Clinical Focus

  • General Surgery
  • Kidney and Pancreas Transplantation
  • Liver Transplantation

Academic Appointments

Administrative Appointments

  • Director, Pediatric Liver Transplant Program, Stanford University (1995 - Present)
  • Vice Chairman, Department of Surgery, Stanford University (1995 - 1997)
  • Director, Abdominal Transplant Fellowship, Stanford University (1998 - Present)
  • Associate Director, Institute for Immunity, Transplantation and Infection, Stanford University (2004 - Present)
  • Chief, Division of Abdominal Transplantation, Stanford University (1998 - Present)

Honors & Awards

  • Medical Staff Distinguished Service Award, Lucile Packard Children's Hospital at Stanford (April 16, 2015)
  • Francis Moore Excellence in Mentorship in the field of Transplantation Surgery Award, American Society of Transplant Surgeons (2015)
  • President, San Francisco Surgical Society (2010 - 2011)
  • Honoree 'Salute to Excellence', American Liver Foundation, Northern California Chapter (2003)
  • 1st Recipient "The Arnold and Barbara Chair in Pediatric Transplantation", Stanford University (1999)
  • Member, American Surgical Association (1997)
  • Premio a la Superacion (Honor al Merito) by Rafael A. Calderon F. Presidente de la Republica, Costa Rica (1991)
  • Fellow, American College of Surgeons (1990)
  • National Research Service Award, NIH (1980)

Professional Education

  • Residency:UC Davis Medical Center (1984) CA
  • Fellowship:University of Pittsburgh School of Medicine (1985) PA
  • Board Certification: General Surgery, American Board of Surgery (1985)
  • Fellowship:University of Lund (1983) Sweden
  • Internship:UC Davis Medical Center (1978) CA
  • Medical Education:University of Costa Rica School of Medicine (1975) Costa Rica
  • Fellowship, University of Pittsburgh, Transplantation (1985)
  • Residency, University of California, Davis, Surgery (1984)
  • Internship, University of California, Davis, Surgery (1978)
  • Ph.D., University of Lund, Sweden, Medicine (1983)
  • MD, University of Costa Rica, Medicine (1975)

Research & Scholarship

Current Research and Scholarly Interests

My role in research is to bring clinical problems to the laboratory to find answers, which in turn, will improve patient care. Thus, my role is translational research in the field of liver and small bowel transplantation. As a senior clinical scientist, I provide leadership over many research projects conducted in the Division of Abdominal Transplantation laboratories. I have ensembled an outstanding research team lead by Olivia Martinez, Ph.D. and Sheri Krams, Ph.D. The investigators include undergraduate and post-graduate students, medical students, surgery residents and transplant fellows.
Research projects involve several models of transplantation of the liver, kidney, intestinal and heart transplantation in rodents. The goals of these research projects are to understand the molecular mechanisms of rejection and by manipulating those mechanisms, we are pursuing full acceptance of the transplanted organs, known as tolerance.

Clinical Trials

  • Biomarkers for Post-Transplant Lymphoproliferative Disorders in Children Recruiting

    Solid organ transplantation is an important therapeutic option for children with a variety of end stage diseases. However, the same immunosuppressive medications that are required to prevent the child's immune system from attacking and rejecting the transplanted organ can predispose these individuals to developing a very serious cancer that is linked to Epstein-Barr virus (EBV).

    View full details

  • Risk Factors and Molecular Genomics of U.S. Patients With Chronic Liver Disease &Hepatocellular CA Not Recruiting

    To identify risk factors for the development and diagnosis of hepatocellular CA in patients with chronic hepatitis C and to use the data to ultimately develop an effective screening program.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

    View full details


2014-15 Courses


All Publications

  • Treatment of Methylmalonic Acidemia by Liver or Combined Liver-Kidney Transplantation JOURNAL OF PEDIATRICS Niemi, A., Kim, I. K., Krueger, C. E., Cowan, T. M., Baugh, N., Farrell, R., Bonham, C. A., Concepcion, W., Esquivel, C. O., Enns, G. M. 2015; 166 (6): 1455-?


    To assess biochemical, surgical, and long-term outcomes of liver (LT) or liver-kidney transplantation (LKT) for severe, early-onset methylmalonic acidemia/acid (MMA).A retrospective chart review (December 1997 to May 2012) of patients with MMA who underwent LT or LKT at Lucile Packard Children's Hospital at Stanford.Fourteen patients underwent LT (n = 6) or LKT (n = 8) at mean age 8.2 years (range 0.8-20.7). Eleven (79%) were diagnosed during the neonatal period, including 6 by newborn screening. All underwent deceased donor transplantation; 12 (86%) received a whole liver graft. Postoperative survival was 100%. At a mean follow-up of 3.25 ± 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. One patient underwent liver re-transplantation because of hepatic artery thrombosis. After transplantation, there were no episodes of hyperammonemia, acidosis, or metabolic decompensation. The mean serum MMA at the time of transplantation was 1648 ± 1492 μmol/L (normal <0.3, range 99-4420). By 3 days, post-transplantation levels fell on average by 87% (mean 210 ± 154 μmol/L), and at 4 months, they were 83% below pre-transplantation levels (mean 305 ± 108 μmol/L). Developmental delay was present in 12 patients (86%) before transplantation. All patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning.LT or LKT for MMA eradicates episodes of hyperammonemia, results in excellent long-term survival, and suggests stabilization of neurocognitive development. Long-term follow-up is underway to evaluate whether patients who undergo early LT need kidney transplantation later in life.

    View details for DOI 10.1016/j.jpeds.2015.01.051

    View details for Web of Science ID 000355018200025

    View details for PubMedID 25771389

  • Employment After Liver Transplantation: A Review TRANSPLANTATION PROCEEDINGS Huda, A., Newcomer, R., Harrington, C., Keeffe, E. B., Esquivel, C. O. 2015; 47 (2): 233-239


    Return to productive employment is often an important milestone in the recovery and rehabilitation process after liver transplantation (OLT). This literature review identifies factors associated with employment in patients who underwent OLT.We searched PubMed for articles that addressed the various factors affecting employment after OLT.The studies demonstrated improvement in the quality of life and examined factors that predicted whether patients would return to work after OLT. Demographic variable associated with posttransplant employment included young age, male sex, college degree, Caucasian race, and pretransplant employment. Patients with alcohol-related liver disease had a significantly lower rate of employment than did those with other etiologies of liver disease. Recipients who were employed after transplantation had a significantly better posttransplant functional status than did those who were not employed.Economic pressures are increasing the expectation that patients who undergo successful OLT will return to work. Thus, transplant teams need to have a better understanding of posttransplant work outcomes for this vulnerable population, and greater attention must be paid to the full social rehabilitation of transplant recipients. Specific interventions for OLT recipients should be designed to evaluate and change their health perceptions and encourage their return to work.

    View details for DOI 10.1016/j.transproceed.2014.10.022

    View details for Web of Science ID 000351480600001

    View details for PubMedID 25769555

  • Recurrent Hepatocellular Carcinoma and Poorer Overall Survival in Patients Undergoing Left-sided Compared With Right-sided Partial Hepatectomy. Journal of clinical gastroenterology Valenzuela, A., Ha, N. B., Gallo, A., Bonham, C., Ahmed, A., Melcher, M., Kim, L. H., Esquivel, C., Concepcion, W., Ayoub, W. S., Lutchman, G. A., Daugherty, T., Nguyen, M. H. 2015; 49 (2): 158-164


    We aimed to determine the incidence and predictors of recurrent hepatocellular carcinoma (HCC) after partial hepatectomy.Liver transplantation is the preferred treatment for selected patients with HCC, but access to donor organs is limited. Partial hepatectomy is another accepted treatment option; however, postoperative recurrence is frequently observed.This is a retrospective cohort study of 107 consecutive patients who underwent partial hepatectomy for HCC between January 1993 and February 2011 at a US University Medical Center. Study endpoints were recurrent HCC, death, loss to follow-up, or last visit without HCC.The study cohort was 78% male with a median age of 61 years and 59% Asians. A total of 50 patients developed recurrent HCC (46.7%) after a median follow-up of 12 (1 to 69) months postresection. Recurrent HCC was significantly higher in patients with left-sided resection (41% at year 1, 54% at year 2, 62% at year 3, 81% at year 4, and 90% at year 5) compared with right-sided resection (18% at year 1, 34% at year 2, 36% at year 3, 44% at year 4, and 72% at year 5). In multivariate Cox proportional hazards model also inclusive of anatomic resection and TNM stage 3/4, left-sided resection was significantly associated with increased HCC recurrence (hazard ratio, 2.13; P=0.02; 95% confidence interval, 1.08-4.2) compared with right-sided resection.HCC recurrence rate is higher among those undergoing left-sided resection: 54% at year 2 and 81% at year 4. Liver transplantation should be considered in patients who are at high risk for recurrence.

    View details for DOI 10.1097/MCG.0000000000000144

    View details for PubMedID 24804988

  • Complications Following Liver Transplantation for Progressive Familial Intrahepatic Cholestasis DIGESTIVE DISEASES AND SCIENCES Berumen, J., Feinberg, E., Todo, T., Bonham, C. A., Concepcion, W., Esquivel, C. 2014; 59 (11): 2649-2652
  • Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure. Pediatric transplantation McKenzie, R. B., Berquist, W. E., Nadeau, K. C., Louie, C. Y., Chen, S. F., Sibley, R. K., Glader, B. E., Wong, W. B., Hofmann, L. V., Esquivel, C. O., Cox, K. L. 2014; 18 (5): 503-509


    In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

    View details for DOI 10.1111/petr.12296

    View details for PubMedID 24930635

  • Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data CLINICAL TRANSPLANTATION Wong, R. J., Chou, C., Bonham, C. A., Concepcion, W., Esquivel, C. O., Ahmed, A. 2014; 28 (6): 713-721


    There is an increasing trend of patients with hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease undergoing liver transplantation in the U.S. Our study utilized data from the 2002-2012 United Network for Organ Sharing registry to evaluate MELD era trends in U.S. liver transplantations focused on patients with non-alcoholic steatohepatitis (NASH), hepatitis C (HCV), alcoholic liver disease, and HCC. Survival outcomes were stratified by liver disease etiology and compared across time periods using Kaplan Meier and Cox proportional hazards models. Patients with NASH were more likely to be women, had higher body mass index, and higher prevalence of diabetes and cardiac disease. However, overall long term survival was significantly higher in NASH and alcoholic liver disease patients (p < 0.001). Compared to HCV, NASH patients had significantly higher post-transplantation survival (HR 0.69, 95% CI 0.63-0.77), and lower risk of graft failure (HR 0.76, 95% CI 0.69-0.83). Despite having higher body mass index and higher prevalence of diabetes and cardiac disease, NASH patients had better post-liver transplantation survival compared to patients with HCV or HCC. Patients with alcoholic liver disease also had superior survival outcomes. However, these survival differences were limited to patients without HCC that underwent liver transplantation. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/ctr.12364

    View details for Web of Science ID 000337690200011

    View details for PubMedID 24654688

  • Primary Surgical Resection Versus Liver Transplantation for Transplant-Eligible Hepatocellular Carcinoma Patients DIGESTIVE DISEASES AND SCIENCES Wong, R. J., Wantuck, J., Valenzuela, A., Ahmed, A., Bonham, C., Gallo, A., Melcher, M. L., Lutchman, G., Concepcion, W., Esquivel, C., Garcia, G., Daugherty, T., Nguyen, M. H. 2014; 59 (1): 183-191


    Hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide. Existing studies comparing outcomes after liver transplantation (LT) versus surgical resection among transplant-eligible patients are conflicting.The purpose of this study was to compare long-term survival between consecutive transplant-eligible HCC patients treated with resection versus LT.The present retrospective matched case cohort study compares long-term survival outcomes between consecutive transplant-eligible HCC patients treated with resection versus LT using intention-to-treat (ITT) and as-treated models. Resection patients were matched to LT patients by age, sex, and etiology of HCC in a 1:2 ratio.The study included 171 patients (57 resection and 114 LT). Resection patients had greater post-treatment tumor recurrence (43.9 vs. 12.9 %, p < 0.001) compared to LT patients. In the as-treated model of the pre-model for end stage liver disease (MELD) era, LT patients had significantly better 5-year survival compared to resection patients (100 vs. 69.5 %, p = 0.04), but no difference was seen in the ITT model. In the multivariate Cox proportional hazards model, inclusive of age, sex, ethnicity, tumor stage, and MELD era (pre-MELD vs. post-MELD), treatment with resection was an independent predictor of poorer survival (HR 2.72; 95 % CI, 1.08-6.86).Transplant-eligible HCC patients who received LT had significantly better survival than those treated with resection, suggesting that patients who can successfully remain on LT listing and actually undergo LT have better outcomes.

    View details for DOI 10.1007/s10620-013-2947-8

    View details for Web of Science ID 000330585500029

  • PI3K Inhibition Augments the Efficacy of Rapamycin in Suppressing Proliferation of Epstein-Barr Virus (EBV) plus B Cell Lymphomas AMERICAN JOURNAL OF TRANSPLANTATION Furukawa, S., Wei, L., Krams, S. M., Esquivel, C. O., Martinez, O. M. 2013; 13 (8): 2035-2043


    Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life-threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhibitor suppressed Akt phosphorylation and showed a greater anti-proliferative effect on EBV+ B lymphoma lines compared to RAPA. EBV+ B cell lymphoma lines expressed high levels of PI3Kδ. We demonstrate that PI3Kδ is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3Kδ by either siRNA, or a small molecule inhibitor, augmented the anti-proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3Kδ is a novel, potential therapeutic target for the treatment of EBV-associated PTLD and that combined blockade of PI3Kδ and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas.

    View details for DOI 10.1111/ajt.12328

    View details for Web of Science ID 000322330000013

    View details for PubMedID 23841834

  • Syk-Induced Phosphatidylinositol-3-Kinase Activation in EpsteinBarr Virus Posttransplant Lymphoproliferative Disorder AMERICAN JOURNAL OF TRANSPLANTATION Hatton, O., Lambert, S. L., Phillips, L. K., Vaysberg, M., Natkunam, Y., Esquivel, C. O., Krams, S. M., Martinez, O. M. 2013; 13 (4): 883-890


    Posttransplant lymphoproliferative disorder (PTLD)-associated Epstein-Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3'-kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies.

    View details for DOI 10.1111/ajt.12137

    View details for Web of Science ID 000316911900011

  • PI3K delta Inhibition Augments the Efficacy of mTOR Inhibitor Rapamycin on the Proliferation of Epstein-Barr Virus (EBV) plus B Cell Lymphomas. Furukawa, S., Hatton, O., Krams, S., Esquivel, C., Martinez, O. WILEY-BLACKWELL. 2013: 96-97
  • Current options for management of biliary atresia PEDIATRIC TRANSPLANTATION Gallo, A., Esquivel, C. O. 2013; 17 (2): 95-98


    It is encouraging that we are improving the technical aspects of treatment modalities for biliary atresia. However, it is clear that more needs to be done to best develop new treatment plans while applying the modalities we have (porto-enterostomy or liver transplantation or both) in a way that will afford the best survival and quality-of-life. This review article will discuss a number of points that are vital to improving care and illustrates the need to further scrutinize treatment decisions.

    View details for DOI 10.1111/petr.12040

    View details for Web of Science ID 000315467000009

    View details for PubMedID 23347466

  • Liver transplantation for urea cycle disorders in pediatric patients: A single-center experience PEDIATRIC TRANSPLANTATION Kim, I. K., Niemi, A., Krueger, C., Bonham, C. A., Concepcion, W., Cowan, T. M., Enns, G. M., Esquivel, C. O. 2013; 17 (2): 158-167


    LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long-term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole-liver graft, seven patients (30%) received a reduced-size graft, and one patient received a living donor graft. Mean five-yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH(3) ) at presentation was 772 μmol/L (median 500, range 178-2969, normal <30-50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long-term follow-up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long-term follow-up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.

    View details for DOI 10.1111/petr.12041

    View details for Web of Science ID 000315467000017

    View details for PubMedID 23347504

  • Geographical Rural Status and Health Outcomes in Pediatric Liver Transplantation: An Analysis of 6 Years of National United Network of Organ Sharing Data JOURNAL OF PEDIATRICS Park, K. T., Bensen, R., Lu, B., Nanda, P., Esquivel, C., Cox, K. 2013; 162 (2): 313-?


    To determine whether children in rural areas have worse health than children in urban areas after liver transplantation (LT).We used urban influence codes published by the US Department of Agriculture to categorize 3307 pediatric patients undergoing LT in the United Network of Organ Sharing database between 2004 and 2009 as urban or rural. Allograft rejection, patient death, and graft failure were used as primary outcome measures of post-LT health. Pediatric end-stage liver disease/model of end-stage liver disease scores >20 was used to measure worse pre-LT health.In a multivariate analysis, we found greater rates of allograft rejection within 6 months of LT (OR 1.27; 95% CI 1.05-1.53) and a lower occurrence of posttransplantation lymphoproliferative disorder (OR 0.64; 95% CI 0.41-0.99) in patients in rural areas. The difference in allograft rejection was eliminated at 1 year of LT (OR 1.18; 95% CI 0.98-1.42). Rural location did not impact other outcome measures.We conclude that rural location makes a negative impact on patient health within the first 6 months of LT by increasing the risk for allograft rejection, although patients in rural areas may have lower rates of developing posttransplantation lymphoproliferative disorder. Long-term adverse health effects were not seen.

    View details for DOI 10.1016/j.jpeds.2012.07.015

    View details for Web of Science ID 000313579900021

    View details for PubMedID 22914224

  • The impact of hepatic portoenterostomy on liver transplantation for the treatment of biliary atresia: Early failure adversely affects outcome PEDIATRIC TRANSPLANTATION Alexopoulos, S. P., Merrill, M., Kin, C., Matsuoka, L., Dorey, F., Concepcion, W., Esquivel, C., Bonham, A. 2012; 16 (4): 373-378


    The most common indication for pediatric LTx is biliary atresia with failed HPE, yet the effect of previous HPE on the outcome after LTx has not been well characterized. We retrospectively reviewed a single-center experience with 134 consecutive pediatric liver transplants for the treatment of biliary atresia from 1 May 1995 to 28 April 2008. Of 134 patients, 22 underwent LTx without prior HPE (NPE), while 112 patients underwent HPE first. HPE patients were grouped into EF, defined as need for LTx within the first year of life, and LF, defined as need for LTx beyond the first year of life. NPE and EF groups differed significantly from the LF group in age, weight, PELD, and ICU status (p < 0.05) with NPE having the highest PELD and ICU status. Patients who underwent salvage LTx after EF following HPE had a significantly higher incidence of post-operative bacteremia and septicemia (p < 0.05), and subsequently lower survival rates. One-year patient survival and graft survival were as follows: NPE 100%, EF 81%, and LF 96% (p < 0.05); and NPE 96%, EF 79%, and LF 96% (p < 0.05). Further investigation into the optimal treatment of biliary atresia should focus on identifying patients at high risk of EF who may benefit from proceeding directly to LTx given the increased risk of post-LTx bacteremia, sepsis, and death after failed HPE.

    View details for DOI 10.1111/j.1399-3046.2012.01677.x

    View details for Web of Science ID 000303998800021

    View details for PubMedID 22463739

  • Grafts too big or too small: Business as usual in pediatric liver transplantation PEDIATRIC TRANSPLANTATION Reding, R., Dhawan, A., Esquivel, C. O. 2012; 16 (3): 212-213
  • Emerging therapeutic strategies for Epstein-Barr virus+ post-transplant lymphoproliferative disorder PEDIATRIC TRANSPLANTATION Hatton, O., Martinez, O. M., Esquivel, C. O. 2012; 16 (3): 220-229


    De novo malignancies represent an increasing concern in the transplant population, particularly as long-term graft and patient survival improves. EBV-associated B-cell lymphoma in the setting of PTLD is the leading malignancy in children following solid organ transplantation. Therapeutic strategies can be categorized as pharmacologic, biologic, and cell-based but the variable efficacy of these approaches and the complexity of PTLD suggest that new treatment options are warranted. Here, we review current therapeutic strategies for treatment of PTLD. We also describe the life cycle of EBV, addressing the viral mechanisms that contribute to the genesis and persistence of EBV+ B-cell lymphomas. Specifically, we focus on the oncogenic signaling pathways activated by the EBV LMP1 and LMP2a to understand the underlying mechanisms and mediators of lymphomagenesis with the goal of identifying novel, rational therapeutic targets for the treatment of EBV-associated malignancies.

    View details for DOI 10.1111/j.1399-3046.2012.01656.x

    View details for Web of Science ID 000302619500013

    View details for PubMedID 22353174

  • A Common Peripheral Blood Gene Set for Diagnosis of Operational Tolerance in Pediatric and Adult Liver Transplantation AMERICAN JOURNAL OF TRANSPLANTATION Li, L., Wozniak, L. J., RODDER, S., Heish, S., Talisetti, A., Wang, Q., Esquivel, C., Cox, K., Chen, R., McDiarmid, S. V., Sarwal, M. M. 2012; 12 (5): 1218-1228


    To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.

    View details for DOI 10.1111/j.1600-6143.2011.03928.x

    View details for Web of Science ID 000303235100020

    View details for PubMedID 22300520

  • Changes in natural killer cell subsets in pediatric liver transplant recipients PEDIATRIC TRANSPLANTATION Pham, B., Piard-Ruster, K., Silva, R., Gallo, A., Esquivel, C. O., Martinez, O. M., Krams, S. M. 2012; 16 (2): 176-182


    NK cells are important in the immune response against tumors and virally infected cells. A balance between inhibitory and activating receptors controls the effector functions of NK cells. We examined the fate of circulating NK cells and the expression of the NK cell-activating receptors in pediatric liver transplant recipients. Blood specimens were collected from 38 pediatric liver transplant recipients before transplant, and at one wk, one, three, six, and nine months, and one yr post-transplant. PBMCs were isolated and analyzed for the levels of NK cell activation receptors NKp30, NKp46, and NKG2D in the CD56(dim) CD16(+) and CD56(bright) CD16(+/-) subsets of NK cells. We demonstrated that there is a significant decrease in the percentage of circulating NK cells post-transplant (pretransplant 7.69 ± 1.54 vs. one wk post-transplant 1.73 ± 0.44) in pediatric liver transplant recipients. Interestingly, NKp30 expression is significantly increased, while NKp46 and NKG2D levels remain stable on the NK cells that persist at one wk post-transplant. These data indicate that the numbers and subsets of circulating NK cells are altered in children after liver transplantation.

    View details for DOI 10.1111/j.1399-3046.2012.01653.x

    View details for Web of Science ID 000300709600017

    View details for PubMedID 22360401

  • Liver Transplantation With Donation After Cardiac Death A Treacherous Field! ARCHIVES OF SURGERY Esquivel, C. O. 2011; 146 (9): 1023-1023

    View details for Web of Science ID 000295002900007

    View details for PubMedID 22029064

  • Effects of rural status on health outcomes in pediatric liver transplantation: A single center analysis of 388 patients PEDIATRIC TRANSPLANTATION Park, K. T., Nanda, P., Bensen, R., Strichartz, D., Esquivel, C., Cox, K. 2011; 15 (3): 300-305


    Rural status of patients may impact health before and after pediatric LT. We used UI codes published by the USDA to stratify patients as urban or rural depending county residence. A total of 388 patients who had LT and who met criteria were included. Rejection, PTLD, and survival were used as primary outcome measures of post-LT health. UNOS Status 1 and PELD/MELD scores >20 were used as secondary outcome measures of poorer pre-LT health. Logistic regression models were run to determine associations. We did not find any statistically significant differences in pre- or post-LT outcomes with respect to rurality. Among rural patients, there was a general trend for decreased incidence of rejection (25.0% vs. 33.4%; OR 0.64, 95% CI 0.29-1.44), increased risk of PTLD (5.6% vs. 3.4%; OR 1.86, 95% CI 0.36-3.31), and decreased survival (OR 0.85, 95% CI 0.34-2.13) after LT. Rural patients also tended to be sicker at the time of LT than patients from urban areas, with increased proportion of Status 1 (OR 1.17, 95% CI 0.51-2.70) and PELD/MELD scores >20 (OR 1.20, 95% CI 0.59-2.45). From a single center experience, we conclude that rurality did not significantly affect health outcomes after LT, although a larger study may validate the general trends that rural patients may have decreased rejection, increased PTLD, and mortality, and be in poorer health at the time of LT.

