) months in the LT group and 83 (54-112) months in the TACE group. The 2 patients in the resection group remain alive after 19 and 71 months. The 2 patients treated with TACE followed by LT died after 13 and 113 months. Extrahepatic disease was identified as a predictor of outcome. Patients with extrahepatic disease treated with TACE fared better than those treated with surgical approaches (mean survival, 83.0 [95% CI, 54.2-111.8] vs 38.8 [23.7-53.8] months; P = .12). CONCLUSIONS: Hepatic EHE is a rare tumor that can be treated with surgical or nonsurgical approaches. In our experience, LT is used for patients with advanced local disease, whereas TACE is the primary modality when extrahepatic disease or comorbid conditions prohibiting LT are present. To our knowledge, this is the largest single-institution experience describing the various therapeutic modalities in the treatment of hepatic EHE.