    View details for DOI 10.1111/j.1399-3046.2010.01452.x

    View details for Web of Science ID 000289628100018

    View details for PubMedID 21450010

  • Successful Cavoatrial Anastamosis in Technically Challenging Liver Transplant Recipients Hwang, C. S., Gallo, A. E., Lightner, A., Bonham, C. A., Concepcion, W., Esquivel, C. O. WILEY-BLACKWELL. 2011: 332-332
  • Targeting Akt for Treatment of Post-Transplant Lymphoproliferative Disorder (PTLD) Hatton, O., Lambert, S., Krams, S. M., Esquivel, C. O., Martinez, O. M. WILEY-BLACKWELL. 2011: 137-137
  • Rejection of Small Intestinal Allografts Associates with a Unique Signature of microRNAs Krams, S. M., Wei, L., Pham, B., Harris, A., Castillo, R. O., Esquivel, C. O., Martinez, O. WILEY-BLACKWELL. 2011: 133-133
  • Toll-Like Receptor 4 Contributes to Small Intestine Allograft Rejection TRANSPLANTATION Krams, S. M., Wang, M., Castillo, R. O., Ito, T., Phillips, L., Higgins, J., Kambham, N., Esquivel, C. O., Martinez, O. M. 2010; 90 (12): 1272-1277


    Although outcomes for small intestine transplantation (SIT) have improved in recent years, allograft rejection rates remain among the highest of solid organ grafts. The high load of commensal bacteria in the small intestine may contribute through activation of the toll-like receptor (TLR) pathway. In this study, we examine the participation of TLR4 in acute allograft rejection in an orthotopic mouse model of SIT.Wild-type C57Bl/6 (H-2b) or TLR49(-/-) (H-2b) mice were transplanted with syngeneic (C57Bl/6), allogeneic (BALB/c; H-2d), or F1 (BALB/cxC57Bl/6; H-2d/b) vascularized, orthotopic small intestine grafts. Graft recipients were killed on days 2 to 6 posttransplant. Serum cytokines were measured by Luminex, and tissue was obtained for histology and quantitative real-time polymerase chain reaction.BALB/c grafts transplanted into C57Bl/6 recipients exhibited mixed inflammatory infiltrates, destruction of the mucosa, and significant apoptosis. TLR2 and TLR4 transcripts were modestly increased in syngeneic grafts on days 2 and 6 compared with native bowel, whereas TLR2 and TLR4 were significantly increased on days 2 and 6 in allogeneic grafts. Although fully mismatched and F1 grafts were rejected by C57Bl/6 recipients (mean survival time=8.2 and 9.3 days, respectively), graft survival was significantly prolonged in TLR4(-/-) recipients (mean survival time=10.6 and 14.3 days, respectively). Proinflammatory cytokines were markedly reduced in TLR4(-/-) graft recipients.Small intestine graft survival is prolonged in the absence of TLR4, suggesting that gut flora associated with the graft may augment alloimmune responses through TLR4. Thus, the TLR pathway may be a novel therapeutic target for improving SIT allograft survival.

    View details for DOI 10.1097/TP.0b013e3181fdda0d

    View details for Web of Science ID 000285377100006

    View details for PubMedID 21197709

  • Analysis of clinical variables associated with tolerance in pediatric liver transplant recipients PEDIATRIC TRANSPLANTATION Talisetti, A., Hurwitz, M., Sarwal, M., Berquist, W., Castillo, R., Bass, D., Concepcion, W., Esquivel, C. O., Cox, K. 2010; 14 (8): 976-979


    Tolerance has been defined as stable graft function off IMS. We reviewed the data of 369 pediatric liver transplant patients to examine demographic differences that may have a PV of pediatric LT tolerance. Of the 369 patients, 280 patients were stable with detectable blood levels of IMS agents and with good graft function without biopsy proven REJ > 1 yr posttransplantation, 18 patients were noted to be TOL off IMS, 27 patients were taking MIS with drug levels below detectable range by standard laboratory parameters, and 44 patients developed one or more episodes of biopsy proven acute or chronic REJ > 1 yr post-transplantation. Variables, including percentage of biliary atresia, type of transplanted organ, history of EBV infection, patient and donor gender, and ABO blood type mismatch between recipient and donor did not have PV of tolerance. Average age in years was 1.37 ± 1.53 (0.3-4.9) for TOL, 1.14 ± 0.89 (0.4-3.1) for MIS and 3.35 ± 4.45 (0.3-16) for REJ. Age difference of TOL/MIS vs. REJ was significant (p =0.002) and TOL vs. REJ was significant (0.01). Age at the time of transplantation is an important predictor in the development of pediatric LT tolerance.

    View details for DOI 10.1111/j.1399-3046.2010.01360.x

    View details for Web of Science ID 000285229500007

    View details for PubMedID 21108705

  • A review of abdominal organ transplantation in cystic fibrosis PEDIATRIC TRANSPLANTATION Lu, B. R., Esquivel, C. O. 2010; 14 (8): 954-960


    With advances in medical treatments, patients with CF are having improved quality of life and living longer. Although pulmonary disease is still the leading cause of morbidity and mortality, this longevity has allowed for the development of other organ dysfunction, mainly liver and pancreas. This review discusses the abdominal organ complications and the role of abdominal organ transplantation in CF. Liver failure and portal hypertension complications are the most common indicators for liver transplantation in CF, and five-yr survival for isolated liver transplantation is >80%. Deficiency of pancreatic enzymes is almost universal and up to 40% of patients with CF can develop insulin-dependent diabetes, although the role of pancreas transplantation is less clear and needs further research. Finally, the need for lung transplantation should always be assessed and considered in combination with liver transplantation on a case-by-case basis.

    View details for DOI 10.1111/j.1399-3046.2010.01412.x

    View details for Web of Science ID 000285229500004

    View details for PubMedID 20946451

  • Expression of Soluble HLA-G Identifies Favorable Outcomes in Liver Transplant Recipients TRANSPLANTATION Zarkhin, V., Talisetti, A., Li, L., Wozniak, L. J., McDiarmid, S. V., Cox, K., Esquivel, C., Sarwal, M. M. 2010; 90 (9): 1000-1005


    Human leukocyte antigen (HLA)-G displays immunotolerogenic properties toward the main effector cells involved in graft rejection through inhibition of natural killer cell- and cytotoxic T-lymphocyte-mediated cytolysis, and CD4 T-cell alloproliferation. An increase in serum and graft levels of HLA-G has been noted in transplant patients with improved allograft survival. However, the clinical relevance of soluble serum HLA-G molecules in tolerant pediatric and young adult liver transplant patients remains to be studied.We examined the serum HLA-G levels in 42 pediatric and young adult liver transplant patients with a mean age of 15 years; 13 patients had operational tolerance (TOL), with complete immunosuppression withdrawal for 2.3 to 13.2 years.Median HLA-G level in patients with acute rejection (AR) was similar to the level in pediatric healthy volunteers (9.9 vs. 4.2 U/mL, P=0.13). HLA-G was higher in patients with stable liver function on immunosuppression (54.6 U/mL) than in patients with AR (P=0.01) and healthy volunteers (P=0.003), but almost 6-fold lower than in TOL patients (325.4 U/mL). HLA-G did not correlate with clinical confounders or a history of posttransplant lymphoproliferative disease or Epstein-Barr virus; although levels in the TOL group were negatively correlated with time after immunosuppression withdrawal (r=-0.75, P=0.003). In rejectors, HLA-G levels trended to negatively correlate with a higher number (r=-0.58) and greater severity of AR episodes (r=-0.56) after 1 year posttransplantation.Increased serum HLA-G levels track with operational tolerance of liver grafts and support favorable outcomes in pediatric and young adult recipients.

    View details for DOI 10.1097/TP.0b013e3181f546af

    View details for Web of Science ID 000283650200011

    View details for PubMedID 20814356

  • Acute Rejection of Small Intestine Allografts Is Associated With Increased Expression of Toll-like Receptors TRANSPLANTATION PROCEEDINGS Castillo, R. O., Wang, M., Ito, T., Higgins, J., Esquivel, C. O., Krams, S. M., Martinez, O. M. 2010; 42 (7): 2676-2678


    Although outcomes after intestinal transplantation have steadily improved owing to advances in immunosuppressive therapy, operative techniques, and postoperative medical management, rejection of the intestinal allograft continues to be a major clinical problem and constitutes the primary reason for graft loss. Although the adaptive immune system has been the major focus of investigation regarding regulation of rejection of the intestinal allograft, the role of the innate immune system has recently become of increased interest. We hypothesized that microbial products of the microflora associated with the intestinal allograft may engage the Toll-like receptor pathway of the innate immune system to potentiate alloimmune responses and rejection of the allograft. To investigate this, we established a murine model for orthotopic intestinal transplantation and allograft rejection. Using this model, we show that the expression of Toll-like receptor 2 is increased 50-fold and the expression of Toll-like receptor 4 is increased 200-fold during rejection of the allograft. We then performed survival studies that showed increased survival of mice, which had the Toll-like receptor knocked out. These preliminary studies suggest an important role for in innate immune system in acute rejection of the small intestinal allografts, and as such represents an emerging and promising area of investigation.

    View details for DOI 10.1016/j.transproceed.2010.05.157

    View details for Web of Science ID 000281942200052

    View details for PubMedID 20832568

  • Complete immunosuppressive drug withdrawal from liver transplant recipients conditioned with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) Gallo, A., Strober, S., Concepcion, W., Esquivel, C. ELSEVIER SCIENCE INC. 2010: S64-S64
  • Biliary Complications Following Liver Transplantation DIGESTIVE DISEASES AND SCIENCES Ayoub, W. S., Esquivel, C. O., Martin, P. 2010; 55 (6): 1540-1546


    The aphorism that reconstruction of the biliary anastomosis is the "Achilles heel" of liver transplantation remains valid as biliary complications following liver transplantation remain a major source of morbidity with an incidence of 5-32%. Biliary complications include biliary strictures, biliary leaks, and stones. Biliary strictures can be divided into anastomotic and non-anastomotic. The management of biliary complications previously relied on surgical intervention. However, advances in endoscopic and radiological interventions have resulted in less-invasive options. The management of biliary complications post-liver transplantation requires a multidisciplinary approach and continues to evolve. Biliary complications also reflect the continued expansion of the donor pool with extended, live, and non-heart beating donors.

    View details for DOI 10.1007/s10620-010-1217-2

    View details for Web of Science ID 000278578800008

    View details for PubMedID 20411422

  • Excellent Outcome in All Patients with Combined Kidney and Liver Transplant for Primary Hyperoxaluria Type 1. Hwang, C. S., Gallo, A. E., Sarwal, M. M., Concepcion, W., Esquivel, C. O. WILEY-BLACKWELL. 2010: 457-457
  • Toll-Like Receptor 4 Contributes to Rejection of Small Intestine Allografts. Krams, S. M., Wang, M., Castillo, R. O., Ito, T., Esquivel, C. O., Martinez, O. M. WILEY-BLACKWELL. 2010: 312-312
  • Syk Inhibits Lymphoma Migration to the Lymph Node in a Xenotransplantaion Model of Epstein Barr Virus (EBV) plus Post-Transplant Lymphomproliferaive Disorder (PTLD) Hatton, O., Lambert, S., Vaysberg, M., Krams, S. M., Esquivel, C. O., Martinez, O. M. WILEY-BLACKWELL. 2010: 62-62
  • A Peripheral Blood 12 Gene-Set for Diagnosis of Pediatric Liver Allograft Tolerance Li, L., Talisetti, A., Hsieh, S., Cox, K., Esquivel, C., Concepcion, W., Sarwal, M. WILEY-BLACKWELL. 2010: 290-290
  • Natural Killer Cell Activation Receptor Expression Is Increased Post-Transplant in Pediatric Liver Transplant Recipients. Pham, B., Silva, R., Piard-Ruster, K., Gallo, A., Esquivel, C. O., Martinez, O. M., Krams, S. M. WILEY-BLACKWELL. 2010: 486-486
  • Liver Transplantation: Where We Are and Where We Are Heading TRANSPLANTATION PROCEEDINGS Esquivel, C. O. 2010; 42 (2): 610-612


    Outcomes after liver transplantation are outstanding; however, the limiting factor is the shortage of organs. Recently, the utilization of donors after cardiac death has been encouraged; however, such transplants are associated with a high complication rate, mainly a high incidence of biliary complications, particularly ischemic cholangiopahty, a serious complication that often leads to retransplantation. The second problem is the morbidity associated with the use of immunosuppressive drugs. In this manuscript, the current status of clinical protocols for induction of tolerance is briefly discussed. Furthermore, the future of research in transplantation will involve basic scientists and clinical scholars working in concert as has been developed at Stanford School of Medicine with the creation of the Institute for Immunity, Transplantation and Infection.

    View details for DOI 10.1016/j.transproceed.2010.02.013

    View details for Web of Science ID 000276051400055

    View details for PubMedID 20304205

  • Long-term outcome following pediatric liver transplantation for metabolic disorders PEDIATRIC TRANSPLANTATION Stevenson, T., Millan, M. T., Wayman, K., Berquist, W. E., Sarwal, M., Johnston, E. E., Esquivel, C. O., Enns, G. M. 2010; 14 (2): 268-275


    In order to determine long-term outcome, including survival, growth and development, following liver transplantation in children with metabolic disorders, we retrospectively reviewed charts of 54 children with metabolic disorders evaluated from 1989-2005 for presenting symptoms, transplantation timing and indications, survival, metabolic parameters, growth, and development. Thirty-three patients underwent liver transplantation (12 received combined liver-kidney transplants) at a median age of 21 months. At a median follow-up of 3.6 yr, patient survival was 100%, and liver and kidney allograft survival was 92%, and 100%, respectively. For the group as a whole, weight Z scores improved and body mass index at follow-up was in the normal range. Two yr post-transplantation, psychomotor development improved significantly (p < 0.01), but mental skills did not; however, both indices were in the low-normal range of development. When compared to patients with biliary atresia, children with metabolic disorders showed significantly lower mental developmental scores at one and two yr post-transplantation (p < 0.05), but psychomotor developmental scores were not significantly different. We conclude that, in patients with metabolic disorders meeting indications for transplantation, liver transplantation or combined liver-kidney transplantation (for those with accompanying renal failure) is associated with excellent long-term survival, improved growth, and improved psychomotor development.

    View details for DOI 10.1111/j.1399-3046.2009.01228.x

    View details for Web of Science ID 000274389600020

    View details for PubMedID 19671092

  • Induced Tolerance to Rat Liver Allografts Involves the Apoptosis of Intragraft T Cells and the Generation of CD4(+)CD25(+)FoxP3(+) T Regulatory Cells LIVER TRANSPLANTATION Fujiki, M., Esquivel, C. O., Martinez, O. M., Strober, S., Uemoto, S., Krams, S. M. 2010; 16 (2): 147-154


    Posttransplant total lymphoid irradiation is a nonmyeloablative regimen that has been extensively studied in rodent models for the induction of tolerance to bone marrow and solid organ allografts. Previous studies of experimental models and clinical transplantation have used total lymphoid irradiation in combination with anti-lymphocyte-depleting reagents and donor cell infusion to promote graft acceptance. In a rat model of orthotopic liver transplantation, we demonstrated that total lymphoid irradiation alone induced long-term graft survival. Apoptotic T cells were detected in markedly higher numbers in the livers of the total lymphoid irradiation-treated group in comparison with the control group of liver allograft recipients. Intragraft CD4(+)CD25(+)FoxP3(+) cells were increased in the total lymphoid irradiation group in the first week post-transplant and remained elevated in the graft and in the spleen. Importantly, the adoptive transfer of splenocytes from recipients that received posttransplant total lymphoid irradiation prolonged the survival of donor heart grafts, but not third-party heart grafts, whereas the depletion of CD4(+)CD25(+) cells from transferred splenocytes abrogated this prolongation. We conclude that posttransplant total lymphoid irradiation significantly increases the apoptosis of T cells in the liver graft and allows the accumulation of CD4(+)CD25(+)FoxP3(+) T regulatory cells, which facilitate the generation of donor-specific tolerance.

    View details for DOI 10.1002/lt.21963

    View details for Web of Science ID 000274437800005

    View details for PubMedID 20104482

  • A Peripheral Blood 12 Gene-Set for Diagnosis of Pediatric Liver Allograft Tolerance Li, L., Talisetti, A., Hsieh, S., Cox, K., Esquivel, C., Concepcion, W., Sarwal, M. WILEY-BLACKWELL PUBLISHING, INC. 2010: 11-11
  • Acute Liver Failure at 26 Weeks' Gestation in a Patient with Sickle Cell Disease LIVER TRANSPLANTATION Greenberg, M., Daugherty, T. J., Elihu, A., Sharaf, R., Concepcion, W., Druzin, M., Esquivel, C. O. 2009; 15 (10): 1236-1241


    Orthotopic liver transplantation (OLT) for acute liver failure (ALF) during pregnancy is an uncommon occurrence with variable outcomes. In pregnancy-related liver failure, prompt diagnosis and immediate delivery are essential for a reversal of the underlying process and for maternal and fetal survival. In rare cases, the reason for ALF during pregnancy is either unknown or irreversible, and thus OLT may be necessary. This case demonstrates the development of cryptogenic ALF during the 26th week of pregnancy in a woman with sickle cell disease. She underwent successful cesarean delivery of a healthy male fetus at 27 weeks with concurrent OLT. This report provides a literature review of OLT in pregnancy and examines the common causes of ALF in the pregnant patient. On the basis of the management and outcome of our case and the literature review, we present an algorithm for the suggested management of ALF in pregnancy.

    View details for DOI 10.1002/It.21820

    View details for Web of Science ID 000270931500014

    View details for PubMedID 19790148

  • Clinical models of tolerance induction in pediatric transplantation PEDIATRIC TRANSPLANTATION Esquivel, C. O., Benden, C. 2009; 13 (4): 397-399
  • Transarterial Chemoinfusion for Hepatocellular Carcinoma as Downstaging Therapy and a Bridge toward Liver Transplantation AMERICAN JOURNAL OF TRANSPLANTATION De Luna, W., Sze, D. Y., Ahmed, A., Ha, B. Y., Ayoub, W., Keeffe, E. B., Cooper, A., Esquivel, C., Nguyen, M. H. 2009; 9 (5): 1158-1168


    Favorable outcomes after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) are well described for patients who fall within defined tumor criteria. The effectiveness of tumor therapies to maintain tumor characteristics within these criteria or to downstage more advanced tumors to fall within these criteria is not well understood. The aim of this study was to examine the response to transcatheter arterial chemoinfusion (TACI) in HCC patients awaiting LT and its efficacy for downstaging or bridging to transplantation. We performed a retrospective study of 248 consecutive TACI cases in 122 HCC patients at a single U.S. medical center. Patients were divided into two groups: those who met the Milan criteria on initial HCC diagnosis (n = 95) and those with more advanced disease (n = 27). With TACI treatment, 87% of the Milan criteria group remained within the Milan criteria and 63% of patients with more advanced disease were successfully downstaged to fall within the Milan criteria. In conclusion, TACI appears to be an effective treatment as a bridge to LT for nearly 90% patients presenting within the Milan criteria and an effective downstaging modality for over half of those whose tumor burden was initially beyond the Milan criteria.

    View details for DOI 10.1111/j.1600-6143.2009.02576.x

    View details for Web of Science ID 000265222200023

    View details for PubMedID 19344435

  • Decreases in circulating CD4(+)CD25(hi)FOXP3(+) cells and increases in intragraft FOXP3(+) cells accompany allograft rejection in pediatric liver allograft recipients PEDIATRIC TRANSPLANTATION Stenard, F., Nguyen, C., Cox, K., Kambham, N., Umetsu, D. T., Krams, S. M., Esquivel, C. O., Martinez, O. M. 2009; 13 (1): 70-80


    We examined CD4(+)CD25(hi)FOXP3(+) cells Treg in children following liver transplantation and determined the relationship between Treg cell levels in the blood and in the graft. Peripheral blood was obtained from pediatric liver transplant patients at sequential time points: pre-transplant, one month, 3-4 months, 6-7 months, and 11-12 months post-transplant. PBMC were isolated, labeled for CD4, CD25 and FOXP3 expression and analyzed by flow cytometry for CD4(+)CD25(hi)FOXP3(+) cells. Sorted CD4(+)CD25(hi) cells were assessed for functional activity. Pretransplant blood levels of CD4(+)CD25(hi)FOXP3(+) Treg cells were not significantly different from post-transplant blood levels of CD4(+)CD25(hi)FOXP3(+) Treg cells. However, the blood levels of CD4(+)CD25(hi)FOXP3(+) Treg cells were significantly decreased during acute rejection compared with levels when graft function was stable. Immunohistochemistry revealed that FOXP3(+) cells were increased in the portal region of livers with histopathologic evidence of acute graft rejection compared with livers without evidence of rejection and were localized primarily within the inflammatory infiltrate. These data indicate that Treg cells are found at the site of allograft rejection and may play a role in regulation of alloreactivity. Moreover, monitoring peripheral CD4(+)CD25(hi)FOXP3(+) Treg cell levels may be useful in improving the post-transplant management of pediatric liver allograft recipients.

    View details for DOI 10.1111/j.1399-3046.2008.00917.x

    View details for Web of Science ID 000262285400012

    View details for PubMedID 18331536

  • SIR 2008 annual meeting film panel case: Alagille syndrome JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Sze, D. Y., Esquivel, C. O. 2008; 19 (9): 1278-1280

    View details for DOI 10.1016/j.jvir.2008.04.016

    View details for Web of Science ID 000259054900003

    View details for PubMedID 18725089

  • Factors affecting survival to intestinal transplantation in the very young pediatric patient TRANSPLANTATION Mian, S. I., Dutta, S., Le, B., Esquivel, C. O., Davis, K., Castillo, R. O. 2008; 85 (9): 1287-1289


    Very young pediatric patients awaiting intestinal transplantation have a high mortality rate due to long waiting times, scarcity of appropriate size donor organs, and mortality due to sepsis and liver failure. To investigate specific risk factors impacting survival to intestinal transplantation, we performed a 4-year institutional retrospective study comparing children who received grafts by age 18 months with children 18 months or younger who died while on the waiting list.Twelve children comprised the transplanted group and had the underlying diagnoses: necrotizing enterocolitis, gastroschisis, Hirschsprung's disease, and omphalocele. Ten children comprised the deceased group and had the underlying diagnoses: intestinal atresia, necrotizing enterocolitis, gastroschisis, and midgut volvulus. Multiple risk factors were assessed in these groups.No differences in residual small bowel length, presence of the colon, number of line infections, or number of central lines were found. The average body weight of the transplanted group trended higher, whereas the deceased group had more impairment of hepatic function. Intestinal atresia was the most common diagnosis in the deceased group while none of the transplanted group carried this diagnosis. Ileocecal valve was retained in 80% of the deceased group and in none of the transplanted group.In children younger than 18 months, risk factors affecting survival to intestinal transplantation include small body size and advanced liver disease. A primary diagnosis of intestinal atresia and the presence of the ileocecal valve may confer additional risk to these very young children.

    View details for DOI 10.1097/TP.0b013e31816dd236

    View details for Web of Science ID 000255904400012

    View details for PubMedID 18475185

  • Syk drives Epstein Barr virus-infected B cell lymphoma growth and survival through activation of the PI3K/Akt pathway Hatton, O., Lambert, S., Vaysberg, M., Sharman, J., Krams, S. M., Esquivel, C. O., Martinez, O. M. WILEY-BLACKWELL. 2008: 477-477
  • Non-adherence to post-transplant care: Prevalence, risk factors and outcomes in adolescent liver transplant recipients PEDIATRIC TRANSPLANTATION Berquist, R. K., Berquist, W. E., Esquivel, C. O., Cox, K. L., Wayman, K. I., Litt, I. F. 2008; 12 (2): 194-200


    This study examined the prevalence, demographic variables and adverse outcomes associated with non-adherence to post-transplant care in adolescent liver transplant recipients. We conducted a retrospective chart review of 111 adolescent patients (age 12-21 yr) greater than six months post-transplantation and defined non-adherence as not taking the immunosuppressive(s) or not attending any clinic visit in 2005. Fifty subjects (45.0%) were non-adherent and 61 (55.0%) were adherent. Twenty percent of the subjects did not attend clinic and 10.9% did not complete laboratory tests. Non-adherence was significantly associated with fewer completed laboratory tests (p < 0.0001), single parent status (p < 0.0186), and older age and greater years post-transplantation by both univariate and multivariate analyses (p < 0.008, p < 0.0141 and p < 0.0012, p < 0.0174, respectively). Non-adherence to medication was significantly associated with a rejection episode in 31 patients (p < 0.0069) but not in the subgroup of seven patients who stopped their immunosuppression completely. Non-adherence to post-transplant care is a prevalent problem in adolescents particularly of an older age and greater years post-transplantation. Rejection was a significant consequence of medication non-adherence except in a subgroup with presumed graft tolerance who discontinued their immunosuppression. These results emphasize the need for strict monitoring of adherence to post-transplant care to improve long-term survival and quality of life in adolescent transplant patients.

    View details for DOI 10.1111/j.1399-3046.2007.00809.x

    View details for Web of Science ID 000253637400013

    View details for PubMedID 18307668

  • Alloimmunization to red blood cell antigens affects clinical outcomes in liver transplant patients LIVER TRANSPLANTATION Boyd, S. D., Stenard, F., Lee, D. K., Goodnough, L. T., Esquivel, C. O., Fontaine, M. J. 2007; 13 (12): 1654-1661


    Transfusion therapy of liver transplant patients remains a challenge. High volumes of intraoperative blood transfusion have been shown to increase the risk of poor graft or patient survival. We conducted a retrospective study of 209 consecutive liver transplant cases at our institution. Only patients receiving their first liver transplant, with no other simultaneous organ transplants, were included. Cox proportional hazard modeling was used to identify clinical variables correlated with postoperative patient mortality. Statistically significant variables for poor patient survival were the number of red blood cell and plasma units transfused, a history of red blood cell alloantibodies, and the immunosuppressive regimen used. History of pregnancy also approached statistical significance but was less robust than the other 3 variables. Our findings suggest that blood transfusion and immune modulation greatly affect the survival of patients after liver transplantation.

    View details for DOI 10.1002/It.21241

    View details for Web of Science ID 000251574100007

    View details for PubMedID 18044783

  • Mutations to bid cleavage sites protect hepatocytes from apoptosis after ischemia/reperfusion injury TRANSPLANTATION Riddle-Taylor, E., Nagasaki, K., Lopez, J., Esquivel, C. O., Martinez, O. M., Krams, S. M. 2007; 84 (6): 778-785


    Apoptosis of hepatocytes contributes to many forms of liver pathology and can compromise liver function. Hepatocytes have been shown to require mitochondrial disruption to execute apoptosis, a process that is controlled by members of the Bcl-2 family. Bid is a proapoptotic Bcl-2 family member that is cleaved to its active form, tBid, by caspase 8 and granzyme B. Studies in the Bid-deficient mouse have established that hepatocytes require Bid to undergo apoptosis.We generated aspartic acid to glutamic acid mutations in the rat Bid protein, at the caspase 8 and granzyme B cleavage sites, and utilized recombinant adenoviruses to express this protein in hepatoma cells and in the livers of rats.Cells transduced with recombinant adenoviruses encoding Bid containing mutations to the caspase 8 and granzyme B cleavage sites are significantly protected from both tumor necrosis factor-alpha-induced and cell-mediated apoptosis. Protection occurs through a mechanism that includes decreased Bid cleavage, caspase activation, and mitochondrial membrane damage. Further, after warm ischemia/reperfusion injury, we show that rats expressing cleavage-resistant Bid in the liver display significantly less hepatocyte apoptosis as compared to control rat livers and this results in improved liver function and survival.Our results suggest that reagents that prevent the cleavage of Bid would be an effective strategy to inhibit hepatocyte apoptosis and decrease liver injury.

    View details for DOI 10.1097/

    View details for Web of Science ID 000249841700017

    View details for PubMedID 17893612

  • Liver allografts are toleragenic in rats conditioned with posttransplant total lymphoid irradiation TRANSPLANTATION Nagasaki, K., Obara, H., Xiong, A., Kambham, N., Strober, S., Esquivel, C. O., Millan, M. T. 2007; 84 (5): 619-628


    Posttransplant total lymphoid irradiation (TLI) treatment has been applied to tolerance induction protocols in heart and kidney transplantation models.We examined the efficacy and mechanism of posttransplant TLI treatment in the induction and maintenance of tolerance in a rat orthotopic liver transplantation model.Posttransplant TLI prolonged ACI (RT1(a)) liver allograft survival in Lewis (RT1(b)) hosts, with 50% long-term engraftment without immunosuppression and without evidence of chronic rejection. Injection of donor-type liver mononuclear cells (LMCs) facilitated the prolongation of graft survival, with more than 70% of grafts in LMC recipients surviving more than 100 days without chronic rejection. Recipients with long-term liver allograft survival accepted ACI but not PVG skin grafts. In TLI-conditioned recipients with accepted grafts, apoptosis occurred predominantly in graft-infiltrating leukocytes. In contrast, there were few apoptotic leukocytes in rejecting grafts. Recipients with long-term graft acceptance (>100 days of survival) demonstrated evidence of immune deviation; mixed lymphocyte reaction to ACI stimulator cells was vigorous, but secretion of interferon-gamma and interleukin-2 was reduced. In tolerant recipients, the number of Foxp3(+) CD25(+) CD4(+) regulatory T cells was increased in the liver allograft as well as in the peripheral blood.We conclude that posttransplant TLI induces tolerance to liver allografts via a mechanism involving apoptotic cell-deletion and immunoregulation.

    View details for DOI 10.1097/

    View details for Web of Science ID 000249574900009

    View details for PubMedID 17876275

  • Outcomes of transplantation in children with primary hepatic malignancy PEDIATRIC TRANSPLANTATION Beaunoyer, M., Vanatta, J. M., Oyihara, M., Strichartz, D., Dahl, G., Berquist, W. E., Castillo, R. O., Cox, K. L., Esquivel, C. O. 2007; 11 (6): 655-660


    HBL and HCC are the most common hepatic malignancies in children. The role of OLT in children with HCC is still a matter of debate. The aim of this study was to review our experience of OLT for HCC. Medical records of patients (<18 yr) who underwent OLT for HCC were reviewed and compared to children who underwent OLT for HBL and for indications other than malignancy. There were 25 patients: HCC (10 cases) and HBL (15 cases). The actuarial patient survival for HCC at one and five yr was 100% and 83.3%, for the HBL group the survival was 86.7% at both one and five yr, and for indications (n=377) other than malignancy the patient survival for pediatric OLT at our center was 87.7% and 84.7% at one and five yr, respectively. The actuarial recurrence free survival at five yr was 83.3% for HCC and 66.8% for HBL. In conclusion, OLT is a good therapeutic modality for children with HCC and HBL.

    View details for DOI 10.1111/j.1399-3046.2007.00751.x

    View details for Web of Science ID 000249004000015

    View details for PubMedID 17663690

  • EBV can protect latently infected B cell lymphomas from death receptor-induced apoptosis JOURNAL OF IMMUNOLOGY Snow, A. L., Lambert, S. L., Natkunam, Y., Esquivel, C. O., Krams, S. M., Martinez, O. M. 2006; 177 (5): 3283-3293


    The relationship between EBV infection and sensitivity to death receptor (DR)-induced apoptosis is poorly understood. Using EBV- and EBV+ BJAB cells, we provide the first evidence that EBV can protect latently infected B cell lymphomas from apoptosis triggered through Fas or TRAIL receptors. Caspase 8 activation was impaired and cellular FLIP recruitment was enriched in death-inducing signaling complexes formed in EBV-infected BJAB cells relative to parent BJAB cells. Furthermore, latent membrane protein 1 expression alone could reduce caspase activation and confer partial resistance to DR apoptosis in BJAB cells. This protective effect was dependent on C-terminal activating region 2-driven NF-kappaB activation, which in turn up-regulated cellular FLIP expression in latent membrane protein 1+ BJAB cells. Thus, the ability of latent EBV to block DR apoptosis may help to ensure the survival of host cells during B cell differentiation, and contribute to the development of B cell lymphomas, especially in immunocompromised individuals.

    View details for Web of Science ID 000240002800065

    View details for PubMedID 16920969

  • Pediatric intestinal transplantation at Packard children's hospital/Stanford University medical center: Report of a four-year experience TRANSPLANTATION PROCEEDINGS Castillo, R. O., Zarge, R., Cox, K., Strichartz, D., Berquist, W., Bonham, C. A., Esquivel, C. O. 2006; 38 (6): 1716-1717


    We report a 4-year experience of a new program in pediatric intestinal transplantation. Among 50 children referred for evaluation, 27 were listed for transplantation. Two children originally listed for combined liver/small bowel transplant were changed to isolated intestinal transplant as rehabilitation efforts resulted in full recovery of hepatic function. Eighteen children received 18 grafts: 12 liver/intestine, 5 isolated intestine, and 1 multivisceral. Mean age at transplant was 3.6 year with 75% of patients aged 0 to 2 years. Five listed children died while waiting and four were still on the list. Immunotherapy included antithymocyte globulin induction and tacrolimus, sirolimus, and prednisone maintenance. At 1 year, patient and graft survivals were 75% and 67%, respectively. For isolated intestine, 1 year survivals were 100% and 75%, while for combined liver/intestine, they were 71% for both. Enteral autonomy is 100% with total parenteral nutrition stopping by 35.8 days (mean). We had two patients develop posttransplant lymphoproliferative disorder and three, exfoliative rejection, one of whom recovered completely. In conclusion, our program in pediatric intestinal transplantation has become well established with a high proportion of smaller/younger children receiving grafts. Outcomes achieved levels expected based on The Intestinal Transplant Registry and UNOS criteria, which were better than expected for isolated intestinal transplants and achievement of enteral autonomy.

    View details for DOI 10.1016/j.transproceed.2006.05.038

    View details for Web of Science ID 000240051700022

    View details for PubMedID 16908259

  • Adolescent non-adherence: Prevalence and consequences in liver transplant recipients PEDIATRIC TRANSPLANTATION Berquist, R. K., Berquist, W. E., Esquivel, C. O., Cox, K. L., Wayman, K. I., Litt, I. F. 2006; 10 (3): 304-310


    Few studies have examined the prevalence, demographic variables and adverse consequences associated with non-adherence to immunosuppressive therapy in the adolescent liver transplant population. Our hypothesis is that a significant proportion of adolescent liver transplant recipients exhibit non-adherence to medical regimens and that certain demographic and medical condition-related characteristics can be identified as potential predictors of non-adherent behavior. Furthermore, non-adherence leads to a greater incidence of morbidity and mortality in this population as compared with the adherent subset of adolescent patients. We reviewed the charts of 97 patients from 1987 to 2002 who by December of 2002 had survived at least 1 yr post-transplant and were followed by the Pediatric Liver Transplant Service at any point during their adolescent period (ages of 12-21). Non-adherence was defined as documentation of a report of non-adherence by a patient, parent or healthcare provider that was recorded in the patient's legal medical record. Descriptive statistics were used to determine the prevalence, demographic variables and adverse outcomes associated with non-adherence to immunosuppressive therapy. Categorical variables were analyzed using the chi-square test or the Fisher exact probability test. The unpaired Student's t-test was used to analyze the continuous variable of age at transplant. Using the inclusion criteria, a total of 97 patients represented the study sample of whom 37 subjects (38.1%) were defined as non-adherent and 60 (61.8%) were adherent. Non-adherent subjects were more likely to be female, older (>18 yr) and from a single-parent household. There was no significant difference in immunosuppressive regimen between non-adherent and adherent patients. Non-adherence was significantly (p<0.025) associated with lower socioeconomic status (SES), older age at transplant (p<0.005, 95% CI: -5.5 to -.99, Student's t-test) and episodes of late acute rejection (p<.001). Non-adherence was also significantly associated with re-transplantation and death secondary to chronic rejection by the Fisher exact test (p<0.006 and p<0.05, respectively). Non-adherence to immunosuppressive therapy is a prevalent problem that is correlated with certain demographic and medical condition-related risk factors and more frequent adverse consequences in the adolescent liver transplant population. The greater incidence of late acute rejection, death and re-transplantation owing to chronic rejection in non-adherent patients suggests that non-adherence is significantly associated with an increased risk of morbidity and mortality. Further investigation to identify patients at greatest risk for non-adherence is necessary to design the most effective intervention to increase patient survival and well being.

    View details for DOI 10.1111/j.1399-3046.2005.00451.x

    View details for Web of Science ID 000237096700007

    View details for PubMedID 16677353

  • Improved pain management in pediatric postoperative liver transplant patients using parental education and non-pharmacologic interventions PEDIATRIC TRANSPLANTATION Sharek, P. J., Wayman, K., Lin, E., Strichartz, D., Sentivany-Collins, S., Good, J., Esquivel, C., Brown, M., Cox, K. 2006; 10 (2): 172-177


    A pain management intervention, consisting of pretransplant parental education and support, pre- and postoperative behavioral pediatrics consultation, postoperative physical and occupational therapy consultation, and implementation of non-pharmacologic pain management strategies, was introduced to all pediatrics patients receiving liver transplants at Lucile Packard Children's Hospital beginning August 2001. Children receiving transplants pre-intervention (May, 2000 to February, 2001) and post-intervention (August, 2001 to March, 2002) were compared using pain scores, parent perception of pain ratings, length of stay, ventilator days, total cost, and opioid use. A total of 27 children were evaluated (13 historical control, 14 intervention). The two populations did not differ on age at transplant (mean age 53.8 vs. 63.6 months), sex (46.1% vs. 50% male), ethnicity (53.8% vs. 57.1% white, non-Hispanic) weight at transplant (17.5 vs. 24.7 kg), percent with biliary atresia as the primary reason for transplant (42.9% vs. 69.2%), percent with status 1 transplant listing score (38.5% vs. 50.0%), or public insurance status (30.8 vs. 57.2% with Medicaid). No differences were found in mean pediatric intensive care unit (PICU) postoperative length of stay (6.7 vs. 5.3 days), total postoperative length of stay (17.5 vs. 17.5 days), total inpatient length of stay (27.0 vs. 24.4 days), time to extubation (30 vs. 24.3 h), total cost (dollar 147,983 vs. dollar 157,882) or opioid use through postoperative day (POD) 6 (0.24 vs. 0.25 mg/kg/day morphine equivalent). A decrease in mean pain score between POD 0 and 6 (2.82 vs. 2.12; p = 0.047), a decrease in mean parental pain perception score (3.1 vs. 2.1; p = 0.001), and an increase in number of pain assessments per 12 h shift (3.43 vs. 6.79; p < 0.005) were seen. A comprehensive non-pharmacologic postoperative pain management program in children receiving a liver transplant was associated with decreased pain scores, improved parent perception of pain, and an increased number of pain assessments per 12 h shift. No increases in lengths of stay (PICU, postoperative, total), time to extubation, or total cost were found.

    View details for DOI 10.1111/j.1399-3046.2005.00438.x

    View details for Web of Science ID 000236026400011

    View details for PubMedID 16573603

  • Keratins as susceptibility genes for end-stage liver disease GASTROENTEROLOGY Ku, N. O., Lim, J. K., Krams, S. M., Esquivel, C. O., Keeffe, E. B., Wright, T. L., Parry, D. A., Omary, M. B. 2005; 129 (3): 885-893


    Keratins 8 and 18 protect the liver from stress. Keratin 8 and 18 variants in 17 of 467 liver disease explants and 2 of 349 blood bank controls were previously reported in 5 analyzed exonic regions. We asked whether mutations were present in the remaining 10 exons of keratins 8 and 18.Exonic regions were polymerase chain reaction-amplified from genomic DNA, isolated from the above-mentioned 2 cohorts, and analyzed for the presence of mutations. Mutant keratins were also studied biochemically.We identified 10 novel keratin 8 and 18 heterozygous variants in 44 of 467 explants and 11 of 349 controls: keratin 18 deletion (delta64-71), a keratin 8 frameshift that truncates the last 14 amino acids; 8 missense keratin 8 and 18 alterations; and several new polymorphisms. The most common variant, keratin 8 R340H, at the highly conserved R340 was found in 30 of 467 explants and 10 of 349 controls (P = .02) and was confirmed in the diseased livers by generation of an R340H-specific antibody. Germline transmission and variant protein expression were verified. The mutations involved a variety of liver diseases, and some variants had an ethnic background preponderance. Mutations that introduced disulfide bonds (keratin 8 G61C or R453C) decreased keratin solubility, particularly after oxidative stress, whereas others decreased keratin 8 phosphorylation (keratin 8 G433S).The overall frequency of keratin 8 and 18 variants was 12.4% in 467 liver disease explants and 3.7% in 349 blood bank controls (P < .0001). Variants can alter keratin solubility or phosphorylation and may render individuals susceptible to end-stage liver disease, depending on their genetic background and exposure to other insults, such as alcohol or viral infection.

    View details for DOI 10.1053/j.gastro.2005.06.065

    View details for Web of Science ID 000231816500016

    View details for PubMedID 16143128

  • IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses AMERICAN JOURNAL OF TRANSPLANTATION Obara, H., Nagasaki, K., Hsieh, C. L., Ogura, Y., Esquivel, C. O., Martinez, O. M., Krams, S. M. 2005; 5 (9): 2094-2103


    The role of NK cells following solid organ transplantation remains unclear. We examined NK cells in acute allograft rejection using a high responder model (DA-->Lewis) of rat orthotopic liver transplantation. Recipient-derived NK cells infiltrated liver allografts early after transplantation. Since chemokines are important in the trafficking of cells to areas of inflammation, we determined the intragraft expression of chemokines known to attract NK cells. CCL3 was significantly increased in allografts at 6 h post-transplant as compared to syngeneic grafts whereas CCL2 and CXCL10 were elevated in both syngeneic and allogeneic grafts. CXCL10 and CX3CL1 were significantly upregulated in allografts by day 3 post-transplant as compared to syngeneic grafts suggesting a role for these chemokines in the recruitment of effector cells to allografts. Graft-infiltrating NK cells were shown to be a major source of IFN-gamma, and IFN-gamma levels in the serum were markedly increased, specifically in allograft recipients, by day 3 post-transplant. Accordingly, in the absence of NK cells the levels of IFN-gamma were significantly decreased. Furthermore, graft survival was significantly prolonged. These data suggest that IFN-gamma-producing NK cells are an important link between the innate and adaptive immune responses early after transplantation.

    View details for DOI 10.1111/j.1600-6143.2005.00995.x

    View details for Web of Science ID 000231023700003

    View details for PubMedID 16095488

  • Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation PEDIATRIC TRANSPLANTATION Hurwitz, M., Desai, D. M., Cox, K. L., Berquist, W. E., Esquivel, C. O., Millan, M. T. 2004; 8 (3): 267-272


    Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients is associated with a high mortality (up to 60%) and the younger age groups, who are predominantly EBV-naïve, are at highest risk for development of this disease. The aim of this study is to assess, in this high-risk group, patient outcome and graft loss to rejection when complete withdrawal of immunosuppressive agents (IMS) is instituted as the mainstay of treatment in addition to the use of standard therapy. A retrospective analysis of 335 pediatric patients whose liver transplants were performed by our team between September 1988 and September 2002, was carried out through review of computer records, database and patient charts. Fifty patients developed either EBV or PTLD; 80% were < or =2 yr of age. Of these 50 patients, 19 had a positive tissue diagnosis for PTLD and 31 were diagnosed with EBV infection, 14 of whom had positive tissue for EBV. Fifty-eight percent of patients who developed PTLD and 51.6% of patients with EBV received antibody for induction or treatment of rejection prior to onset of disease. Forty-six patients (92%) received post-transplant antiviral prophylaxis with ganciclovir or acyclovir. Antiviral treatment included ganciclovir in 76%, acyclovir in 20% and Cytogam (in addition to one of the former agents) in 44%. In those with PTLD, treatment included chemotherapy (n = 1), Rituximab (n = 2), and ocular radiation (n = 1). IMS was stopped in all patients with PTLD and in 19 with EBV infection and was held as long as there was no allograft rejection. Eight patients have remained off IMS for a mean of 1535.5 +/- 623 days. Of the 21 patients who were restarted on IMS for acute rejection, 18 responded to steroids and/or reinstitution of low-dose calcineurin inhibitors. The mean time to rejection while off IMS in this group was 107.43 +/- 140 days (range: 7-476). Two patients were re-transplanted for chronic rejection; one had chronic rejection that existed prior to discontinuing IMS. The mortality rate in our series was 31.6% in those with PTLD and 6% in those with EBV disease. The cause of death was related to PTLD or sepsis in all cases; no deaths were due to graft loss from acute or chronic rejection. PTLD is associated with high mortality in the pediatric population. Based on this report, we advocate aggressive management of PTLD that is composed of early cessation of IMS, the use of antiviral therapy, and chemotherapy when indicated. Episodes of rejection that occur after stopping IMS can be successfully treated with standard therapy without graft loss to acute rejection.

    View details for Web of Science ID 000221693200014

    View details for PubMedID 15176965

  • Our new president - Emmet B Keeffe, MD GASTROENTEROLOGY Omary, M. B., Esquivel, C. O. 2004; 126 (5): 1454-1460

    View details for DOI 10.1053/j.gastro.2004.03.031

    View details for Web of Science ID 000221217100026

    View details for PubMedID 15131805

  • One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: A single-center experience TRANSPLANTATION Millan, M. T., Berquist, W. E., So, S. K., Sarwal, M. M., Wayman, K. I., Cox, K. L., Filler, G., Salvatierra, O., Esquivel, C. O. 2003; 76 (10): 1458-1463


    Combined liver-kidney transplantation is the definitive treatment for end-stage renal disease caused by primary hyperoxaluria type I (PH1). The infantile form is characterized by renal failure early in life, advanced systemic oxalosis, and a formidable mortality rate. Although others have reported on overall results of transplantation for PH1 covering a wide age spectrum, none has specifically addressed the high-risk infantile form of the disease.Six infants with PH1 underwent simultaneous liver-kidney transplantation at our center between May 1994 and August 1998. Diagnosis was made at 5.2+/-3.3 months of age, they were on dialysis for 11.8+/-2.3 months, and they underwent transplantation at 14.8+/-3.0 months of age when they weighed 10.6+/-1.7 kg.At a mean follow-up of 6.4+/-1.7 years (range, 3.9-8.1 years), we report 100% patient and kidney allograft survival. There were no cases of acute tubular necrosis. Long-term kidney allograft function remained stable in all patients, with serum creatinine values of less than 1.1 mg/dL and a mean creatinine clearance of 99 mL/min/1.73 m2 at follow-up. Those who received combined hemodialysis and peritoneal dialysis pretransplant had lower posttransplant urinary oxalate values than those receiving peritoneal dialysis alone. There was improvement in growth and psychomotor and mental developmental scores after transplantation.Combined liver-kidney transplantation for the infantile presentation of PH1 is associated with excellent outcome when the approach includes early diagnosis and early combined transplantation, aggressive pretransplant dialysis, and avoidance of posttransplant renal dysfunction.

    View details for DOI 10.1097/01.TP.0000084203.76110.AC

    View details for Web of Science ID 000186833400014

    View details for PubMedID 14657686

  • Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ku, N. O., Darling, J. M., Krams, S. M., Esquivel, C. O., Keeffe, E. B., Sibley, R. K., Lee, Y. M., Wright, T. L., Omary, M. B. 2003; 100 (10): 6063-6068


    Keratin 8 and 18 (K8K18) mutations are found in patients with cryptogenic cirrhosis, but the role of keratin mutations in noncryptogenic cirrhosis and the incidence of keratin mutations in the general population are not known. We screened for K8K18 mutations in genomic DNA isolated from 314 liver explants of patients who primarily had noncryptogenic cirrhosis, and from 349 blood bank volunteers. Seven unique K8K18 mutations were found in 11 independent patients with biliary atresia, hepatitis BC, alcohol, primary biliary cirrhosis, and fulminant hepatitis. Seven of the 11 patients had mutations previously described in patients with cryptogenic cirrhosis: K8 Tyr-53 --> His, K8 Gly-61 --> Cys, and K18 His-127 --> Leu. The four remaining patients had mutations at one K8 and three other K18 new sites. Of the 349 blood bank control samples, only one contained the Tyr-53 --> His and one the Gly-61 --> Cys K8 mutations (P < 0.004 when comparing cirrhosis versus control groups). Two additional mutations were found in both the liver disease and blood bank groups and, hence, likely represent polymorphisms. Livers with keratin mutations had cytoplasmic filamentous deposits that were less frequent in livers without the mutations (P = 0.03). Therefore, K8K18 are likely susceptibility genes for developing cryptogenic and noncryptogenic forms of liver disease.

    View details for DOI 10.1073/pnas.0936165100

    View details for Web of Science ID 000182939400089

    View details for PubMedID 12724528

  • Identification of Epstein-Barr virus-specific CD8(+) T lymphocytes in the circulation of pediatric transplant recipients TRANSPLANTATION Falco, D. A., Nepomuceno, R. R., Krams, S. M., Lee, P. P., DAVIS, M. M., Salvatierra, O., Alexander, S. R., Esquivel, C. O., Cox, K. L., Frankel, L. R., Martinez, O. M. 2002; 74 (4): 501-510


    Pediatric transplant recipients are at increased risk for Epstein Barr virus (EBV)-related B cell lymphomas. In healthy individuals, the expansion of EBV-infected B cells is controlled by CD8+ cytotoxic T cells. However, immunosuppressive therapy may compromise antiviral immunity. We identified and determined the frequency of EBV-specific T cells in the peripheral blood of pediatric transplant recipients.HLA-B*0801 and HLA-A*0201 tetramers folded with immunodominant EBV peptides were used to detect EBV-specific CD8+ T cells by flow cytometry in peripheral blood mononuclear cells from 24 pediatric liver and kidney transplant recipients. The expression of CD38 and CD45RO on EBV-specific, tetramer-binding cells was also examined in a subset of patients by immunofluorescent staining and flow cytometry.Tetramer-binding CD8+ T cells were identified in 21 of 24 transplant recipients. EBV-specific CD8+ T cells were detected as early as 4 weeks after transplant in EBV seronegative patients receiving an organ from an EBV seropositive donor. The frequencies (expressed as a percentage of the CD8+ T cells) of the tetramer-binding cells were HLA-B8-RAKFKQLL (BZLF1 lytic antigen peptide) tetramer, range=0.96 to 3.94%; HLA-B8-FLRGRAYGL (EBNA3A latent antigen peptide) tetramer, range=0.03 to 0.59%; and HLA-A2-GLCTLVAML (BMLF1 lytic antigen peptide) tetramer, range=0.06 to 0.76%. The majority of tetramer reactive cells displayed an activated/memory phenotype.Pediatric transplant recipients receiving immunosuppression can generate EBV-specific CD8+ T cells. Phenotypic and functional analysis of tetramer cells may prove useful in defining and monitoring EBV infection in the posttransplant patient.

    View details for Web of Science ID 000177808600012

    View details for PubMedID 12352909

  • Thirteen years' experience in pediatric liver transplantation: Differences between tacrolimus and cyclosporine TRANSPLANTATION PROCEEDINGS Zajicek, A., Esquivel, C., MILLAN, M., Cox, K., Berquist, R., Berquist, W. 2002; 34 (5): 1976-1978

    View details for Web of Science ID 000177369700254

    View details for PubMedID 12176653

  • Liver transplantation for fulminant hepatitis at Stanford University JOURNAL OF GASTROENTEROLOGY Lu, A., Monge, H., Drazan, K., MILLAN, M., Esquivel, C. O. 2002; 37: 82-87


    To review the clinical characteristics and outcomes of 26 patients evaluated for liver transplantation for fulminant hepatic failure at Stanford University and Lucile Packard Children's Hospital in an attempt to identify risk factors and prognostic predictors of survival.A retrospective review of the records of 26 consecutive patients who were evaluated for possible liver transplantation for acute liver failure from May 1, 1995, to January 1, 2000. Pretransplant patient demographics and clinical characteristics were collected, and the data were analyzed by univariate and multivariate analysis.Clinical assessment of encephalopathy did not predict outcome. Patients with abnormal computed tomography (CT) of the brain had a twofold increase in mortality compared with those patients with normal studies (p = 0.03). Patients requiring mechanical ventilation and continuous venovenous hemofiltration (CVVH) also had a poor prognosis.Predictors of poor outcome after fulminant hepatic failure include abnormal CT scan, mechanical ventilation, and requirement for hemofiltration.

    View details for Web of Science ID 000176596300017

    View details for PubMedID 12109673

  • Epstein-Barr virus infection is associated with endothelial bcl-2 expression in transplant liver allografts TRANSPLANTATION Millan, M. T., Natkunam, Y., Clarke-Katzenberg, R., Desai, D., Prapong, W., So, S. K., Esquivel, C. O., Sibley, R., Ferran, C., Martinez, O. M. 2002; 73 (3): 465-469


    In liver transplant recipients with Epstein-Barr virus (EBV) disease, we reported a low rate of acute rejection after stopping or markedly lowering immunosuppression. This observation led to the hypothesis that EBV, as a means of viral persistence, induces expression of antiapoptotic factors and these factors, in turn, confer protection to the transplanted organ. Bcl-2, an antiapoptotic factor induced by EBV in various host cells, is not normally expressed in the liver. We questioned whether bcl-2 is expressed in the transplanted liver and whether its expression is modified by EBV.Retrospective liver biopsy specimen from liver transplant patients diagnosed with EBV (n=12) were examined for the presence of bcl-2 by immunohistochemistry and compared with EBV (-) transplant (n=15), and nontransplant (n=13) livers.The most significant finding was the presence of endothelial bcl-2 expression in the majority of EBV (+) transplant samples examined (67%) and its relative absence in the other two groups (P<0.005). There was also bcl-2 expression in the hepatocytes and lymphocytes of the majority of transplant liver samples, irrespective of EBV status.We have identified a strong association between EBV infection and endothelial bcl-2 expression in transplant livers. We also found that transplantation, in itself, was associated with bcl-2 expression in the hepatocytes and lymphocytes of liver allografts.

    View details for Web of Science ID 000174115400023

    View details for PubMedID 11884946

  • Resistance to Fas-mediated apoptosis in EBV-infected B cell lymphomas is due to defects in the proximal Fas signaling pathway JOURNAL OF IMMUNOLOGY Snow, A. L., Chen, L. J., Nepomuceno, R. R., Krams, S. M., Esquivel, C. O., Martinez, O. M. 2001; 167 (9): 5404-5411


    Post-transplant lymphoproliferative disorder is characterized by the outgrowth of EBV-infected B cell lymphomas in immunosuppressed transplant recipients. Using a panel of EBV-infected spontaneous lymphoblastoid cell lines (SLCL) derived from post-transplant lymphoproliferative disorder patients, we assessed the sensitivity of such lymphomas to Fas-mediated cell death. Treatment with either an agonist anti-Fas mAb or Fas ligand-expressing cells identifies two subsets of SLCL based on their sensitivity or resistance to Fas-driven apoptosis. Fas resistance in these cells cannot be attributed to reduced Fas expression or to mutations in the Fas molecule itself. In addition, all SLCL are sensitive to staurosporine-induced cell death, indicating that there is no global defect in apoptosis. Although all SLCL express comparable levels of Fas signaling molecules including Fas-associated death domain protein, caspase 8, and caspase 3, Fas-resistant SLCL exhibit a block in Fas-signaling before caspase 3 activation. In two SLCL, this block results in impaired assembly of the death-inducing signaling complex, resulting in reduced caspase 8 activation. In a third Fas-resistant SLCL, caspase 3 activation is hindered despite intact death-inducing signaling complex formation and caspase 8 activation. Whereas multiple mechanisms exist by which tumor cells can evade Fas-mediated apoptosis, these studies suggest that the proximal Fas-signaling pathway is impeded in Fas-resistant post-transplant lymphoproliferative disorder-associated EBV(+) B cell lymphomas.

    View details for Web of Science ID 000171858500080

    View details for PubMedID 11673559

  • Apoptosis and allograft rejection in the absence of CD8(+) T cells TRANSPLANTATION Ogura, Y., Martinez, O. M., Villanueva, J. C., Tait, J. F., Strauss, H. W., Higgins, J. P., Tanaka, K., Esquivel, C. O., Blankenberg, F. G., Krams, S. M. 2001; 71 (12): 1827-1834


    The requirement for cytotoxic T lymphocytes during allograft rejection is controversial. We previously demonstrated that CD8+ T cells are not necessary for allograft rejection or for the induction of apoptosis in rat small intestinal transplantation. In this study, we examined the mechanisms of apoptosis and rejection after liver transplantation in the absence of CD8+ T cells.Either Lewis or dark agouti rat liver grafts were transplanted into Lewis recipients to create syngeneic and allogeneic combinations. CD8+ T cells were depleted in an additional allogeneic group by treatment with OX-8 mAb on day -1 and day 1 after liver transplant.Apoptosis and rejection were observed in both the CD8+ T cell-depleted allogeneic and allogeneic grafts by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and radiolabeled-annexin V in vivo imaging. Granzyme B and FasL were expressed in all allogeneic transplants, including those depleted of CD8+ T cells, indicating that a mononuclear cell other than a CD8+ T cell can be the source of these molecules during allograft rejection. Activation of the caspase cascade was detected in all rejecting allografts. Caspases 3, 8, and 9 were activated at similar significantly elevated levels in both allogeneic and CD8+ T cell-depleted liver grafts.These data indicate that in the absence of CD8+ T cells an alternative pathway, associated with granzyme B and FasL expression and activation of the caspase cascade, can mediate apoptosis and graft rejection.

    View details for Web of Science ID 000169753800020

    View details for PubMedID 11455265

  • Mortality rate correlated with the number of pediatric liver transplants performed at a center Cox, K., Rodriguez-Baez, N., Nasr, A., Esquivel, C. ELSEVIER SCIENCE INC. 2001: 1512-1513

    View details for Web of Science ID 000167629900707

    View details for PubMedID 11267400

  • Center experience in liver transplantation for hepatocellular carcinoma associated with cirrhosis Lai, K. M., MILLAN, M., Razavi, M., Keeffe, E. B., Prapong, W., Fisher, G. A., Esquivel, C. O., So, S. K. ELSEVIER SCIENCE INC. 2001: 1490-1491

    View details for Web of Science ID 000167629900694

    View details for PubMedID 11267387

  • Liver transplantation for hepatocellular carcinoma and the role of preoperative chemoembolization. Millan, M. T., Lai, K. M., Keeffe, E. B., Fisher, G. A., Razavi, M. K., Prapong, W., Barry, C. T., Esquivel, C. O., So, S. K. LIPPINCOTT WILLIAMS & WILKINS. 2000: S215-S215
  • Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Claure, R. E., Drover, D. D., Haddow, G. R., Esquivel, C. O., Angst, M. S. 2000; 47 (4): 334-337


    To report the anesthetic management of a patient with carcinoid tumour metastatic to the liver who presented for orthotopic liver transplantation. Anesthetic implications of metastatic carcinoid tumour on liver transplantation and the use of octreotide are discussed.A 51-yr-old woman with intestinal carcinoid tumour metastatic to the liver presented for orthotopic liver transplantation, a recent treatment option for patients with extensive hepatic carcinoid metastases and disabling symptoms unresponsive to conventional therapy. Despite continuous administration of the somatostatin analogue octreotide via a hepatic artery infusate pump, the patient suffered from daily break through symptoms, which included flushing, palpitations, paroxysmal hypertension, and dyspnea. The patient presented to the operating room with sinus tachycardia and severe arterial hypertension. Octreotide and phentolamine were used to prevent further mediator release and to control the paroxysmal hypertension. Midazolam, fentanyl, thiopental, succinylcholine, vecuronium, and isoflurane were used to induce and maintain anesthesia safely. An intravenous octreotide infusion was initiated after induction and continued throughout the case. Infrequent and non-threatening peaks in arterial blood pressure were readily treated with small intravenous doses of vasoactive drugs and octreotide. No other manifestations of the carcinoid syndrome occurred. The patient had an uneventful recovery and was discharged on postoperative day #6.The patient safely underwent orthotopic liver transplantation for treatment of symptomatic carcinoid tumour metastatic to the liver. The anesthetic management followed recent recommendations favouring the use of octreotide to prevent patients from becoming symptomatic. Outlined dosing regimen for octreotide provided satisfactory hemodynamic stability.

    View details for Web of Science ID 000089776300009

    View details for PubMedID 10764178

  • Radiolabeled annexin V imaging: Diagnosis of allograft rejection in an experimental rodent model of liver transplantation RADIOLOGY Ogura, Y., Krams, S. M., Martinez, O. M., Kopiwoda, S., Higgins, J. P., Esquivel, C. O., Strauss, H. W., Tait, J. F., Blankenberg, F. G. 2000; 214 (3): 795-800


    To assess the value of imaging rejection-induced apoptosis with technetium 99m and annexin V, a human protein-based radiopharmaceutical used in the diagnosis of acute rejection of a liver transplant, in a well-characterized rodent model of orthotopic liver transplantation.99mTc-radiolabeled annexin V was intravenously administered to six allografted (immunologically mismatched) and five isografted (immunologically matched) recipient rats on days 2, 4, and 7 after orthotopic liver transplantation. Animals were imaged 1 hour after injection of 0.2-2.0 mCi (8.0-74.0 MBq) of radiolabeled annexin V by use of clinical nuclear scintigraphic equipment.All animals in the allografted group demonstrated marked increases of 55% and 97% above the activity in the isografted group in hepatic uptake of annexin V on days 4 and 7, respectively. Severe acute rejection was histologically detected in all allografted livers on day 7. There was no histologic evidence of acute rejection in isografted animals. Dynamic hepatobiliary imaging with 99mTc and mebrofenin, an iminodiacetic acid derivative, demonstrated no correlation with the presence or absence of acute rejection or with annexin V uptake.Noninvasive imaging with radiolabeled annexin V is more sensitive and specific than imaging with 99mTc-mebrofenin in the diagnosis of acute rejection of a liver transplant.

    View details for Web of Science ID 000085478800029

    View details for PubMedID 10715048

  • Significance of detecting Epstein-Barr-Specific sequences in the peripheral blood of asymptomatic pediatric liver transplant recipients Krieger, N. R., Martinez, O. M., Krams, S. M., Cox, K., So, S., Esquivel, C. O. JOHN WILEY & SONS INC. 2000: 62-66


    Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)-associated illnesses. The early identification and diagnosis of EBV-associated disorders is critical because disease progression can often be curtailed by modification of immunosuppression. We have previously shown that detection of EBV-specific sequences in the circulation by polymerase chain reaction (PCR) correlated well with the clinical symptoms of EBV infection. The purpose of the current study is to determine the significance of detecting EBV-specific sequences by PCR in asymptomatic pediatric liver transplant recipients. Peripheral-blood DNA was analyzed for the EBV genes, coding from the nuclear antigen 1 (EBNA-1) and the viral capsid antigen (gp220) by PCR. Samples from asymptomatic pediatric liver transplant recipients were analyzed from the immediate postoperative period and at 2- to 4-month intervals thereafter. We followed up 13 of these asymptomatic recipients who tested positive for EBV compared with 7 asymptomatic recipients who tested negative for EBV during the early posttransplantation period. Follow-up ranged from 1.5 to 4 years posttransplantation. Nine patients (69%) initially positive for EBV and asymptomatic ultimately developed symptoms of EBV infection, including fever, lymphadenopathy, rash, respiratory and gastrointestinal symptoms, and/or hepatitis. Five of these patients (56%) went on to develop posttransplant lymphoproliferative disorder based on histological examination of biopsied tissue and immunohistochemical identification of the EBV antigen/DNA in tissue. This is the first report suggesting that detection of EBV-specific sequences in the absence of symptoms may herald impending EBV-associated disorders. Thus, routine monitoring for circulating EBV sequences in asymptomatic recipients may be useful in the early identification of those at risk for developing EBV-associated disease and its ultimate prevention.

    View details for Web of Science ID 000085673100008

    View details for PubMedID 10648579

  • Major hepatic resection without blood transfusion: Experience with total vascular exclusion So, S. K., Monge, H., Esquivel, C. O. WILEY-BLACKWELL PUBLISHING, INC. 1999: S28-S31


    Thirty consecutive, major liver resections performed with total vascular exclusion in both non-cirrhotic and cirrhotic patients were analysed retrospectively. The patients' ages ranged from 6 months to 80 years. Ten were Asians and five had cirrhosis associated with chronic hepatitis B or C. There was no perioperative death and the mean hospital stay was 6 days for adults and 9.2 days for children. The average vascular exclusion or warm ischaemia time was 25 min (range 10-55 min) and the average intraoperative blood volume given was 275 mL (range 0-3000 mL) packed red blood cells. Sixty per cent required no intraoperative blood transfusion. The mean total bilirubin and aspartate aminotransferase were 1.0 mg/dL (range 0.3-2.3 mg/dL) and 84 IU/L (range 14-306 IU/L) when measured prior to discharge at postoperative day 4-7. In our experience, total vascular exclusion is invaluable in major or difficult liver resections, especially lesions adjacent to the hepatic veins and vena cava. It is associated with a low blood transfusion requirement and a low incidence of complications. It further obviates the need for dissection of the porta hepatis and its associated risks. Total vascular exclusion time of 30 min appears to be well tolerated, even in patients with compensated cirrhosis.

    View details for Web of Science ID 000081033600007

    View details for PubMedID 10382635

  • Does Asian race affect hepatitis B virus recurrence or survival following liver transplantation for hepatitis B cirrhosis? So, S. K., Esquivel, C. O., Imperial, J. C., Garcia, G., Monge, H., Keeffe, E. B. WILEY-BLACKWELL PUBLISHING, INC. 1999: S48-S52


    To assess whether Asian race is an independent variable affecting survival and hepatitis B virus (HBV) recurrence after liver transplantation, the results of 27 consecutive liver transplants performed between June 1994 and April 1997 for HBV cirrhosis were analysed. In the group of 13 Asians, 38% had associated hepatocellular carcinoma and 62% had positive hepatitis B virus early antigen (HBeAg) or elevated HBV-DNA before transplant. Prophylactic hepatitis B immunoglobulin (HBIG) was administered perioperatively and long term at 4-6 weekly interval. Four patients with elevated HBV-DNA received lamivudine before transplantation. The 3 year actuarial patient survival rate was 100% in both Asian and non-Asian patients. Twenty-six patients remained seronegative for hepatitis B virus surface antigen after transplantation. The incidence of post-transplant HBV recurrence was similar: 0% in Asians compared with 7% in non-Asians. There was no recurrence in the group of 12 patients who were HBV-DNA or HBeAg negative pretransplant.

    View details for Web of Science ID 000081033600011

    View details for PubMedID 10382639

  • Resection versus transplantation for hepatocellular carcinoma Esquivel, C. O., Keeffe, E. B., Garcia, G., Imperial, J. C., Millan, M. T., Monge, H., So, S. K. WILEY-BLACKWELL PUBLISHING, INC. 1999: S37-S41


    Hepatocellular carcinoma is responsible for more than 1 million deaths per year worldwide and thus remains a challenging medical problem. It causes few or no symptoms and the tumour frequently reaches an enormous size by the time of diagnosis in countries where screening is seldom used. It is generally resistant to commercially available anti-neoplastic agents and radiation therapy. The principal treatment continues to be resection, either partial or complete, with liver transplantation. However, less than one-third of patients are surgical candidates for either resection or transplantation at the time of clinical presentation. This review will address the results observed following resection or transplantation for hepatocellular carcinoma.

    View details for Web of Science ID 000081033600009

    View details for PubMedID 10382637

  • Long-term outcomes in pediatric liver recipients: comparison between cyclosporin A and tacrolimus. Pediatric transplantation Cao, S., Cox, K. L., Berquist, W., Hayashi, M., Concepcion, W., Hammes, G. B., Ojogho, O. K., So, S. K., Frerker, M., Castillo, R. O., Monge, H., Esquivel, C. O. 1999; 3 (1): 22-26


    In recent years, tacrolimus (FK506, TAC) has been increasingly utilized in liver transplantation. However, long-term risks and benefits as compared with conventional cyclosporin A (CsA) have not been fully elucidated. This retrospective study examined the potential outcome differences between TAC- and CsA-based immunosuppressive therapy in pediatric liver transplant recipients. From March 1988 to December 1996, 218 children (aged 0.1-17 yr) underwent 238 orthotopic liver transplantations; 58.7% (128/218) were under 2 yr of age at time of transplant. Initially, the maintenance immunosuppressive regimen consisted of CsA and prednisone, with antilymphocytic preparations (MALG, ATGAM, and OKT3) as induction therapy. Subsequently, TAC was used first as rescue therapy for steroid refractory rejection in CsA patients and then as maintenance immunosuppression. Fifty-seven out of the 147 CsA patients were converted to TAC for various reasons while 71 patients were placed on TAC as primary maintenance immunosuppression. 62.6 per cent (92/147) of liver recipients on CsA experienced at least one biopsy-proven acute rejection episode as compared to 50.7% (36/71) for TAC patients (p = 0.09); likewise, 34% (50/147) of CsA patients had more than one episode of rejection vs. 18.3% (13/71) for patients on TAC (p < 0.02). Rejection was the reason for conversion from CsA to TAC in 29 of 57 patients. Conversely, 19.0% (28/147) of CsA patients had to be switched to TAC for reasons not related to rejection (i.e. side-effects). The overall incidence of histologically proven chronic rejection was 7.8% (17/218). 10.9 per cent (16/147) of the children who were on CsA initially developed chronic rejection, which was significantly higher compared with one of 71 TAC recipients (p < 0.02). Of these 16 CsA patients with chronic rejection, 50.0% (8/16) underwent retransplantation for graft failure (mean interval from time of diagnosis of chronic rejection to re-transplant, 4.0 months; range 1-8 months), whereas the TAC patient has remained clinically stable with normal liver function tests after 23 months of follow-up. One year after liver transplantation, 72.8% (107/147) of CsA patients were still on steroids (mean dosage 0.20 mg/kg/d), as compared to 42.3% (30/71) of the TAC patients (mean dosage 0.14 mg/kg/d). The incidence of post-transplant lymphoproliferative disorder (PTLD) in Epstein-Barr virus (EBV)-infected patients was 2.2% (2/90), 7.0% (5/71) and 12.3% (7/57) for CsA, primary and TAC-converted groups, respectively. The overall incidence of PTLD was 6.9% (15/218). In summary, pediatric liver transplant recipients treated with TAC as primary maintenance immunosuppressive medication experienced significantly fewer episodes of rejection; especially chronic rejection, which lead to graft loss. However, the trade-off is a potential increased incidence of EBV-related PTLD in these patients.

    View details for PubMedID 10359027

  • Effect of intraoperative blood transfusion on patient outcome in hepatic transplantation ARCHIVES OF SURGERY Cacciarelli, T. V., Keeffe, E. B., Moore, D. H., BURNS, W., Busque, S., Concepcion, W., So, S. K., Esquivel, C. O. 1999; 134 (1): 25-29


    To evaluate the effect of intraoperative transfusion of red blood cells (RBCs) on patient and graft survival.A retrospective study.A tertiary care referral center.Between January 1, 1992, and December 31, 1994, medical records from 225 adult patients who underwent primary liver transplantations were analyzed.Overall patient survival was 90% at 1 year and 86% at 3 years, while graft survival was 89% at 1 year and 85% at 3 years. The following factors were associated with patient and graft survival: age, sex, medical condition at the time of transplantation, and intraoperative transfusion of RBCs. When these factors were subjected to a multivariate analysis, all were independently associated with survival. Fifty-four recipients (24%) underwent transplantation without intraoperative transfusion of RBCs, while 171 recipients (76%) received at least 1 U of RBCs intraoperatively. Recipients who did not receive transfusion of RBCs had higher patient and graft survival rates than patients who did receive RBCs. By multivariate analysis, transplantation without intraoperative transfusion of RBCs no longer remained statistically significant, and only sex and the patient's medical condition were independently associated with patient and graft survival. Patient and graft survival decreased if 5 or more U were transfused, but transfusion of 5 or more U was not independently associated with survival by multivariate analysis.Increased transfusion requirement for RBCs was independently associated with patient and graft survival. While transplantation without transfusion of intraoperative RBCs was associated with superior patient and graft survival, these effects were overridden by patient sex and medical condition at the time of transplantation.

    View details for Web of Science ID 000078053500006

    View details for PubMedID 9927126

  • Increased dosage requirement and rejection after neoral conversion in pediatric liver transplant patients TRANSPLANTATION PROCEEDINGS Cao, S., Cox, K. L., Berquist, W., So, S., Concepcion, W., Monge, H., Esquivel, C. O. 1998; 30 (8): 4322-4324

    View details for Web of Science ID 000077593000129

    View details for PubMedID 9865373

  • Posttransplant lymphoproliferative disorders and gastrointestinal manifestations of Epstein-Barr virus infection in children following liver transplantation TRANSPLANTATION Cao, S., Cox, K., Esquivel, C. O., Berquist, W., Concepcion, W., Ojogho, O., Monge, H., Krams, S., Martinez, O., So, S. 1998; 66 (7): 851-856


    Epstein-Barr virus (EBV) infection is common after liver transplantation in children and is associated with the risk of posttransplant lymphoproliferative disorders (PTLD).This retrospective study examined the frequency of gastrointestinal (GI) symptoms and the risk of PTLD in pediatric liver recipients who developed symptomatic EBV infection. We reviewed 172 children who received orthotopic liver transplants between March 1988 to December 1994. Twenty-two cases were retransplants. The mean age at transplantation was 3.7 years (range, 0.1-17 years). The immunosuppressive regimens consisted of induction therapy with Minnesota antilymphocyte globulin/antithymocyte globulin/OKT3 in most cases and maintenance therapy with prednisone and either cyclosporine or tacrolimus (FK506).After 1 year of minimum follow-up, 54 of 172 patients had symptomatic EBV infections (confirmed by serology, histology, or whole blood polymerase chain reaction. At the time of infection, 38.5% (21/54) had either diarrhea or GI bleeding or both. PTLD developed in 11 patients (6.4%). The incidence of PTLD was 42.9% (9/21) when GI bleeding or diarrhea was associated with EBV infections, compared with 6.1% (2/33) when EBV infection was not associated with GI symptoms. Seven of 10 (70%) patients with GI bleeding and 2 of 11 (18.2%) with diarrhea developed PTLD. Of seven patients examined by endoscopy for GI bleeding, two had biopsy-proven PTLD of the GI tract, whereas one of two patients examined by endoscopy for diarrhea had biopsy-proven PTLD.In summary, a high incidence of PTLD was found in patients who developed GI bleeding or diarrhea associated with EBV infection after pediatric liver transplantation. In these patients, endoscopy and biopsy may lead to early diagnosis of PTLD.

    View details for Web of Science ID 000076585400007

    View details for PubMedID 9798693

  • Combined viral prophylactic and immunosuppressive strategy in liver transplantation (OLT) for HBV cirrhosis So, S. K., Esquivel, C. O., Imperial, J. C., Garcia, G., Keeffe, E. B. WILEY-BLACKWELL. 1998: 346A-346A
  • Liver transplantation in the first three months of life TRANSPLANTATION Woodle, E. S., Millis, J. M., So, S. K., McDiarmid, S. V., Busuttil, R. W., Esquivel, C. O., Whitington, P. F., Thistlethwaite, J. R. 1998; 66 (5): 606-609


    Pediatric liver transplant recipients have traditionally been grouped according to age. Age-based classification schemes are useful in identifying clinical problems in selected age groups and also for developing solutions to these problems. Although infants in the first 3 months of life have not traditionally been considered a distinct age group, several features of these infants may distinguish them from other pediatric liver transplant recipients.The experience with liver transplantation in infants during the first 3 months of life in three large pediatric liver transplant programs (University of Chicago, Stanford University, and UCLA) was analyzed in order to characterize this group.A total of 23 liver transplants were performed at these three centers in children younger than 3 months of age. This group of patients comprised approximately 37% of the U.S. experience between 1988 and 1994 according to United Network for Organ Sharing statistics. Age distribution at the time of transplantation included the following: <1 month, 28%; 1-2 months, 35%; and 2-3 months, 36%. Median age at the time of transplantation was 37 days (range, 7-90 days), and mean age was 57+/-30 days. Mean weight at the time of transplantation was 3.8+/-1.0 kg. Etiology of liver disease included idiopathic hepatitis, 52%; iron storage disease, 17%; and other causes, 31%. Types of liver allografts used included cadaveric, 85% (reduced size, 60%, and full-size, 25%); living donor, 15%; ABO-identical, 65%; and ABO-compatible, 35%. Actuarial patient and graft survival rates were 60% and 60% at 1 year and 60% and 42% at 2 years, respectively. Median follow-up was 1.5 years. Rejection occurred in 42% of patients, with a median time to first rejection of 13 days. Of these patients, 28% required steroids only and 14% required OKT3. Three patients (14%) were retransplanted at a median time to retransplantation of 1.6 years. Vascular thrombosis occurred in three patients (14%).Liver transplantation performed in infants younger than 3 months of age (1) provides acceptable short- and long-term patient and graft survival, (2) is associated with significant rates of rejection, and (3) is not associated with excessive rates of vascular thrombosis. The etiology of end-stage liver disease occurring in the first 3 months of life is distinct from that in other pediatric liver transplant recipient age groups. These infants should be referred promptly for liver transplantation as reasonable survival can be expected.

    View details for Web of Science ID 000075996500010

    View details for PubMedID 9753340

  • CD30 expression identifies a functional alloreactive human T-lymphocyte subset TRANSPLANTATION Martinez, O. M., Villanueva, J., Abtahi, S., Beatty, P. R., Esquivel, C. O., Krams, S. M. 1998; 65 (9): 1240-1247


    CD30 is a member of the tumor necrosis factor/nerve growth factor receptor family and has been proposed as a marker of specific cytokine-producing subsets in humans. Previous studies have examined the expression of CD30 on established T helper type 1 and T helper type 2 cell clones and the function of CD30+ cells after mitogenic stimulation. In this study, we examined the development and function of CD30+ T cells generated in response to alloantigen.Primary one-way mixed lymphocyte reactions were established, and the expression of CD30 on T lymphocytes was determined by immunofluorescence and flow cytometry. Fluorescence-activated cell sorting was utilized to define the cytokine profile of alloactivated CD30+ cells after restimulation with anti-CD3 monoclonal antibodies or alloantigen. The effect of cyclosporine on the development of CD30+ cells, and on cytokines produced by CD30+ T lymphocytes, in response to alloantigen was determined.CD30+ T lymphocytes could be detected on day 2 of mixed lymphocyte reactions and continued to increase in number and proportion through day 6. Both CD4 and CD8 T cells expressed CD30 after primary alloantigenic stimulation. CD30+ T cells are a subset of alloactivated T cells and are the major source of interferon-gamma and interleukin-5 produced in response to alloantigen. Cyclosporine partially, but not completely, inhibits the development of CD30+ cells, and has a greater effect on interferon-gamma production than on interleukin-5 production.CD30+ T lymphocytes may constitute an important immunoregulatory subset in human allograft rejection.

    View details for Web of Science ID 000073676600016

    View details for PubMedID 9603174

  • Effect of cyclosporine and tacrolimus on the growth of Epstein-Barr virus-transformed B-cell lines TRANSPLANTATION Beatty, P. R., Krams, S. M., Esquivel, C. O., Martinez, O. M. 1998; 65 (9): 1248-1255


    Transplant patients receiving immunosuppressive drugs are at increased risk for Epstein-Barr virus (EBV)-associated disorders including posttransplant lymphoproliferative disorder. The function of T lymphocytes, which are critical to preventing the expansion of EBV-infected B cells, is inhibited by immunosuppressive drugs. The purpose of this study was to determine whether immunosuppressive drugs have direct effects on EBV-infected B cells.The growth and proliferation of EBV-infected spontaneous lymphoblastoid cell lines (SLCLs), cultured in the presence or absence of cyclosporine (CsA) and tacrolimus (TAC), were measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and [3H]thymidine incorporation assays. The effect of CsA and TAC on the viability of SLCLs was determined by cell counts with trypan blue. Apoptosis of SLCLs was induced with an anti-Fas agonist monoclonal antibody in the presence or absence of CsA and TAC and measured by flow cytometry after terminal deoxynucleotidyl transferase end-labeling and propidium iodide staining.CsA and TAC, but not sirolimus, increased the growth of SLCLs. The increased growth in the presence of CsA and TAC was attributable to enhanced cell viability and not increased cell division of SLCLs. In addition, CsA and TAC inhibited Fas-mediated apoptosis of SLCLs.CsA and TAC enhance the survival of EBV-transformed B-cell lines. CsA and TAC promote or augment SLCL growth through protection from cell death but do not affect cell division. The inhibition of cell death by CsA and TAC may contribute to the expansion of EBV-infected cells in immunosuppressed individuals.

    View details for Web of Science ID 000073676600017

    View details for PubMedID 9603175

  • Allograft rejection after liver transplantation for autoimmune liver diseases LIVER TRANSPLANTATION AND SURGERY Hayashi, M., Keeffe, E. B., Krams, S. M., Martinez, O. M., Ojogho, O. N., So, S. K., Garcia, G., Imperial, J. C., Esquivel, C. O. 1998; 4 (3): 208-214


    Autoimmune liver diseases (AILD) may progress to liver failure, requiring liver transplantation as definitive therapy, and these immune-mediated disorders may predispose the patient to more frequent graft rejection. The objective of this study was to determine the effect of preexisting AILD on the incidence of allograft rejection after liver transplantation. Sixty-three patients who underwent liver transplantation between March 1988 and December 1994 for AILDs that included autoimmune hepatitis (AIH; n = 33) and primary biliary cirrhosis (PBC; n = 30) were retrospectively compared with 47 patients who underwent liver transplantation for alcoholic cirrhosis during the same time period. There was a lower incidence of acute allograft rejection in patients with AILD who received tacrolimus-based compared with cyclosporine-based immunosuppression (50% v 85.5%; P = .02). However, patients with AILDs overall had a higher incidence of acute rejection than patients with alcoholic cirrhosis (81% v 46.8%; P < .001), regardless of the type of immunosuppression. In addition, steroid-resistant rejection occurred more frequently in patients with AILDs than in patients with alcoholic cirrhosis (38.1% v 12.8%; P = .003). There was also a trend toward a higher incidence of chronic rejection in patients with AILDs compared with patients with alcoholic cirrhosis (11.1% v 2.1%), but this difference did not reach statistical significance. Patient and graft survivals at 1 and 3 years were similar between patients with AILDs and alcoholic liver disease. Compared with alcoholic cirrhosis, preexisting AILDs are associated with a higher incidence of acute allograft rejection and a trend toward more frequent chronic rejection.

    View details for Web of Science ID 000077183800004

    View details for PubMedID 9563959

  • CD8(+) cells are not necessary for allograft rejection or the induction of apoptosis in an experimental model of small intestinal transplantation JOURNAL OF IMMUNOLOGY Krams, S. M., Hayashi, M., Fox, C. K., Villanueva, J. C., Whitmer, K. J., BURNS, W., Esquivel, C. O., Martinez, O. M. 1998; 160 (8): 3673-3680


    Allospecific CTL can function as cellular effectors of solid organ graft rejection; however, the specific mechanisms of cell damage remain undetermined. In this study we examined the role of CD8+ T cells in apoptosis and rejection of small intestinal allografts. ACI rat intestinal grafts transplanted into Lewis rat recipients showed apoptosis of epithelial crypt cells on day 3 posttransplant as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining. By day 7 numerous apoptotic crypt cells were detected in allografts, but were rarely observed in FK506-treated allograft recipients, isografts, or native intestine of allograft recipients. To further investigate the mechanism of rejection, recipient rats were depleted of CD8+ cells by treatment with OX-8 mAbs the day before and the day after transplantation of rat small intestinal allografts. Depletion of CD8+ cells from allograft recipients did not alter the tempo or the histologic features of rejection compared with those in the control (IgG-treated) group. Moreover, there was no difference in the number of apoptotic crypt epithelial cells in the grafts of control and CD8-depleted rats. Reverse transcriptase-PCR analyses determined there were similar levels of transcripts for Fas, Fas ligand, perforin, and granzyme B in control and CD8-depleted allograft recipients. By Western blot it was determined that the levels of Fas ligand protein were increased in the CD8-depleted group compared with those in control and FK506-treated allograft recipients. These data suggest that CD8 cells are not required for tissue injury or apoptotic cell death in small intestine allograft rejection.

    View details for Web of Science ID 000072970400008

    View details for PubMedID 9558067

  • Human hepatocytes produce an isoform of Fas that inhibits apoptosis TRANSPLANTATION Krams, S. M., Fox, C. K., Beatty, P. R., Cao, S., Villanueva, J. C., Esquivel, C. O., Martinez, O. M. 1998; 65 (5): 713-721


    Fas (Apo-1/CD95), a member of the tumor necrosis factor receptor family, can mediate apoptosis when engaged by its ligand or by anti-Fas antibody. Fas is expressed by cells of the immune system and by some nonlymphoid tissues. Numerous studies have suggested that the Fas pathway may play a role in the rejection of allografts. Functional, soluble forms of the Fas receptor are produced by activated peripheral blood mononuclear cells and some transformed cell lines. The purpose of this study was to determine if soluble variants of Fas are produced in the liver and to determine if blockade of the Fas pathway, by liver-derived soluble Fas, inhibits Fas-mediated apoptosis.Liver and purified hepatocyte specimens were analyzed for Fas transcripts by reverse transcriptase-polymerase chain reaction with primers that span the transmembrane region of the molecule. Bile and cell lysates were analyzed for soluble Fas by specific enzyme-linked immunosorbent assay. Lysates were prepared from normal liver and hepatocytes and utilized to block Fas-mediated apoptosis of Jurkat cells as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometry.A variant form of Fas is abundantly expressed in normal liver and purified hepatocytes. This variant form of Fas is expressed in all normal liver specimens but only in half of the liver specimens obtained during allograft rejection. The levels of soluble Fas diminish in patients undergoing liver allograft rejection in contrast to patients with stable grafts. Importantly, a soluble form of Fas is produced in the liver by hepatocytes and can specifically inhibit Fas-mediated apoptosis.These data raise the possibility that soluble Fas, produced by hepatocytes, may influence the immune response by blocking Fas-mediated apoptosis and, thus, may have a role in liver transplantation.

    View details for Web of Science ID 000072573800019

    View details for PubMedID 9521208

  • Current status of living-related liver transplantation. Pediatric transplantation Hayashi, M., Cao, S., Concepcion, W., Monge, H., Ojogho, O., So, S., Esquivel, C. O. 1998; 2 (1): 16-25


    Living-related liver transplantation has come of age. This manuscript addresses the most important facets of the living-related liver transplant procedure including selection of the donor, the recipient operation, immunosuppression and rejection as well as the most common surgical complications. It also describes the results in terms of patient and graft survival, retransplantation and quality of life. Although living-related liver transplantation has not solved the problem of organ shortage, it has provided many children with an opportunity to live and enjoy life.

    View details for PubMedID 10084755

  • Experience with the piggyback technique without caval occlusion in adult orthotopic liver transplantation TRANSPLANTATION Busque, S., Esquivel, C. O., Concepcion, W., So, S. K. 1998; 65 (1): 77-82


    To assess the feasibility and outcome of a piggyback technique without caval occlusion or veno-venous bypass (VB), we retrospectively reviewed 131 consecutive adult orthotopic liver transplantation (OLT) performed in 129 patients between May 1993 and February 1995. Six were second transplants, and six were combined liver-kidney transplants. The piggyback technique was attempted in all cases.We were able to perform the piggyback technique in 98 OLTs (75%). The remaining 33 OLTs (25%) were converted to the standard technique; of these, 20 (15%) required VB. The reasons for conversion to the standard technique were: anatomical (22 transplants), severe portal hypertension requiring VB (8 transplants), tumor (1 transplant), and other reasons (2 transplants). Six retransplantations were performed (four piggyback, two standard).There was no significant difference in age, United Network for Organ Sharing status, Child's classification, and diagnosis between the patients in whom piggyback was possible or not. The actuarial patient and graft survival at 1 year were similar between the piggyback group and the group of patients converted to standard technique (87/85% vs. 86/86%, respectively). No death was related to either technique. With piggyback, the average operative time was 8.6+/-1.9 hr, median amount of blood transfused intraoperatively was 2 U (33% did not require transfusion), and median intensive care unit and hospital stays were 3 and 11 days, respectively. With the piggyback technique, the mean preoperative and maximum postoperative serum creatinine levels were 1.4+/-1.0 and 1.8+/-1.5 mg/dl.The piggyback technique without caval occlusion is possible in the majority of patients. It is safe and has reduced the use of VB to 15% of our adult OLTs. The piggyback technique avoids retrocaval dissection, facilitates retransplantation, and is associated with a short anhepatic phase, low blood product usage, and short intensive care unit stay.

    View details for Web of Science ID 000071516900014

    View details for PubMedID 9448148

  • New approaches to supporting the failing liver ANNUAL REVIEW OF MEDICINE Cao, S., Esquivel, C. O., Keeffe, E. B. 1998; 49: 85-94


    With the continued, growing disparity between the numbers of organ donations and patients waiting for liver transplantation, various efforts have been made to optimize the allocation of organs, as well as to devise means to support the failing liver. Over the years, the development of bioartificial liver-assist devices has aimed at replacing the three main functions of hepatocytes, which are synthetic, metabolic, and excretory. The application of porcine hepatocytes in humans to carry out biotransformation, as well as other metabolic functions and refinement of the membrane separator, have yielded some promising results in supporting patients with acute liver failure. Further advances will need to be made before these bioartificial devices can be considered for routine application in clinical settings.

    View details for Web of Science ID 000073046600006

    View details for PubMedID 9509251

  • Liver transplantation at Stanford University Medical Center. Clinical transplants Millan, M. T., Keeffe, E. B., Berquist, W. E., Castillo, R. O., Cox, K. L., Garcia, G., Imperial, J. C., Monge, H., So, S. K., Esquivel, C. O. 1998: 287-296


    Because of the unique demographics of our patient population, we have had the opportunity to dedicate further studies of the management of hepatitis B and hepatitis C. We have experienced a very low HBV recurrence rate with the use of HBIG in patients transplanted for hepatitis B. Investigations, including the use of new antiviral agents, and the development of approaches to minimize or abrogate disease recurrence such as lower levels of immunosuppression are ongoing. Using a standardized approach to the proper evaluation and selection of patients for liver transplantation with alcoholic liver disease or other liver diseases with coexistent alcohol abuse, we report favorable long-term results in these patients. We have reviewed our results and our approach to the management of EBV and posttransplant lymphoproliferative disorder. There is a firm commitment in our laboratories and outpatient clinics to the investigation of disease prevention, reliable detection and screening methods, and treatment modalities for EBV-related disease. We have addressed specific technical considerations to pediatric liver transplant and have discussed unique aspects of postoperative management in these patients. One-third of the transplants performed at Stanford are in children, 42% of whom are less than one year old. Results with our pediatric transplant recipients compare favorably with those of our adult recipients with patient and graft survival rates approaching 90% at one year and exceeding 80% at 46 months for both groups. As a response to the limited organ supply, we have extended our criteria for suitable donors. Most notably, we have utilized older donors and grafts with significant microsteatosis and have observed good results with these grafts as long as ischemia time is minimized. We have also successfully used reduced size grafts for our pediatric patients with good results and are continuing to expand the use of living-related partial grafts and split allografts.

    View details for PubMedID 10503106

  • Cholic acid synthesis is reduced in pediatric liver recipients during graft dysfunction due to ischemic injury and allograft rejection TRANSPLANTATION Lang, T., Sendl, A. F., Esquivel, C. O., Berquist, W. E., Cox, K. L. 1997; 64 (11): 1585-1590


    Bile acids are synthesized and secreted by the liver. During liver failure and hepatic dysfunction, a marked reduction of bile acid synthesis has been shown. The purpose of this study was to determine whether the biliary bile acid pattern was affected by preservation injury and rejection and whether it was a reliable marker for graft function in pediatric liver recipients after liver transplantation.We prospectively measured the biliary bile acid pattern in 126 serial bile samples obtained from 15 consecutive pediatric liver recipients by reversed phase high pressure liquid chromatography and correlated our results with clinical findings: preservation injury, no rejection, rejection, or infection.There was a significant change of the bile acid pattern during the first 3 days after transplant. Total biliary bile acids, cholic acid (CA), and CA/chenodeoxycholic acid (CDCA) ratio increased in 12 of 15 patients with mild preservation injury. These changes of the bile acid pattern were markedly delayed in patients with severe preservation injury. During 16 rejection episodes, total biliary bile acid, CA, and CA/CDCA ratio decreased significantly, but returned to normal after successful treatment of rejection. Bacterial infection, observed in nine children, and cyclosporine toxicity, observed in three children, seemed to have no affect on the biliary bile acids.Liver cell damage as a result of preservation injury or rejection leads to a reduction of biliary CA, resulting in a decrease of total biliary bile acids and the CA/CDCA ratio in pediatric liver recipients. This might be caused by a diminished secretion of bile acids and by a decreased synthesis of bile acids.

    View details for Web of Science ID 000071034100014

    View details for PubMedID 9415561

  • Neurodevelopmental outcome of young children with extrahepatic biliary atresia 1 year after liver transplantation JOURNAL OF PEDIATRICS Wayman, K. I., Cox, K. L., Esquivel, C. O. 1997; 131 (6): 894-898


    Forty children < 2 years of age receiving extrahepatic liver transplantation were tested with the Bayley Scales of Infant Development before transplantation and again at 3 and 12 months after transplantation. Neurodevelopmental status 1 year after transplantation was organized by a descriptive statistic of normal, suspect, or delayed. Disease and transplantation variables were investigated for association with delayed neurodevelopmental outcome.Before transplantation mental development was in the low-average range (92 +/- 13.2) with psychomotor development 1 SD below the norm (82.5 +/- 13). Three months after transplantation both mental (80.1 +/- 12.6) and psychomotor (69 +/- 16.1) scores dropped 1 SD, but 1 year after transplantation mental and psychomotor scores recovered to the pretransplantation level of functioning. One year after transplantation 35% of the study group was diagnosed as developmentally delayed. Delayed development was associated with decreased weight (p < 0.04), low albumin (p < 0.02), length of hospital stay (p < 0.04), and age at transplantation (p < 0.05).Young children undergoing liver transplantation are at risk for developmental delay. Aggressive nutritional support before transplantation and timing of transplantation before malnutrition develops may reduce developmental delays.

    View details for Web of Science ID 000071165100021

    View details for PubMedID 9427896

  • Transjugular intrahepatic portosystemic shunt placement in a child complicated by perforated Roux-en-Y portoenterostomy JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Wang, J., Cox, K. L., Dake, M., Esquivel, C. O., So, S. K. 1997; 25 (4): 421-425

    View details for Web of Science ID A1997XY50500011

    View details for PubMedID 9327374

  • Current status and outcome of pediatric liver transplantation. Clinics in liver disease Esquivel, C. O. 1997; 1 (2): 397-?


    In this article the diagnostic indications for hepatic transplantation are addressed in detail. The outcome of liver transplantation is also examined, including the impact of the following factors on survival: age and weight at transplantation, type of liver disease, and size of liver allograft, including living related transplantation. Morbidity and quality of life after transplantation are other aspects reviewed in this chapter.

    View details for PubMedID 15562575

  • Factors affecting survival after orthotopic liver transplantation in infants TRANSPLANTATION Cacciarelli, T. V., Esquivel, C. O., Moore, D. H., Cox, K. L., Berquist, W. E., Concepcion, W., Hammer, G. B., So, S. K. 1997; 64 (2): 242-248


    The technical and medical management of small infants requiring orthotopic liver transplantation remains a challenge. The present study examined 117 orthotopic liver transplantations performed in 101 infants from <1 to 23 months of age between March 1988 and February 1995 to determine factors that influence patient and graft outcome. Factors analyzed included etiology of liver disease, recipient and donor age and weight, United Network for Organ Sharing (UNOS) status, retransplantation, ABO-compatibility, full-size (FS) versus reduced-size grafts, vascular thrombosis (VT), including hepatic artery and portal vein (PVT), and the presence of lymphoproliferative disease (LPD). UNOS status 1, fulminant hepatic failure, and the development of Epstein-Barr virus-associated LPD were each associated with 10-20% lower patient and graft survival rates. Of 101 infants, 11 (11%) developed LPD with an associated 36% mortality. VT occurred in 10 (9 hepatic artery and 1 portal vein) of 117 orthotopic liver transplantations (9%), all less than 1 year of age, and was associated with significantly poorer 1-year (50% vs. 85% no VT, P<0.01) and 5-year patient survival rates (50% vs. 83% no VT, P<0.01). One-year graft survival rates for FS grafts in recipients <12 months versus 12-23 months were 67% vs. 94% (P<0.01); the patient survival rate was also significantly lower in FS graft recipients <12 months (76% vs. 100%, P<0.05). Recipients <5 months of age had the worst survival rates: 1-year and 5-year patient survival rates were 65% and 46% for recipients 0-4 months (n=17) versus 82% and 82% for recipients 5-11 months (n=56), and 93% and 93% for recipients age 12-23 months (n=28; P<0.05). In summary, factors associated with reduced survival rates include recipient age <5 months, recipient age <12 months who received FS grafts, development of VT and donor weight <6 kg. There was a trend for UNOS status 1, fulminant hepatic failure, and presence of LPD to be associated with reduced survival rates.

    View details for Web of Science ID A1997XN86900011

    View details for PubMedID 9256181

  • Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation - A report of the US Multicenter Liver Study Group TRANSPLANTATION Sher, L. S., Cosenza, C. A., Michel, J., Makowka, L., Miller, C. M., Schwartz, M. E., Busuttil, R., McDiarmid, S., Burdick, J. F., Klein, A. S., Esquivel, C., Klintmalm, G., Levy, M., Roberts, J. P., Lake, J. R., Kalayoglu, M., DALESSANDRO, A. M., Gordon, R. D., Stieber, A. C., Shaw, B. W., Thistlethwaite, J. R., Whittington, P., Wiesner, R. H., Porayko, M., Bynon, J. S., Eckhoff, D. E., Freeman, R. B., Rohrer, R. J., Lewis, W. D., Marsh, J. W., Peters, M., Powelson, J., Cosimi, A. B. 1997; 64 (2): 258-263


    A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection.Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study.Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients.Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.

    View details for Web of Science ID A1997XN86900014

    View details for PubMedID 9256184

  • Orthotopic liver transplantation from non-heart-beating donor rats: Effect of flushing with cold/warm UW/SLS preservation solutions Tojimbara, T., Winston, W. N., So, S. K., Esquivel, C. O. ELSEVIER SCIENCE INC. 1997: 1371-1373

    View details for Web of Science ID A1997WM12700610

    View details for PubMedID 9123344

  • Emergency transjugular intrahepatic portosystemic shunt (TIPS) in an infant: A case report JOURNAL OF PEDIATRIC SURGERY Cao, S., Monge, H., Semba, C., Cox, K. L., Berquist, W., Concepcion, W., So, S. K., Esquivel, C. O. 1997; 32 (1): 125-127


    Since the first successful report regarding the feasibility of transjugular intrahepatic portosystemic shunt (TIPS) as an alternative to surgical decompression of portal hypertension, this method has been used extensively as a temporizing measure in controlling refractory variceal bleeding before liver transplantation in adults with cirrhosis. There are few reports of TIPS in pediatric patients because variceal bleeding in most of these patients can often be managed conservatively without invasive intervention. Recently, successful use of TIPS to treat complications of portal hypertension has been described in two children ages 10 and 13. To our knowledge, there are no reports of TIPS used in infants under the age of 1 year. The authors report a case in which TIPS was used to successfully control variceal bleeding in a 10-month-old infant before consideration for hepatic transplantation.

    View details for Web of Science ID A1997WE27500040

    View details for PubMedID 9021592

  • Liver transplantation from non-heart beating donors in rats: influence of viscosity and temperature of initial flushing solutions on graft function. Liver transplantation and surgery Tojimbara, T., Wicomb, W. N., Garcia-Kennedy, R., BURNS, W., Hayashi, M., Collins, G., Esquivel, C. O. 1997; 3 (1): 39-45


    We evaluated the effect of warm (37 degrees C) versus cold (4 degrees C) solutions as the initial flush for liver preservation from non-heart beating donors in rats.An initial flush was performed just before donor hepatectomy with cold or warm University of Wisconsin solution (UW), UW without hydroxyethyl starch, sodium lactobionate sucrose solution, or lactated Ringer's solution as the control group. A separate group also used as control received no initial flushing. Liver transplantation was performed, and the graft function was determined by survival and assessment of enzyme release. The viscosity of each solution and the vascular resistance of the graft were measured.The 7-day survival rate was 83% and 100% in the warm and cold sodium lactobionate sucrose solution groups and 60% and 50% in the warm and cold lactated Ringer's solution groups, respectively. In the no-initial-flush group, rats did not survive. The 7-day survival rate was 67% and 0% in the warm and cold UW groups, respectively. Eliminating the hydroxyethyl starch from the cold UW improved the survival to 67%. Serum alanine aminotransferase levels 1 day after transplantation in the no-initial-flush and the cold UW groups were significantly higher than those of the remaining groups. At 4 degrees C the viscosity was higher in the UW (86.2 cp) compared to hydroxyethyl starch-free UW solution (30.9 cp), lactated Ringer's solution (24.5 cp), and sodium lactobionate sucrose solution (32.7 cp). The viscosity of UW at 37 degrees C was 34.7 cp. Vascular resistance correlated well with the viscosity. Livers flushed with solutions with a low viscosity showed lower vascular resistance than those flushed with cold UW and led to better survival.These data suggest that the viscosity of the initial flushing solution may play an important role in determining the outcome of organ procurement from non-heart beating donors.

    View details for PubMedID 9377757

  • Liver transplantation in Asian patients with chronic hepatitis B HEPATOLOGY HO, B. M., So, S. K., Esquivel, C. O., Keeffe, E. B. 1997; 25 (1): 223-225


    It has been suggested that Asian patients have reduced survival after liver transplantation because of greater recurrence of hepatitis B virus (HBV). We analyzed the outcome of Asian and non-Asian patients receiving transplants for chronic hepatitis B between May 1988 and March 1994. Baseline Child-Pugh score and United Network for Organ Sharing (UNOS) status, HBV recurrence, and survival were compared between the two groups. All but one patient received variable doses of hepatitis B immune globulin. Mean follow-up of surviving patients was 28 months (range, 3-71 months). Fifteen Asians and 20 non-Asians underwent transplantation. Six of 15 Asians (40%) and 4 of 20 non-Asians (20%) died during the study period. Although Asians had a lower 1-year survival than non-Asians (59% for Asians and 94% for non-Asians), the 5-year actuarial survival was not different (59% and 57% for Asians and non-Asians, respectively). The causes of death in 5 of 6 Asians were factors other than recurrent hepatitis B, and 4 of 5 deaths occurred within 60 days after transplantation. Eighty percent of Asian patients were Child-Pugh class C at referral, compared with 50% of non-Asians, and Asians were more likely to be status 1 at transplantation (40% vs. 10%; P < .05). By contrast, all four deaths in non-Asians occurred late and were secondary to recurrent HBV infection. Of patients surviving more than 60 days after transplantation, 7 of 11 Asians (64%) and 10 of 20 non-Asians (50%) developed recurrent HBV infection (NS). Late mortality attributable to HBV recurrence was lower but not significantly different in Asians (1 of 7 [14%]) than in non-Asians (4 of 10 [40%]). In summary, HBV recurrence and late HBV-related mortality in Asians and non-Asians is similar after liver transplantation for chronic hepatitis B. Late referral and more advanced chronic liver disease at the time of transplantation probably account for the lower 1-year survival of Asians after liver transplantation.

    View details for Web of Science ID A1997WA90200040

    View details for PubMedID 8985294

  • Rapid development of hepatocellular siderosis after liver transplantation for neonatal hemochromatosis TRANSPLANTATION Egawa, H., Berquist, W., GARCIAKENNEDY, R., Cox, K., Knisely, A. S., Esquivel, C. O. 1996; 62 (10): 1511-1513


    A male infant with neonatal iron storage disease, also known as neonatal hemochromatosis (NH), underwent orthotopic liver transplantation (OLT) at the age of 55 days. The native liver contained an incidental hepatocellular carcinoma. Scant iron accumulation was found in a biopsy specimen of the implanted liver on the seventh postoperative day (POD); successive biopsies showed increasing siderosis. On POD 62, the patient died of a cardiac arrhythmia. Autopsy showed siderosis at many sites, including the implanted liver. We discuss the possibility that hemochromatosis recurred in the liver allograft and review possible factors contributing to the siderosis.

    View details for Web of Science ID A1996VV54900023

    View details for PubMedID 8958282

  • Primary liver transplantation without transfusion of red blood cells Cacciarelli, T. V., Keeffe, E. B., Moore, D. H., BURNS, W., Chuljian, P., Busque, S., Concepcion, W., So, S. K., Esquivel, C. O. MOSBY-ELSEVIER. 1996: 698-704


    This study examines factors associated with the performance of orthotopic liver transplantation (OLT) without red blood cell (RBC) transfusion.Between January 1992 and December 1994, 306 primary OLTs were performed with recipients divided into two groups: group 1 patients (61 recipients, 20% of total) underwent transplantation without packed RBCs, and group 2 patients (245 recipients, 80% of cases) received a transfusion of at least 1 unit of RBCs during operation.Recipients in group 1 compared with group 2 had less advanced liver disease (20% hospitalized and 48% Child's class C versus 58% hospitalized and 73% Child's class C, p < 0.01) and lower frequency of right upper quadrant surgery (13% versus 25%, p < 0.05). Group 1 recipients also had significantly higher preoperative hematocrits (38% versus 33%, p < 0.01), lower prothrombin times (15.4 versus 16.7 seconds, p < 0.001) and partial thromboplastin times (36.9 versus 42.2 seconds, p < 0.01), a greater proportion of patients transplanted by piggyback technique (87% versus 59%, p < 0.001), and shorter operative times (7.9 hours versus 9.2 hours, p < 0.001). Moreover, a greater percentage of patients underwent OLT without RBC transfusion in each successive year: 9% in 1992, 21% in 1993, and 31% in 1994 (p < 0.001). Logistic regression analysis showed the following factors to be independent predictors of OLT without RBC transfusion. Preoperative Hct, United Network of Organ Sharing status, piggyback technique, operative time, and year of transplantation.OLT can be performed without transfusion of RBCs in recipients with less advanced liver disease, and surgical technique, along with increased experience by the transplant team, are important factors.

    View details for Web of Science ID A1996VP42300036

    View details for PubMedID 8862380

  • Orthotopic liver transplantation for hepatocellular carcinoma - Factors affecting long-term patient survival Ojogho, O. N., So, S. K., Keeffe, E. B., Berquist, W., Concepcion, W., GARCIAKENNEDY, R., Imperial, J., Esquivel, C. O. AMER MEDICAL ASSOC. 1996: 935-939


    To determine the influence of several clinicopathologic factors on the 3-year actuarial survival of patients with nonfibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation (OLT).A case series of 26 consecutive patients with HCC treated with OLT, with a maximum follow-up of 90 months.A tertiary care center.Between March 1988 and December 1993, 521 OLTs were performed in 480 patients, 27 of whom had HCC. One patient was excluded because of donor-transmitted melanoma. Of the remaining 26 patients, there were 18 adults and 8 children, with a mean age of 41 years (range, 0.2-67.4 years). Fourteen patients (54%) had either hepatitis B (n = 6) or hepatitis C (n = 8), while 15 (58%) had coincidental tumor.OLT was performed using standard techniques.The effect of several clinicopathologic factors on 3-year actuarial patient survival.The overall actuarial survival rates for the 26 patients with HCC were 73%, 65.4%, and 65.4%, at 1, 2, and 3 years, respectively. Sixteen patients (62%) were alive at the time of this report, with 14 (54%) free of disease. None of the clinicopathologic factors significantly affected the 3-year patient survival rate. However, the rate of recurrent HCC was significantly higher in nonincidental vs coincidental tumors and in solitary vs multiple tumors.Our results suggest that HCC should not contraindicate OLT, as long-term patient survival and cure can be achieved. While patient selection is important, survival in patients with HCC after OLT is not always predictable using the usual clinicopathologic prognostic factors.

    View details for Web of Science ID A1996VF46900009

    View details for PubMedID 8790178

  • Continuous venovenous hemofiltration with dialysis in combination with total hepatectomy and portocaval shunting - Bridge to liver transplantation TRANSPLANTATION Hammer, G. B., So, S. K., ALUZRI, A., Conley, S. B., Concepcion, W., Cox, K. L., Berquist, W. E., Esquivel, C. O. 1996; 62 (1): 130-132


    Children who experience acute liver failure following liver transplantation will have multiple organ failure and a high rate of mortality unless emergency retransplantation can be performed. Transplant hepatectomy with portocaval shunting has been described as a bridge to transplantation in the most severe cases, as well as in patients with fulminant hepatic failure at high risk for mortality who have not undergone liver transplantation. Patients with multiple organ failure who have undergone hepatectomy require renal replacement therapy. Continuous hemofiltration may be used in patients with fulminant hepatic failure to facilitate fluid removal and circulatory and metabolic balance. We used continuous venovenous hemofiltration with dialysis following hepatectomy with portocaval shunting in a patient who remained anhepatic for 66 hr in order to achieve circulatory and metabolic homeostasis as well as stable neurologic function prior to successful retransplantation.

    View details for Web of Science ID A1996UX68500026

    View details for PubMedID 8693530

  • Cyclosporine and tacrolimus both suppress activation of kupffer cells in vitro Tojimbara, T., Bermudez, L. E., Egawa, H., Hayashi, M., So, S. K., Esquivel, C. O. ELSEVIER SCIENCE INC. 1996: 1381-1382

    View details for Web of Science ID A1996UR78100105

    View details for PubMedID 8658704

  • Liver transplantation CURRENT OPINION IN GASTROENTEROLOGY Keeffe, E. B., Esquivel, C. O. 1996; 12 (3): 290-299
  • Oral tacrolimus (FK506) induction therapy in pediatric orthotopic liver transplantation TRANSPLANTATION Cacciarelli, T. V., Esquivel, C. O., Cox, K. L., Hayashi, M., Berquist, W. E., Concepcion, W., So, S. K. 1996; 61 (8): 1188-1192


    We have adopted the use of an oral tacrolimus induction protocol in pediatric liver transplantation since the commercial release of tacrolimus in 1994. In this study we analyzed the efficacy of oral tacrolimus induction therapy in 17 consecutive transplants (15 patients) performed between 6/94 and 2/95 and 4 additional patients who were retransplanted between 11/93-5/94 and received compassionate oral tacrolimus induction. Sixteen transplants were treated with oral tacrolimus induction only; 5 transplants, oral tacrolimus + ATGAM/OKT3 induction. The protocol consisted of 0.2 mg/kg of tacrolimus orally on the first postoperative day with a corticosteroid taper. Oral tacrolimus was started at day 1-8 in the 5 patients receiving ATGAM/OKT3 induction. Dosages were adjusted over time to maintain a whole-blood trough level of 12-15 ng/ml at 0-1 month, 10-12 ng/ml at 1-3 months, and 5-10 ng/ml after 3 months. The incidence of acute rejection was 50% (8/16) in children on oral tacrolimus induction alone and 80% (4/5) in the tacrolimus + ATGAM/OKT3 group. Epstein-Barr virus infection occurred in 6 of 19 children (32%), with no child developing lymphoproliferative disorder. No adverse effect on renal function was noted. Serum fasting glucose was stable over time while a trend was noted in decreasing serum cholesterol levels at 6 months. Antihypertensive medication was required in 4 of 19 children (21%) posttransplantation. Corticosteroids were withdrawn in 11% (2/19) of patients. Actuarial 1-year patient and graft survivals were 95% and 86%, respectively. The use of oral tacrolimus induction therapy was associated with excellent survival and a low incidence of complications.

    View details for Web of Science ID A1996UJ00300012

    View details for PubMedID 8610416

  • Elevations in IFN-gamma, IL-5, and IL-10 in patients with the autoimmune disease, primary biliary cirrhosis. Association with autoantibodies and soluble CD30. Krams, S. M., Cao, S., Hayashi, M., Esquivel, C. O., Martinez, O. M. W B SAUNDERS CO-ELSEVIER INC. 1996: A1240-A1240
  • Suggested guidelines for the use of tacrolimus in pediatric liver transplant patients TRANSPLANTATION Esquivel, C. O., So, S. K., McDiarmid, S. V., Andrews, W. S., Colombani, P. M. 1996; 61 (5): 847-848

    View details for Web of Science ID A1996UA76800033

    View details for PubMedID 8607198

  • Ganciclovir treatment of hepatitis B virus infection in liver transplant recipients HEPATOLOGY Gish, R. G., Lau, J. Y., Brooks, L., Fang, J. W., Steady, S. L., Imperial, J. C., GARCIAKENNEDY, R., Esquivel, C. O., Keeffe, E. B. 1996; 23 (1): 1-7


    To determine the safety and efficacy of ganciclovir treatment of hepatitis B virus (HBV) infection after liver transplantation, nine patients (seven males, two females; mean age, 38 years) with posttransplant HBV infection were treated with ganciclovir for 3 to 10 months. Ganciclovir was administered intravenously at an initial dose of 5 mg/kg/d and then increased to 10 mg/kg/d. Immunosuppressive drug therapy was maintained at low levels. There were no major side effects of ganciclovir therapy. Serum HBV DNA levels decreased by a mean of 90% (range, 42% to 100%), and four of nine patients had no measurable HBV DNA at the completion of therapy. Mean serum alanine aminotransferase levels decreased by 83%. Hepatic expression of HBV antigens and HBV DNA was assessed before and after therapy in six patients and found to be reduced in three patients. The histology activity index was also stabilized or improved in all patients. After discontinuation of therapy, four of nine patients underwent retreatment for 4- to 12-fold elevation of serum HBV DNA and/or biochemical and clinical relapse, that was severe in one patient. This pilot study shows the safety and efficacy of ganciclovir therapy for reducing HBV replication in patients with HBV infection after liver transplantation.

    View details for Web of Science ID A1996TN80100001

    View details for PubMedID 8550028

  • Expression of cytokines and immune mediators during chronic liver allograft rejection Hayashi, M., Martinez, O. M., GARCIAKENNEDY, R., So, S., Esquivel, C. O., Krams, S. M. WILLIAMS & WILKINS. 1995: 1533-1538


    To determine the immune processes involved in chronic liver allograft rejection (CR) we examined in situ cytokine production in tissue from 15 patients with both clinical and histopathological diagnoses of CR. Total RNA was isolated from liver samples, reverse-transcribed and analyzed by RT-PCR for the production of proinflammatory cytokines and immunoregulatory mediators. Transcripts for the Th1-like cytokines IL-2 and IFN-gamma were detected in 53.3% and 46.7% of CR grafts, while they were detected in only 16% and 0% of stable grafts, respectively. The cytotoxic T cell mediator granzyme B was expressed in the majority of liver grafts undergoing CR, but was expressed only in a minority of stable grafts (80% vs. 16%, P < 0.05). The T cell product IL-5 was also significantly upregulated in CR as compared with stable livers (80% vs. 16%, P < 0.01). Other Th2 cytokines--IL-4 and IL-10--and macrophage products--IL-1 beta, IL-6, IL-8, TGF-beta, and TNF-alpha--were not substantially upregulated in CR grafts as compared with stable grafts. PDGF-beta transcripts were detected in the majority of the CR grafts, but were not detected in stable liver grafts (73% vs. 0, P < 0.05). By immunohistochemical staining, we observed that CD3+CD4+, and CD3+CD4- T cells were detected in CR grafts along with CD20+ B cells and CD68+ macrophages. There was, however, a predominant infiltration of CD3+CD4+ lymphocytes. Taken together, these data suggest that infiltrating cells produce proinflammatory and immunoregulatory cytokines that have a role in mediating graft damage in CR.

    View details for Web of Science ID A1995TN23000027

    View details for PubMedID 8545886

  • Elevated biliary interleukin 5 as an indicator of liver allograft rejection. Transplant immunology Lang, T., Krams, S. M., Berquist, W., Cox, K. L., Esquivel, C. O., Martinez, O. M. 1995; 3 (4): 291-298


    Interleukin 5 (IL-5) is a T cell-derived cytokine that acts as a potent and specific eosinophil differentiation factor in humans. During liver allograft rejection, intragraft IL-5 mRNA and eosinophilia have been observed. The objective of this study was to correlate the levels of IL-5 in bile and serum with eosinophilia and allograft rejection in paediatric liver recipients. IL-5 levels were determined by ELISA (enzyme-linked immunosorbent assay) in bile (n = 85) and serum (n = 106) and obtained prospectively from 15 patients during the first 3 weeks post-transplantation. Biliary and serum IL-5 levels were significantly elevated during allograft rejection compared to IL-5 levels when no rejection was apparent or during infectious complications. The highest IL-5 levels were measured in the bile during the early rejection period (3 days prior to biopsy-proven rejection). Fifteen of 16 rejection episodes were marked by increases in IL-5 as revealed by analysis of sequential samples from individual patients. In all patients with rejection, elevations in serum IL-5 were associated with elevations in peripheral eosinophil counts. These results indicate that IL-5 is produced in the liver and may be a useful and specific marker of allograft rejection. Furthermore, these findings provide further evidence for a pathway of liver allograft rejection mediated by IL-5 activated eosinophils.

    View details for PubMedID 8665147

  • THE USE OF NON-HEART-BEATING CADAVER DONORS IN EXPERIMENTAL LIVER-TRANSPLANTATION TRANSPLANTATION Tojimbara, T., Kennedy, R. G., BURNS, W., Hayashi, M., Krams, S., Martinez, O., So, S., Esquivel, C. O. 1995; 60 (10): 1179-1180

    View details for Web of Science ID A1995TH32800020

    View details for PubMedID 7482728

  • THE IMPACT OF IMMUNOSUPPRESSIVE REGIMENS ON THE COST OF LIVER-TRANSPLANTATION - RESULTS FROM THE US FK506 MULTICENTER TRIAL TRANSPLANTATION Lake, J. R., Gorman, K. J., Esquivel, C. O., Wiesner, R. H., Klintmalm, G. B., Miller, C. M., Shaw, B. W., Gordon, J. A. 1995; 60 (10): 1089-1095


    In an effort to determine the total one-year cost of liver transplantation, the underlying drivers of that cost, and any cost differences between alternative immunosuppressive regimens, an analysis was performed comparing the average one-year posttransplant charges of 322 patients participating in the "U.S. Multi-center Prospective Randomized Trial Comparing FK-506 to Cyclosporine in Liver Transplantation." Total one-year inpatient charges including all readmissions were examined. Professional fees and outpatient charges were excluded. Costs for tacrolimus drug and blood assays were assumed to be equal to those in the CsA group. For patients completing the study, the tacrolimus group had an average length of stay and average one-year cost seven days (P = .06) and $19,290 (P = .05) lower than the CsA group. The difference in rejection profiles between the two arms seems to largely account for the lower costs. The tacrolimus arm consistently had fewer patients in the more severe rejection groups. Increased incidence and severity of rejection were directly related to higher average lengths of stay and costs of transplantation (P < .001). Tacrolimus immunosuppression during the first year after liver transplantation is more cost-effective than CsA in achieving similar patient and graft survival rates. Differing incidence and severity of rejection can dramatically affect the first-year cost of liver transplantation.

    View details for Web of Science ID A1995TH32800005

    View details for PubMedID 7482713

  • A REASSESSMENT OF ABO INCOMPATIBILITY IN PEDIATRIC LIVER-TRANSPLANTATION TRANSPLANTATION Cacciarelli, T. V., So, S. K., Lim, J., Concepcion, W., Cox, K., Esquivel, C. O. 1995; 60 (7): 757-760


    The present study examined 144 pediatric liver transplants to determine the impact of ABO matching on liver allograft outcome. Pediatric transplants were divided into 3 groups: ABO identical (ABO-Id; n = 108), ABO-compatible nonidentical (ABO-Comp; n = 22), and ABO incompatible (ABO-Inc; n = 14). A higher proportion of United Network for Organ Sharing status 4 recipients in the ABO-Comp group (50% vs. 22% and 36% for ABO-Id and ABO-Inc, P < 0.05) and less time spent on the waiting list for ABO-Inc recipients (46 +/- 12 vs. 87 +/- 11 and 61 +/- 20 days for ABO-Id and ABO-Comp, P < 0.01) were noted. OKT3 induction therapy was greater in ABO-Inc grafts (57% vs. 19% and 14% for ABO-Id and ABO-Comp, P < 0.05), as was incidence of acute cellular rejection (79% vs. 59% and 41% for ABO-Id and ABO-Comp, P = 0.08). One- and 3-year patient survival rates were 87% and 83% in the ABO-Id group, 95% and 88% in the ABO-Comp group, and 79% and 79% in the ABO-Inc group (P = NS). One- and 3-year graft survival rates were 83% and 78% in the ABO-Id group, 87% and 80% in the ABO-Comp group, and 71% and 71% in the ABO-Inc group (P = NS). ABO-Inc transplantations can be performed successfully in pediatric recipients and warrant a reassessment of the utilization of ABO-Inc livers.

    View details for Web of Science ID A1995RZ96800024

    View details for PubMedID 7570989

  • LIVER-TRANSPLANTATION IN A CHILD WITH SICKLE-CELL-ANEMIA TRANSPLANTATION Lang, T., Berquist, W. E., So, S. K., Cox, K. L., RICH, E. J., Vichinsky, E., Concepcion, W., Esquivel, C. O. 1995; 59 (10): 1490-1492

    View details for Web of Science ID A1995RB42900025

    View details for PubMedID 7770941

  • EFFECTS OF PENTOXIFYLLINE PRETREATMENT ON KUPFFER CELLS IN RAT-LIVER TRANSPLANTATION HEPATOLOGY Kozaki, K., Egawa, H., Bermudez, L., Keefe, E. B., So, S. K., Esquivel, C. O. 1995; 21 (4): 1079-1082


    Previous research with pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor, suggests that this drug may be capable of suppressing the activation of Kupffer cells and thereby help decrease liver injury after transplantation. To investigate this possibility, the current study sought to determine whether the release of O2- and tumor necrosis factor (TNF) from Kupffer cells in donor livers can be suppressed if the organs are exposed to PTX before preservation. In an in vitro experiment, rat livers were flushed with PTX (25 mg/kg body weight) in University of Washington (UW) solution or UW solution alone (control) and then and stored in UW solution for either 4 or 24 hours. Kupffer cells then were purified and their degree of activation determined by measuring O2- release and the production of TNF after lipopolysaccharide stimulation. In an in vivo experiment, a group of rats underwent orthotopic liver transplantation with grafts prepared in the same manner as in the in vitro study. TNF and aspartate transaminase (AST) were measured in blood samples taken 3 hours and 24 hours after transplantation. Compared with controls, the Kupffer cells from grafts pretreated with PTX produced significantly less O2- and TNF, and the recipients of PTX-pretreated grafts had lower levels of TNF and AST 3 hours after transplantation. The current data indicate that O2- and TNF production in liver grafts is suppressed by PTX pretreatment. Through its suppressive effect on Kupffer cells, PTX may help minimize preservation-reperfusion injury and improve graft survival.

    View details for Web of Science ID A1995RC07100028

    View details for PubMedID 7705782



    A 3-year-old female had fulminant hepatic and renal failure due to massive iron ingestion, despite gastric lavage, deferoxamine administration, hemodialysis and continuous arteriovenous hemofiltration. She underwent a successful emergency liver transplantation on 5th day after ingestion and was discharged 25 days later with excellent liver and renal function.

    View details for Web of Science ID A1995QV67600004

    View details for PubMedID 7599407


    View details for Web of Science ID A1995QM65600028

    View details for PubMedID 7533958

  • Liver transplantation for treatment of giant hepatocellular adenomas. Liver transplantation and surgery Mueller, J., Keeffe, E. B., Esquivel, C. O. 1995; 1 (2): 99-102


    Giant hepatocellular adenomas are associated with a high incidence of rupture with intra-abdominal hemorrhage and may also undergo malignant transformation. If resection is not technically feasible, liver transplantation should be a treatment option. The aim of this report is to describe the indications, feasibility, and outcome of liver transplantation for hepatocellular adenomas. A 66-year-old man with a 17-cm hepatocellular adenoma originating in the left lobe but involving nearly the entire liver and a 35-year-old woman with a 20-cm tumor involving the right lobe of the liver and compressing the left lobe underwent liver transplantation without complication. In both cases, a histological diagnosis was made by core needle biopsy preoperatively, and resection was technically not possible. Hepatocellular adenoma involving nearly all of the liver with no evidence of malignant change was confirmed in the explant liver from both cases. Giant hepatocellular adenomas may be unresectable and require liver transplantation for complete removal to prevent potential rupture with hemorrhage or malignant transformation.

    View details for PubMedID 9346548



    Recurrent hepatitis B virus infection after liver transplantation performed for chronic hepatitis B with cirrhosis is influenced by a number of factors, including coinfection with the hepatitis D virus, the level of HBV replication, and administration of hepatitis B immune globulin. Another potentially important factor in modulating HBV infection after liver transplantation is the degree of immunosuppression post-transplant. We reviewed an institutional experience with liver transplantation for chronic hepatitis B and analyzed the impact of using lower doses of corticosteroids on HBV reinfection, expression of recurrent HBV disease and patient survival.Of 17 patients undergoing liver transplantation for chronic hepatitis B, 16 patients received variable doses of hepatitis B immune globulin for up to 6 months.Fifteen of the 16 patients remained HBsAg-negative during hepatitis B immune globulin therapy, but ultimately 13 of the 17 patients had HBV reinfection, including 3 of 4 patients with hepatitis D virus coinfection. Long-term survival (82%) of the 17 chronic hepatitis B patients was not different from the survival (75%) of 195 patients transplanted for other indications. Three of 13 patients who were reinfected died from chronic hepatitis B with liver failure. Reinfection did not appear to be related to the pretransplant degree of viral replication. Compared to an age- and sex-matched control group, patients undergoing liver transplantation for chronic hepatitis B received less cumulative intravenous methylprednisolone and oral prednisone, but did not experience a higher rate of graft rejection.We postulate that use of lower doses of corticosteroids after liver transplantation for chronic hepatitis B is safe and not associated with a higher incidence of graft rejection. Moreover, low-dose maintenance prednisone therapy may modify the course of post-transplant HBV reinfection by leading to less viral replication, milder HBV-related liver disease and better patient survival.

    View details for Web of Science ID A1995RL11200001

    View details for PubMedID 7608474



    The incidence of Epstein-Barr virus (EBV) infection and lymphoproliferative disorder (LPD) was determined in a pediatric liver transplant population consisting of 51 children treated with FK506 and 91 treated with cyclosporine. The incidence of symptomatic EBV infection was 21.9% (23 of 105 cases) in children < 5 yr old and 10.8% (4 of 37 cases) in children 5 to 17 yr old as compared with 2.7% (9 of 323 cases) in adults (P < 0.0001). In the under 5 yr old group on cyclosporine, the incidences of EBV infection and LPD were 9 of 68 (13.2%) and 2 of 68 children, (2.9%), respectively. In contrast, in children under 5 yr old group on FK506, the incidences of EBV infection and LPD in the FK506 group were 14 of 37 (37.8%) and 7 of 37 children (18.9%), respectively. The difference between these two groups was statistically significant (P < 0.02). There were no cases of LPD in the 5-17 yr-old children on either cyclosporine (n = 23) or FK506 (n = 14). The incidence of EBV infections in the 5 to 17 yr age group, 17.4% on cyclosporine and 0% on FK506, was less than for the younger children on FK506 (37.8%). A total of 39% (9 of 23) of children under 5 yr old who had symptomatic EBV infections developed LPD, and 44% (4 of 9) with LPD died. The higher incidence of EBV infections and LPD in the younger children treated with FK506 was probably related to a greater intensity of immunosuppression for patients on FK506 than those on cyclosporine.

    View details for Web of Science ID A1995QK22500015

    View details for PubMedID 7533344

  • FK506 (TACROLIMUS) COMPARED WITH CYCLOSPORINE FOR PRIMARY IMMUNOSUPPRESSION AFTER PEDIATRIC LIVER-TRANSPLANTATION - RESULTS FROM THE US MULTICENTER TRIAL McDiarmid, S. V., Busuttil, R. W., Ascher, N. L., Burdick, J., DALESSANDRO, A. M., Esquivel, C., Kalayoglu, M., Klein, A. S., Marsh, J. W., Miller, C. M., Schwartz, M. E., Shaw, B. W., So, S. K. WILLIAMS & WILKINS. 1995: 530-536


    We report on the efficacy and safety of FK506 (tacrolimus) compared with a cyclosporine (CsA)-based immunosuppressive regimen after 1 year of treatment in pediatric liver allograft recipients (< 12 years) participating in a multicenter U.S. randomized trial. Patients received either FK506 or CsA as primary immunosuppression following a first ABO-compatible liver transplant. Intravenous FK506 was initiated at 0.1 mg/kg per day, followed by oral FK506 beginning at 0.3 mg/kg per day. The dose was adjusted to maintain plasma trough levels of 0.5-2.0 ng/ml. The CsA group was treated according to each center's usual protocol. Both groups received the same initial doses of corticosteroids. All rejection episodes were biopsy-proven and a standardized algorithm was adopted for the treatment of rejection. Thirty patients were randomized to the FK506 group and 20 to the CsA group. After twelve months of follow-up 20 patients remained in the FK506 group and 13 in the CsA group. Patient survivals were 80% and graft survival 70% in the FK506 group compared with 81% and 71% respectively, in the CsA group. 48% of the FK506 group remained rejection-free compared with 21% of the CsA group, and 79% of FK506-treated patients did not require OKT3 compared with 68% of CsA treated patients. The cumulative corticosteroid dose was less at each time point throughout the first year in the FK506 group. The incidence of serious and minor infections was similar in both groups. Nephrotoxicity, neurotoxicity, and gastrointestinal disturbances were the major toxicities reported. Differences did not reach statistical significance between the two groups although major neurologic events, diarrhea and dyspepsia were more often reported in the FK506 group. There was no difference in mean serum creatinine at 12 months between the two groups. There was a tendency toward lower mean serum cholesterol in the FK506 group. There was no hirsuitism in the FK506 group compared with a 30% incidence in the CsA group. In conclusion, compared with CsA, there is a trend toward less rejection in FK506-treated pediatric allograft recipients, while both drugs have a similar spectrum of side effects.

    View details for Web of Science ID A1995QK22500016

    View details for PubMedID 7533345


    View details for Web of Science ID A1995QJ19900456

    View details for PubMedID 7533367


    View details for Web of Science ID A1995QJ19900497

    View details for PubMedID 7878864

  • LONG-TERM NONRESPONSIVENESS TO A LIVER ALLOGRAFT MAY BE CYTOKINE-MEDIATED Egawa, H., Martinez, O. M., QUINN, M. B., Villanueva, J. C., So, S., Esquivel, C. O., Krams, S. M. ELSEVIER SCIENCE INC. 1995: 241-242

    View details for Web of Science ID A1995QJ19900085

    View details for PubMedID 7533390


    View details for Web of Science ID A1995QJ19900201

    View details for PubMedID 7879079


    View details for Web of Science ID A1995QJ19900484

    View details for PubMedID 7533372


    View details for Web of Science ID A1995QJ19900457

    View details for PubMedID 7533368

  • ACUTE LIVER ALLOGRAFT-REJECTION IN THE RAT - AN ANALYSIS OF THE IMMUNE RESPONSE TRANSPLANTATION Egawa, H., Martinez, O. M., QUINN, M. B., Villanueva, J. C., So, S., Esquivel, C. O., Krams, S. M. 1995; 59 (1): 97-102


    Liver allografts are vigorously rejected in 9-12 days in Lewis recipients of fully histoincompatible DA livers. The purpose of this study was to examine the initial events in this cascade, specifically the role of CD4+ T helper cells. Lewis recipients of DA or Lewis livers were killed at days 1, 2, 3, 4, and 7 days after transplant. Indicators of acute liver rejection, including a marked inflammatory infiltrate and decreased liver function, progressed in untreated recipients of allografts. Splenocytes taken from allogeneic recipients on days 1-4 and 7 proliferated in response to donor and third-party stimulators, whereas graft-infiltrating cells did not respond to donor and third-party antigens until day 3 after transplant, but thereafter maintained a good response. To further characterize the host T helper cell response to liver allografts, cytokine expression was analyzed in graft tissue and in the periphery. IL-4 mRNA was present in both syngeneic and allogeneic liver grafts, while message for IL-10 was present early in all liver grafts but persisted only in allografts. In contrast, IL-2 and IFN-gamma transcripts were specific to rejecting allografts. Similar patterns of cytokine expression were observed in the spleen, indicating the immune response to the graft involves the peripheral lymphoid organs. Thus, the cytokine profile detected during liver allograft rejection is extremely similar to that observed in other experimental models of transplantation.

    View details for Web of Science ID A1995QB42700017

    View details for PubMedID 7839435



    The histology of 72 livers from 72 children who underwent liver transplantation was reviewed. Nine children (12.5%) had hepatocellular carcinoma (HCC) and/or liver cell dysplasia (LCD) in their native livers. Ages at the time of transplantation ranged from 2 months to 11 years. Primary liver diseases included tyrosinemia (3), biliary atresia (2), chronic active hepatitis B (1), chronic active non-A non-B non-C hepatitis (1), idiopathic neonatal hepatitis (1), and neonatal iron storage disease (1). Explanted livers showed large multifocal HCC in two cases, incidental HCC in three, and dysplastic nodules in four. LCD also was present in three cases in conjunction with HCC. All patients had cirrhosis. Alpha-fetoprotein was measured in six children and was elevated in all six (range, 300 to 1,770,000 ng/mL; normal, 0 to 15 ng/mL). Abdominal computed tomography, ultrasonography, and/or magnetic resonance imaging showed large masses in two cases, but did not detect the tumors of less than 2 cm or the dysplastic nodules in the other seven children. After a follow-up period of 2 months to 3 years (mean, 19.8 +/- 12.1 months), eight children are alive and have no evidence of recurrence. The patient with neonatal iron storage disease died 2 months after transplantation, without evidence of tumor recurrence. The authors conclude that children with end-stage liver disease of diverse causes referred for liver transplantation may have LCD and/or HCC. Serial determination of alpha-fetoprotein and images studies may detect early lesions curable by liver transplantation.

    View details for Web of Science ID A1994PQ67000016

    View details for PubMedID 7844722


    View details for Web of Science ID A1994PQ16900016

    View details for PubMedID 7952466



    Transjugular intrahepatic portosystemic shunt (TIPS) is being increasingly utilized prior to liver transplantation for portal hypertensive bleeding refractory to sclerotherapy or as initial management of variceal bleeding. The impact of TIPS on subsequent orthotopic liver transplantation (OLT) is uncertain. The purpose of this study was to analyze the effect of TIPS on OLT in terms of operative transfusion requirements, operative time, length of hospital stay, and graft and patient survival. The results in 17 patients undergoing TIPS for control of initial or recurrent variceal bleeding prior to OLT between June 1991 and December 1992 were compared to two other groups undergoing transplantation: 32 control patients with a history of variceal bleeding not treated by TIPS and 11 patients with a previous surgical portosystemic shunt. Compared with control and surgical shunt patients, patients who underwent TIPS had less transfusion requirement for packed red blood cells and fresh frozen plasma during OLT. The operative time and hospital stay of the TIPS patients were slightly, but not significantly, less. In contrast to patients having TIPS, the patients with a history of a previous surgical shunt had an increased requirement for packed red blood cells, longer operative time, and longer stay in the intensive care unit and hospital. Two patients had recurrent variceal bleeding after TIPS; one patient was found to have an occluded stent, and the other patient (with a patent stent) responded to sclerotherapy. Of the 14 patients with ascites, 8 patients improved and 6 patients had complete resolution after TIPS. There were no major complications related to TIPS, although 3 patients had new or recurrent hepatic encephalopathy that was easily manageable.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994PY17700011

    View details for PubMedID 7846910

  • A COMPARISON OF TACROLIMUS (FK-506) AND CYCLOSPORINE FOR IMMUNOSUPPRESSION IN LIVER-TRANSPLANTATION NEW ENGLAND JOURNAL OF MEDICINE Busuttil, R. W., McDiarmid, S., Klintmalm, G. B., Goldstein, R., Miller, C. M., Schwartz, M., Shaw, B. W., Roberts, J. P., Hebert, M. F., Esquivel, C. O., Nakazato, P., Wiesner, R. H., Krom, R. A., Kalayoglu, M., DALESSANDRO, A. M., Marsh, J. W., Peters, M. G., Burdick, J., Klein, A., Lewis, W. D., Jenkins, R., Thistlethwaite, J. R., Emond, J. C., Jusko, W. J., DAMBROSIO, R., Buell, D., Fitzsimmons, W. E. 1994; 331 (17): 1110-1115


    Two patients with liver failure secondary to isoniazid hepatotoxicity were successfully treated with orthotopic liver transplantation. A 49-year-old man received isoniazid prophylaxis for a positive tuberculin test, and a 60-year-old woman was treated for active pulmonary tuberculosis with isoniazid, rifampin, and pyrazinamide. Both patients developed hepatic failure 4 and 1.5 months after initiation of antituberculous drug therapy, respectively. Liver transplantation was performed for progressive hepatic failure and was successful in both patients. The patient with active pulmonary tuberculosis was successfully treated with a modified antituberculous drug regimen while taking standard doses of immunosuppressive drugs after transplantation. In conclusion, liver transplantation is feasible and effective therapy for patients with isoniazid-induced hepatic failure, and active pulmonary tuberculosis may represent a relative rather than absolute contraindication to transplantation.

    View details for Web of Science ID A1994PL97200031

    View details for PubMedID 7924752

  • COMPARISON OF TRANSJUGULAR AND SURGICAL PORTOSYSTEMIC SHUNTS ON THE OUTCOME OF LIVER-TRANSPLANTATION ARCHIVES OF SURGERY Menegaux, F., Keeffe, E. B., Baker, E., Egawa, H., Concepcion, W., Russell, T. R., Esquivel, C. O. 1994; 129 (10): 1018-1024


    To analyze the effect of previous transjugular intrahepatic portosystemic shunt (TIPS) vs surgical portosystemic shunt (SPS) on the outcome of orthotopic liver transplantation (OLT).A case series of 38 patients who underwent OLT: 25 with a previous TIPS and 13 with a previous SPS.A liver transplant center and interventional radiology service in a private, tertiary referral medical center.Eighteen men and seven women who had a TIPS before OLT were compared with nine men and four women who had an SPS before OLT.Operative transfusion requirements, operative time, length of hospital stay, postoperative liver chemistry studies, and graft and patient survival.Compared with patients who had an SPS, patients who had a TIPS had significantly less median transfusion requirements for packed red blood cells (5 vs 12 U), fresh-frozen plasma (0 vs 8 U), and thrombocytes (0 vs 1 U). The median operative time (9 vs 13 hours), length of intensive care unit stay (3 vs 5 days), and length of hospital stay (12 vs 24 days) were also significantly less in patients who had a TIPS. The 2-year actuarial patient survival rate was 92% in both groups.In patients undergoing OLT, TIPS is associated with reduced operative transfusion requirements, operative time, and length of intensive care unit and hospital stays compared with SPS. In the potential liver transplant candidate with refractory complications of portal hypertension, TIPS is preferred to SPS.

    View details for Web of Science ID A1994PL49300006

    View details for PubMedID 7944930



    A small number of liver transplant candidates experience variceal bleeding that cannot be controlled by standard medical therapy. The objective of this study was to analyze the role of urgent liver transplantation for this subset of patients with acute, refractory, portal hypertensive bleeding.Retrospective review of data from 416 patients undergoing 449 liver transplantations between March, 1988 and February, 1993 revealed seven patients (1.7%) with endstage liver disease who underwent transplantation for uncontrollable variceal bleeding. All patients failed therapy with intravenous pitressin, endoscopic sclerotherapy, balloon tamponade, and/or transjugular intrahepatic portosystemic shunt and continued to bleed. Patients ranged in age from 6 months to 56 years. All patients were Child's class C. Two patients were listed for transplantation with the United Network for Organ Sharing as status 3, and five patients were listed as status 4.All patients underwent successful liver transplantation with immediate control of bleeding. One patient expired on the 26th postoperative day from multiple organ failure, and another patient expired with recurrent hepatocellular carcinoma on the 110th postoperative day. No patients experienced late rebleeding from varices after transplantation.Urgent liver transplantation is effective and feasible for the small subset of patients with uncontrollable variceal bleeding and endstage liver disease. Prompt and complete evaluation of the potential recipient and availability of a donor organ are critical to the success of this approach.

    View details for Web of Science ID A1994PK76700014

    View details for PubMedID 7942675

  • AORTIC-VALVE ENDOCARDITIS AFTER ORTHOTOPIC LIVER-TRANSPLANTATION TRANSPLANTATION Egawa, H., Woodley, S., Keeffe, E. B., Concepcion, W., WIVIOTT, L. D., Menegaux, F., Esquivel, C. O. 1994; 58 (6): 732-734

    View details for Web of Science ID A1994PK26700019

    View details for PubMedID 7940698

  • NEUROLOGICAL COMPLICATIONS OF LIVER-TRANSPLANTATION IN ADULT VERSUS PEDIATRIC-PATIENTS TRANSPLANTATION Menegaux, F., Keeffe, E. B., Andrews, B. T., Egawa, H., Monge, H., Concepcion, W., So, S. K., Esquivel, C. O. 1994; 58 (4): 447-450


    Neurological complications are important contributors to morbidity and mortality after liver transplantation. We reviewed 391 patients who underwent 427 consecutive orthotopic liver transplantations to analyze the clinical features of patients who experienced one or more neurological complication (74 patients [19%]) and to compare postoperative neurological problems in adults versus children. Neurological complications were more frequent in adults (64 of 273 patients [23%]) than children (10 of 118 patients [8%]) (P < 0.01). The most common neurological complication was encephalopathy (59%), which ranged widely in severity and occurred with similar frequency in adults and children. Other common neurological complications were seizures (12 patients), brachial plexus and peripheral nerve injuries (16 patients, 15 of whom were adults), stroke (5 patients), and central nervous system infections (5 patients). In 27 patients, drug toxicity was the primary cause of neurological complications, all of which reversed with dosage reduction or discontinuation of drug. Cyclosporine and FK506, primarily during intravenous administration for induction of immunosuppression, accounted for 25 of 27 drug-induced neurological complications, which included encephalopathy, seizures, severe tremor, and severe headache. Despite a higher rate of neurological complications in adults, those in children were more severe and associated with a higher mortality rate. When compared with liver transplant recipients without neurological complications, patients with neurological complications had a higher posttransplant mortality rate (14% vs. 5% for adults, and 50% vs. 7% for children). In conclusion, neurological complications after liver transplantation are more common in adults, more severe and associated with a higher mortality rate in children, and associated with a higher mortality rate in both children and adults when compared with transplant recipients without neurological complications.

    View details for Web of Science ID A1994PE12000010

    View details for PubMedID 8073514



    A man undergoing evaluation for liver transplantation was found to have an asymptomatic chest mass, which further evaluation revealed to be pulmonary varices. The left hilar lesion was discovered on a screening chest x-ray film and confirmed by a computed tomographic scan of the thoracic cavity. Bronchoscopy was nondiagnostic, and a thoracotomy was required to diagnose the vascular lesion and exclude carcinoma. The pathophysiology of this pulmonary venous anomaly appeared to be related to portal hypertension, since esophagogastric and colonic varices also were present and the pulmonary varices resolved after liver transplantation. This is the first reported case of pulmonary varices caused by portal hypertension.

    View details for Web of Science ID A1994NX37200056

    View details for PubMedID 8020292

  • FK506 CONVERSION THERAPY IN PEDIATRIC LIVER-TRANSPLANTATION TRANSPLANTATION Egawa, H., Esquivel, C. O., So, S. K., Cox, K., Concepcion, W., Lawrence, L. 1994; 57 (8): 1169-1173


    The safety and efficacy of conversion to FK506 after failing immunosuppression with cyclosporine was prospectively evaluated in 31 pediatric liver transplant recipients between April 1991 and March 1993. The patients, who ranged in age from 40 days to 14 years, accounted for 28 primary transplantations and 3 retransplantations. The initial immunosuppression regimen consisted of cyclosporine in combination with prednisone. The indications for conversion were acute or chronic rejection refractory to OKT3, Minnesota antilymphocyte globulin, or steroids (13 patients); hypertension (8 patients); inability to reach a therapeutic level of cyclosporine (6 patients); hirsutism (3 patients); and growth retardation (1 patient). After an average follow-up of 10 months (range, 2 to 25 months), 27 (87%) of the patients are alive and have functioning grafts. Of the 13 patients who were converted for refractory rejection, 9 are alive. Six of these 9 patients experienced a complete biochemical reversal of the rejection process within 3 months of conversion; 2 had a partial response to conversion, and 1 patient failed but underwent successful retransplantation. Three of the 4 patients who died did so without showing any improvement. The remaining 18 patients who were converted for various other reasons are alive and have functioning grafts. Of the 8 patients who developed hypertension on cyclosporine and prednisone, 6 experienced a resolution of this problem within 3 months of conversion. Three of the 18 children who underwent rescue therapy for reasons other than refractory rejection experienced rejection episodes after conversion to FK506. Two of these 3 children achieved resolution with either steroid therapy or an increased dosage of FK506, while the third child developed chronic rejection. The side effects of FK506 were generally minor and resolved by lowering the dose. Lymphoproliferative disease developed in 2 patients (6%). The present study suggests that FK506 is a relatively safe and effective rescue therapy for pediatric liver transplant recipients who have failed immunosuppression with cyclosporine. Longer follow-up is needed to assess the effect of FK506 on growth.

    View details for Web of Science ID A1994NJ20800005

    View details for PubMedID 7513911



    The use of polyethylene glycol (PEG) in preservation solutions has been associated with a decreased incidence of rejection in clinical and experimental organ transplantation. In this study, we examined the effect of PEG with different molecular configurations on rejection of small bowel allografts in the rat. Male ACI and LEW rats were used as donors and recipients, respectively. Orthotopic small bowel transplantation was performed using the following preservation solutions: lactated Ringer's solution (n = 7), University of Wisconsin solution (n = 7), University of Wisconsin solution without hydroxyethyl starch (sUW; n = 7), sUW with PEG20M (n = 9), sUW with PEG8000 (n = 6), and sUW with PEG20L (n = 7). No immunosuppression was given. In orthotopic small bowel transplantation, only groups with a high molecular weight PEG, PEG20M and PEG20L, demonstrated longer survival (P < 0.01 and P < 0.001, respectively) and delayed onset of unkempt appearance (P < 0.05 and P < 0.001, respectively). In heterotopic small bowel transplantation, sUW was compared with sUW with PEG20L. Rejection occurred later and its progression was slower in the sUW with PEG20L than in the sUW alone. Our observations suggest that the onset and progression of rejection after small bowel transplantation were influenced by the molecular weight and configuration of the PEG molecule. The mechanism is unclear, but high molecular weight PEG appears to reduce or change the immunogenicity of the small bowel allograft.

    View details for Web of Science ID A1994NC19000001

    View details for PubMedID 8140625


    View details for Web of Science ID A1994MU93900034

    View details for PubMedID 8310529

  • Liver transplantation at California Pacific Medical Center, San Francisco, California. Clinical transplants Esquivel, C. O., Martinez, O., Krams, S., Lim, J., So, S. K., Concepcion, W., Cox, K. L., Keeffe, E. B. 1994: 163-171


    A number of modifications in patient selection, operative technique, and immunosuppressive management have greatly contributed to the success of the liver transplant program at CPMC. Graft rejection and the timely detection of EBV infection are ongoing problems in hepatic transplantation that are foci of active research in our field. To address these issues, our group is investigating the activity of cytokines and adhesion molecules using sophisticated molecular techniques, and we are developing a sensitive assay for EBV markers in blood. These and other projects currently in progress will continue when we move our liver transplant program to Stanford University Medical Center in January 1995.

    View details for PubMedID 7547535


    View details for Web of Science ID A1993ML92400017

    View details for PubMedID 8266439

  • CHARACTERIZATION OF CHOLECYSTOKININ RECEPTORS ON THE HUMAN SPHINCTER OF ODDI SURGERY Tokunaga, Y., Cox, K. L., Itasaka, H., Concepcion, W., Nakazato, P., Esquivel, C. O. 1993; 114 (5): 942-950


    The present in vitro study investigated the interaction between cholecystokinin (CCK) and receptors on human sphincter of Oddi tissue obtained from donated human livers that were being transplanted.Radiolabeled ligands with cholecystokinin receptor specificity, autoradiography, and crystal scintillation counting were used to directly characterize cholecystokinin receptors on tissue sections.The binding of 125I-BH-CCK-8 to the tissue was saturable, specific, and dependent on time, pH, and temperature. Saturable binding of 125I-BH-CCK-8 was localized on the smooth muscle layer, and binding was inhibited only by cholecystokinin-related peptides. Computer analysis of 125I-BH-CCK-8 binding indicated the presence of two classes of binding sites, one with a high affinity and the other with a low affinity for CCK-8. CCK-8 caused relaxation (half-maximal concentration, 6 nmol/L) and carbachol caused contraction (half-maximal concentration, 10 nmol/L) of circular, cross-sectional strips of the tissue. Longitudinal strips were less responsive. The relative 125I-BH-CCK-8 binding inhibition potency of CCK-8 agreed closely with its relative ability to cause sphincter relaxation. Tetrodotoxin (1 mumol/L) and atropine (1 mumol/L) caused a rightward shift of the dose-response curve for CCK-8-stimulated sphincter relaxation.The present results indicate that cholecystokinin receptors on the human sphincter of Oddi are sulfate dependent and mediate sphincter relaxation.

    View details for Web of Science ID A1993MF75400013

    View details for PubMedID 8236019



    Liver transplantation for alcoholic cirrhosis remains controversial. In particular, criteria for the selection of patients who will remain recovered from alcoholism post-transplant require better definition. We analyzed the long-term predictive value of categorizing transplant referral patients with alcoholism and end-stage liver disease into risk groups for recidivism and noncompliance. Forty-seven patients with the diagnosis of alcoholism and advanced liver disease were evaluated and placed into predefined risk groups (low-, moderate-, and high-risk) for recidivism and noncompliance. No absolute period of abstinence from alcohol was required. All patients were asked to sign a contract not to drink alcohol and comply with a rehabilitation program before and after transplantation. Compliance with alcohol rehabilitation, abstinence, functional level, employment, and survival were assessed. Patients who were not compliant with the rehabilitation program or consumed alcohol were scored as failures. Thirty-one patients were ranked as low risk, and were accepted for liver transplantation; 27 patients were transplanted. Five of 31 patients (16%) drank alcohol. One patient drank before and four patients drank transiently after transplantation. Ten patients were categorized as moderate risk, and were deferred for transplantation; two patients underwent later transplantation. All 10 patients (100%) were noncompliant or drank alcohol, including two patients who drank after transplantation after a period of abstinence and rehabilitation. Six patients were ranked as high risk, and were denied liver transplantation. Five patients (83%) drank alcohol and were noncompliant. Minimum follow-up was 12 months (mean, 24 months; range, 12-41 months). The mean Karnofsky performance score was 34 before and 84 after liver transplantation. Actuarial survival of alcoholic patients undergoing transplantation was 93%. We conclude that categorization of transplant referral patients with alcoholism and liver failure into predefined risk groups for recidivism and noncompliance accurately predicts pre- and post-transplant behavior. As defined, only low-risk alcoholic patients are good candidates for liver transplantation.

    View details for Web of Science ID A1993LW16600006

    View details for PubMedID 8362826


    View details for Web of Science ID A1993KY21900104

    View details for PubMedID 7682357



    A portoenterostomy (PE) procedure for extrahepatic biliary atresia (EHBA) is sometimes performed with a stoma in an attempt to reduce the incidence of acute cholangitis. The purpose of this study was to determine if the presence of a stoma increased the complication rate of patients undergoing orthotopic liver transplantation (OLT) for EHBA. The medical records of 42 consecutive patients with EHBA who underwent primary OLT between October 1988 and October 1991 were retrospectively reviewed. Three patients were excluded, since their grafts were lost within 3 days of OLT. The remaining 39 patients were divided into three groups: no PE (n = 7), PE without stoma (n = 23), and PE with stoma (n = 9). The mean age of the whole group was 19.62 +/- 24.37 months, with a range of 5 to 132 months. Mean weight was 9.62 kg, with a range of 4.2 to 41 kg. Survival at 3 and 12 months as well as number of retransplantations were similar among the three groups. However, at the time of OLT increased morbidity was observed, consisting of increased operative time and number of reoperations, whether or not the stoma had been closed prior to OLT.

    View details for Web of Science ID A1993KR55100019

    View details for PubMedID 8468652

  • PROGNOSTIC FACTORS FOR SUCCESSFUL CONVERSION FROM CYCLOSPORINE TO FK-506 - BASED IMMUNOSUPPRESSIVE THERAPY FOR REFRACTORY REJECTION AFTER LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Klintmalm, G. B., Goldstein, R., Gonwa, T., Wiesner, R. H., Krom, R. A., Shaw, B. W., Stratta, R., Ascher, N. L., Roberts, J. W., Lake, J., Busuttil, R. W., McDiarmid, S., Esquivel, C. O., Nakazato, P., Marsh, J. W., Woodle, E. S., Kalayoglu, M., DALESSANDRO, A. M., Pirsch, J. D., Miller, C., Schwartz, M., Lewis, W. D., Monaco, A. P., Jenkins, R. L., Emond, J. C., Thistlethwaite, J. R., Whitington, P. F., Steinmuller, D. R., Fitzsimmons, W. E., Lawrence, I. 1993; 25 (1): 641-643
  • USE OF PROGRAF (FK-506) AS RESCUE THERAPY FOR REFRACTORY REJECTION AFTER LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Klintmalm, G. B., Goldstein, R., Gonwa, T., Wiesner, R. H., Krom, R. A., Shaw, B. W., Stratta, R., Ascher, N. L., Roberts, J. W., Lake, J., Busuttil, R. W., McDiarmid, S., Esquivel, C. O., Nakazato, P., Marsh, J. W., Woodle, E. S., Kalayoglu, M., DALESSANDRO, A. M., Pirsch, J. D., Miller, C., Schwartz, M., Lewis, W. D., Monaco, A. P., Jenkins, R. L., Emond, J. C., Thistlethwaite, J. R., Whitington, P. F., Steinmuller, D. R., Fitzsimmons, W. E., Lawrence, I. 1993; 25 (1): 679-688
  • CHARACTERIZATION OF CHOLECYSTOKININ RECEPTORS ON THE HUMAN GALLBLADDER SURGERY Tokunaga, Y., Cox, K. L., Coleman, R., Concepcion, W., Nakazato, P., Esquivel, C. O. 1993; 113 (2): 155-162


    Several studies examined in vivo and in vitro biologic activity of the human gallbladder in response to cholecystokinin (CCK). However, few studies have demonstrated directly the interaction of CCK with receptors on the human gallbladder, which is responsible for this biologic activity.To characterize CCK receptors on human gallbladder tissue, gallbladders were removed from human donor grafts that were being used for liver transplantation. The gallbladders were rapidly frozen and sectioned for measurement of binding of 125I-Bolton-Hunter-labeled-CCK-8 and were cut into strips for in vitro bioassay.Binding of 125I-BH-CCK-8 to human gallbladder was saturable, specific, and dependent on time, pH, and temperature. The binding was inhibited only by cholecystokinin-related peptides including CCK-8 (IC50 10 +/- 1.0 nmol/L) (mean +/- SD), des(SO3) CCK-8 (IC50 0.9 +/- 0.2 mumol/L), and gastrin-17-I (IC50 9.0 +/- 2.0 mumol/L) or specific CCK receptor antagonist L-364,718. Computer analysis of binding of 125I-BH-CCK-8 to gallbladder tissue showed a single class of binding sites with high affinity for CCK-8. Autoradiography localized binding of 125I-BH-CCK-8 only to the smooth muscle layer of the gallbladder. In the bioassay des(SO3) CCK-8 (EC50 1.2 +/- 0.7 mumol/L) and gastrin-17-I (EC50 4.5 +/- 2.4 mumol/L) were 150- and 563-fold less potent than CCK-8 (EC50 8.0 +/- 2.2 nmol/L). The relative potencies of CCK agonists for inhibiting binding of 125I-BH-CCK-8 agreed closely with their relative potencies for causing gallbladder contraction. The dose-response curve for CCK-8 alone to induce gallbladder contraction was not significantly different from those caused by CCK-8 plus 1 mumol/L tetrodotoxin or 1 mumol/L atropine.These results characterized the CCK receptors on smooth muscle of human gallbladder as sulfate dependent and causing gallbladder contraction.

    View details for Web of Science ID A1993KL37600007

    View details for PubMedID 7679224

  • USE OF FK-506 FOR THE PREVENTION OF RECURRENT ALLOGRAFT-REJECTION AFTER SUCCESSFUL CONVERSION FROM CYCLOSPORINE FOR REFRACTORY REJECTION TRANSPLANTATION PROCEEDINGS Klintmalm, G. B., Goldstein, R., Gonwa, T., Wiesner, R. H., Krom, R. A., Shaw, B. W., Stratta, R., Ascher, N. L., Roberts, J. W., Lake, J., Busuttil, R. W., McDiarmid, S., Esquivel, C. O., Nakazato, P., Marsh, J. W., Woodle, E. S., Kalayoglu, M., DALESSANDRO, A. M., Pirsch, J. D., Miller, C., Schwartz, M., Lewis, W. D., Monaco, A. P., Jenkins, R. L., Emond, J. C., Thistlethwaite, J. R., Whitington, P. F., Steinmuller, D. R., Fitzsimmons, W. E., Lawrence, I. 1993; 25 (1): 635-637
  • TRANSIENT DETERIORATION OF INTRAPULMONARY SHUNTING AFTER PEDIATRIC LIVER-TRANSPLANTATION TRANSPLANTATION Itasaka, H., Hershon, J. J., Cox, K. L., Tokunaga, Y., Concepcion, W., Nakazato, P., Esquivel, C. O. 1993; 55 (1): 212-214

    View details for Web of Science ID A1993KH66000042

    View details for PubMedID 8420052

  • TOTAL ABDOMINAL EVISCERATION - AN EN-BLOC TECHNIQUE FOR ABDOMINAL ORGAN HARVESTING SURGERY Nakazato, P. Z., Concepcion, W., Bry, W., Limm, W., Tokunaga, Y., Itasaka, H., FEDUSKA, N., Esquivel, C. O., Collins, G. M. 1992; 111 (1): 37-47


    This paper describes an en bloc total abdominal evisceration (TAE) technique that has been used successfully in 81 consecutive multi-organ procurements in donors ranging from 2.5 to 85 kg. Preliminary dissection performed by the surgeon and physician's assistant averaged 30 to 45 minutes before aortic cross-clamping. Removal of all abdominal organs (liver, kidneys, pancreas, bowel) en bloc averaged 16 to 24 minutes after aortic cross-clamping, depending on the speed of the thoracic procurement. Organ grafts were preserved with the University of Wisconsin preservation solution. Total procurement time for the removal of the liver, pancreas, and kidneys averaged 1.5 to 2.25 hours. Because all vascular anomalies were easily recognized ex vivo, vascular reconstruction was possible, so that all donors could potentially provide for combined liver, pancreas, and kidney transplantation. In the TAE group, primary liver graft nonfunction was 1.2% (1/81 grafts), which is less than the non-TAE liver graft nonfunction rate of 7% (7/99 grafts); this is statistically significant (p less than 0.05). Also, the incidence of fresh frozen plasma support after liver transplantation in the TAE group (2/81 transplantations) was lower than the non-TAE group (9/99 transplantations) (p less than 0.05). The overall liver recipient survival rate was 87% (non-TAE; 78/94 recipients; TAE; 65/70 recipients). Kidney-graft initial function has been similar in both the TAE and non-TAE groups. All pancreas tissue was histologically normal, and extraction of viable islet cells (average, 3600 islets per gram pancreas) was possible with yields similar to standard pancreatic (average, 379 islets per gram pancreas) harvest techniques. Preliminary experience with combined liver and whole-organ pancreas transplantations has been encouraging, with immediate discontinuation of intraoperative insulin during transplantation.

    View details for Web of Science ID A1992GY46500006

    View details for PubMedID 1728073

  • LIVER-TRANSPLANTATION - EXPERIENCE WITH 100 CASES WESTERN JOURNAL OF MEDICINE Szpakowski, J. L., Cox, K., Nakazato, P., Concepcion, W., Levin, B., Esquivel, C. O. 1991; 155 (5): 494-499


    Between March 1988 and November 1989, 100 liver transplants were performed on 90 patients at Pacific Presbyterian (now California Pacific) Medical Center in San Francisco. The immunosuppressive regimen was a combination of prophylactic Minnesota antilymphocyte globulin, cyclosporine, and low-dose corticosteroids. Rejections were treated with OKT3, a monoclonal antibody, or corticosteroids. Of the 100 transplants, 32 were done on 30 children, 18 of whom weighed less than 10 kg and 9 of whom received livers that had been surgically reduced in size to fit the recipient. The overall patient survival at 2 years was 85%. Of 100 liver transplants, treatment was given for 80 (80%) for at least 1 episode of rejection. At least 1 episode of serious infection occurred in 34 of the 60 adult patients and 25 of the 30 children. Of the entire group, 2% had hepatic artery thrombosis, and 12% had biliary complications that necessitated reoperation. The quality of life has been good, with a follow-up from 1 to almost 3 years (mean = 22 months). Comparing these data with those of other published series shows a decreased incidence of surgical complications and a lower rate of fungal and viral infections. We attribute this to the reduction of steroid dosage during convalescence without jeopardizing patient or graft survival.

    View details for Web of Science ID A1991GP12600003

    View details for PubMedID 1815388

  • THE IMPACT OF LIVER REDUCTIONS IN PEDIATRIC LIVER-TRANSPLANTATION Esquivel, C. O., Nakazato, P., Cox, K., Concepcion, W., Berquist, W., Russell, T. R. AMER MEDICAL ASSOC. 1991: 1278-1286


    Reduced-size liver transplantation (RSLT) in children was introduced to alleviate a shortage of small-organ donors. The impact of RSLT on the waiting time for an organ and on morbidity and mortality was investigated. Between March 25, 1988, and August 11, 1990, 61 hepatic transplantations were performed in 55 children at the Pacific Transplant Institute in San Francisco, Calif. Full-size liver transplantation was performed in 41 cases and RSLT in 20 cases. The overall 30-month actuarial patient and graft survival rates were 89% and 73%, respectively. A comparison between full-size liver transplantation and RSLT showed no difference in patient and graft survival, reoperations, infections, or rejection. Benefits of RSLT were an increase in the donor pool size, a decrease in waiting time for a suitable donor, and a decrease in the rate of arterial thrombosis. The main morbidity of RSLT was an increase in perioperative blood requirement. We conclude that RSLT offers small children with end-stage liver disease a chance for long-term survival.

    View details for Web of Science ID A1991GJ52400018

    View details for PubMedID 1929830



    Apolipoprotein (apo) E and the two B apolipoproteins, apoB48 and apoB100, are important proteins in human lipoprotein metabolism. Commonly occurring polymorphisms in the genes for apoE and apoB result in amino acid substitutions that produce readily detectable phenotypic differences in these proteins. We studied changes in apoE and apoB phenotypes before and after liver transplantation to gain new insights into apolipoprotein physiology. In all 29 patients that we studied, the postoperative serum apoE phenotype of the recipient, as assessed by isoelectric focusing, converted virtually completely to that of the donor, providing evidence that greater than 90% of the apoE in the plasma is synthesized by the liver. In contrast, the cerebrospinal fluid apoE phenotype did not change to the donor's phenotype after liver transplantation, indicating that most of the apoE in CSF cannot be derived from the plasma pool and therefore must be synthesized locally. The apoB100 phenotype (assessed with immunoassays using monoclonal antibody MB19, an antibody that detects a two-allele polymorphism in apoB) invariably converted to the phenotype of the donor. In four normolipidemic patients, we determined the MB19 phenotype of both the apoB100 and apoB48 in the "chylomicron fraction" isolated from plasma 3 h after a fat-rich meal. Interestingly, the apoB100 in the chylomicron fraction invariably had the phenotype of the donor, indicating that the vast majority of the large, triglyceride-rich apoB100-containing lipoproteins that appear in the plasma after a fat-rich meal are actually VLDL of hepatic origin. The MB19 phenotype of the apoB48 in the plasma chylomicron fraction did not change after liver transplantation, indicating that almost all of the apoB48 in plasma chylomicrons is derived from the intestine. These results were consistent with our immunocytochemical studies on intestinal biopsy specimens of organ donors; using apoB-specific monoclonal antibodies, we found evidence for apoB48, but not apoB100, in donor intestinal biopsy specimens.

    View details for Web of Science ID A1991FU44300036

    View details for PubMedID 2056122

  • LIVER-TRANSPLANTATION IN INFANTS WEIGHING LESS THAN 10-KILOGRAMS TRANSPLANTATION PROCEEDINGS Cox, K., Nakazato, P., Berquist, W., Concepcion, W., Tokunaga, Y., Esquivel, C. 1991; 23 (1): 1579-1580

    View details for Web of Science ID A1991EV39100273

    View details for PubMedID 1989298

  • LIVER-TRANSPLANTATION IN LANGERHANS CELL HISTIOCYTOSIS (HISTIOCYTOSIS-X) SEMINARS IN ONCOLOGY Concepcion, W., Esquivel, C. O., Terry, A., Nakazato, P., GARCIAKENNEDY, R., Houssin, D., Cox, K. L. 1991; 18 (1): 24-28


    Two children with biopsy-proven LCH underwent successful hepatic transplantation for end-stage liver disease. These patients were thought not to have active LCH disease at the time of transplantation, although one had developed a new osteolytic lesion a few months before the operation and the other had suspicious osteolytic lesions at the time of transplantation. The histologic examination of the excised liver showed features consistent with primary sclerosing cholangitis. The two patients had an excellent recovery with no evidence of progression of LCH or recurrence of the underlying disease in the hepatic allograft at 1 and 3 years after organ transplantation.

    View details for Web of Science ID A1991EX24100005

    View details for PubMedID 1992520



    The histological findings in patients with primary biliary cirrhosis have been well-defined and are often used in the clinical staging of disease. However, it has only been with the development of reagents that phenotypically characterize the lymphoid infiltrate that attempts have been made to correlate pathophysiology with immune effector populations. Indeed, the inflammatory hepatic lesions in primary biliary cirrhosis have been described as containing CD4-positive and CD8-positive T cells. Less clear, however, have been the T cell receptors in these lesions. Further, the data on immunoglobulin deposits in hepatic lesions have been less well-defined; this deficit may be a result of the quality of polyspecific sera and difficulties in background. To address these issues, we have used a battery of well-defined monospecific and polyspecific reagents to phenotypically define the occurrence of lymphoid cells in the livers of patients undergoing transplantation. Furthermore, we have defined these same markers on T cell lines derived from liver, regional lymph node and peripheral blood. The predominant cell type in the mononuclear infiltrate is the CD3+, CD4+ T lymphocyte bearing the T cell receptor alpha beta. T cell lines from the same patients demonstrate similar findings. Of special importance, however, was the detection of CD20+ B cells and Ig+ cells in the lymphoid infiltrate. Indeed, we also readily demonstrated the presence of immunoglobulin on the surface of biliary epithelium. These data suggest that mechanisms involved in the pathophysiology of primary biliary cirrhosis may include both T cell and antibody mechanisms. The results also underscore the need to develop a functional, and not just a phenotypical, assay of the inflammatory infiltrate.

    View details for Web of Science ID A1990DW92100018

    View details for PubMedID 2202637

  • LYMPHOMA AND HYPERCALCEMIA IN A PEDIATRIC ORTHOTOPIC LIVER-TRANSPLANT PATIENT TRANSPLANTATION Nakazato, P., Esquivel, C. O., URBACH, A. H., Makowka, L., Scantlebury, V., Jaffe, R., Starzl, T. E. 1989; 48 (6): 1003-1006


    We present a case report of a pediatric orthotopic liver transplant recipient who developed lymphoma with hypercalcemia on cyclosporine and prednisone immunosuppression. This is the first reported posttransplant lymphoproliferative disorder complicated by hypercalcemia, with a finding of an elevated 1,25 dihydroxyl vitamin D state, suggesting that it has a role in the pathophysiology of this B cell lymphoma hypercalcemia. The clinical course and management of this disorder with a 31-month follow-up are described.

    View details for Web of Science ID A1989CL69800022

    View details for PubMedID 2595760

  • INFECTIONS IN PEDIATRIC LIVER RECIPIENTS TREATED FOR ACUTE REJECTION TRANSPLANTATION PROCEEDINGS Koneru, B., Scantlebury, V. P., Makowka, L., Esquivel, C. O., Todo, S., Tzakis, A. G., Marsh, J. W., Iwatsuki, S., Douglas, L., Starzl, T. E. 1989; 21 (1): 2251-2252

    View details for Web of Science ID A1989U152400412

    View details for PubMedID 2652730

  • LIVER-TRANSPLANTATION FOR HEREDITARY TYROSINEMIA IN THE PRESENCE OF HEPATOCELLULAR-CARCINOMA TRANSPLANTATION PROCEEDINGS Esquivel, C. O., Mieles, L., Marino, I. R., Todo, S., Makowka, L., Ambrosino, G., Nakazato, P., Starzl, T. E. 1989; 21 (1): 2445-2446

    View details for Web of Science ID A1989U152400491

    View details for PubMedID 2540570



    A 17-yr-old female received a liver transplant for type I glycogen storage disease. A year later, when she experienced variceal gastrointestinal hemorrhage, an angiogram revealed thrombosis of the portal vein with hepatopetal collateral channels. A distal splenorenal shunt was performed because of failure of sclerotherapy to control subsequent bleeding episodes and the fact that the liver function was normal. This patient continues to have normal hepatic function with a patent splenorenal shunt 4 yr after the shunting procedure. This case illustrates the feasibility of a distal splenorenal shunt to alleviate portal hypertension in cases of thrombosis of the portal vein following hepatic transplantation if the liver function is normal.

    View details for Web of Science ID A1989R822000017

    View details for PubMedID 2643299

  • TREATMENT OF HEPATIC EPITHELIOID HEMANGIOENDOTHELIOMA WITH LIVER-TRANSPLANTATION CANCER Marino, I. R., Todo, S., Tzakis, A. G., Klintmalm, G., Kelleher, M., Iwatsuki, S., Starzl, T. E., Esquivel, C. O. 1988; 62 (10): 2079-2084


    Ten patients received liver transplants for unresectable epithelioid hemangioendothelioma (EHE). At the time of transplantation, four patients had microscopic metastases to the hilar lymph nodes, and one of the four also had metastases to a rib. The fifth patient had metastases to the lung, pleura, and diaphragm. The remaining five patients were believed to be free of metastatic disease. Two of these five patients died of metastatic disease at 3 and 16 months, respectively, after transplantation. Interestingly, all five patients with metastatic involvement are currently alive 40.6 +/- 22 months (mean +/- standard error of mean [SEM]) after transplantation, although one of these patients currently has metastatic disease to the lungs and mediastinum. Thus, the projected 5-year actuarial survival rate is 76%, with two patients at risk after the third year. In conclusion, liver transplantation is a reasonable procedure for bulky, otherwise unresectable, EHE even in the presence of metastatic disease.

    View details for Web of Science ID A1988Q718400001

    View details for PubMedID 3052779

  • APLASTIC-ANEMIA COMPLICATING ORTHOTOPIC LIVER-TRANSPLANTATION FOR NON-A, NON-B HEPATITIS NEW ENGLAND JOURNAL OF MEDICINE Tzakis, A. G., Arditi, M., Whitington, P. F., Yanaga, K., Esquivel, C., Andrews, W. A., Makowka, L., MALATAK, J., Freese, D. K., Stock, P. G., Ascher, N. L., Johnson, F. L., Broelsch, C. E., Starzl, T. E. 1988; 319 (7): 393-396


    Aplastic anemia developed in 9 of 32 patients (28 percent) undergoing orthotopic liver transplantation for acute non-A, non-B hepatitis, at one to seven weeks after the procedure. No patient previously had evidence of hematologic dysfunction or conditions known to be associated with aplastic anemia. No other cases of aplastic anemia were identified among 1463 patients undergoing liver transplantation for all other indications at the four centers participating in the study (chi-square = 415, P less than 0.001; 95 percent confidence interval for the incidence of aplastic anemia after transplantation for non-A, non-B hepatitis, 13 to 44 percent, vs. 0.00 to 0.13 percent for all other indications). The operative and postoperative treatment of these patients was not otherwise different, indicating that the aplastic anemia was a complication of the hepatitis, not of the transplantation procedure. Four of the nine patients died of complications due to infections. Three of the surviving patients have been followed for less than six months, one for one year, and one for two years. The two patients followed the longest have recovered marrow function to an appreciable degree, and two of the others have evidence of early recovery. We conclude that patients undergoing orthotopic liver transplantation for non-A, non-B hepatitis are at a high risk for the development of aplastic anemia.

    View details for Web of Science ID A1988P684200002

    View details for PubMedID 3135496

  • TRANSPLANTATION FOR PRIMARY BILIARY-CIRRHOSIS GASTROENTEROLOGY Esquivel, C. O., VANTHIEL, D. H., Demetris, A. J., Bernardos, A., Iwatsuki, S., Markus, B., Gordon, R. D., Marsh, J. W., Makowka, L., Tzakis, A. G., Todo, S., GAVALER, J. S., Starzl, T. E. 1988; 94 (5): 1207-1216


    Primary biliary cirrhosis is a frequent indication for liver transplantation. The purpose of this report is to present our experience with liver transplantation for primary biliary cirrhosis. Attention is given to the causes of hepatic dysfunction seen in allografts. In addition, we review the postoperative problems encountered and the quality of life at time of last follow-up in patients with transplants for primary biliary cirrhosis. A total of 97 orthotopic liver transplant procedures were performed in 76 patients with advanced primary biliary cirrhosis at the University of Pittsburgh from March 1980 through September 1985. The transplant operation was relatively easy to perform. The most common technical complications experienced were fragmentation and intramural dissection of the recipient hepatic artery, which required an arterial graft in 20% of the cases. Most of the postoperative mortality occurred in the first 6 mo after transplantation, with an essentially flat actuarial life survival curve from that time point to a projected 5-yr survival of 66%. Common causes of death included rejection and primary graft nonfunction. Thirteen of the 76 patients had some hepatic dysfunction at the time of the last follow-up, although none were jaundiced. Recurrence of primary biliary cirrhosis could not be demonstrated in any of the patients. Antimitochondrial antibody was detected in the serum of almost all of the patients studied postoperatively for it. Most important, almost all of the 52 surviving patients have been rehabilitated socially and vocationally.

    View details for Web of Science ID A1988M938200014

    View details for PubMedID 3280389

  • OCCURRENCE OF CYTOMEGALO-VIRUS HEPATITIS IN LIVER-TRANSPLANT PATIENTS JOURNAL OF MEDICAL VIROLOGY Bronsther, O., Makowka, L., Jaffe, R., Demetris, A. J., BREINIG, M. K., Ho, M., Esquivel, C. O., Gordon, R. D., Iwatsuki, S., Tzakis, A., Marsh, J. W., Mazzaferro, V., Vanthiel, D., Starzl, T. E. 1988; 24 (4): 423-434


    The differential diagnosis of liver dysfunction after orthotopic liver transplantation can be difficult. Cytomegalovirus (CMV) hepatitis is one possibility. This report reviews our experience with 17 cases of pathologically proven CMV hepatitis following liver transplantation and demonstrates the need for percutaneous liver biopsies to establish the diagnosis. There were seven pediatric patients (ages 2-11 years, five males, two females) and ten adult patients (ages 17-53 years, eight males, two females). The most common symptoms were prolonged fever (15 patients, with a mean duration of 22 +/- 5.5 days), elevation in total bilirubin (14 patients), and elevation in liver enzymes (15 patients); all symptoms were also found in rejection. Leukopenia and thrombocytopenia, reported to frequently occur with CMV infection, were found in only three and five patients, respectively. Twelve patients with the above symptoms underwent percutaneous biopsy on one or more occasions to differentiate CMV hepatitis from rejection. The diagnosis was made at retransplantation in five patients. CMV hepatitis followed treatment for acute rejection in 14 patients and occurred without additional immunosuppression in three patients. All patients were maintained on cyclosporine and prednisone. Acute rejection episodes were treated with a 5-day tapering dose of steroids (17 courses in 12 patients), OKT3 monoclonal antibody [Ortho (4 patients)] antithymocyte globulin [Upjohn (2 patients)], and azathioprine (1 patient). CMV was isolated from urine (nine patients), blood (nine patients), throat (seven patients), lungs (two patients), and other organs (two patients). CMV was cultured from the liver biopsy specimens in five of the seven attempts in pediatric patients. When the diagnosis was confirmed in the absence of rejection, immunosuppression was routinely lowered. When rejection occurred concomitantly with CMV hepatitis, therapy had to be individualized. Retrospectively, three patients treated for rejection were noted at retransplantation to have only CMV hepatitis, and all three patients died. A high index of suspicion and the judicious use of liver biopsies is essential in order to differentiate CMV hepatitis from other causes of posttransplant liver dysfunction.

    View details for Web of Science ID A1988M850200008

    View details for PubMedID 2835433



    Liver transplantation has provided individuals with cholestatic disorders a chance for long-term near-normal quality and quantity of survival. The experience at the University of Pittsburgh with hepatic transplantation for chronic cholestatic liver disease is presented in brief in this article.

    View details for Web of Science ID A1988N568500009

    View details for PubMedID 3292424

  • AN UNUSUAL COMPLICATION OF CHOLEDOCHOCHOLEDOCHOSTOMY IN ORTHOTOPIC LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Stieber, A. C., Ambrosino, G., Kahn, D., Mieles, L., Makowka, L., Lerut, J., Iwatsuki, S., Todo, S., Marsh, J. W., Tzakis, A. G., Gordon, R. D., Esquivel, C. O., Starzl, T. E. 1988; 20 (1): 619-621
  • EXPERIENCE WITH ORTHOCLONE OKT3 MONOCLONAL-ANTIBODY IN LIVER-TRANSPLANTATION AMERICAN JOURNAL OF KIDNEY DISEASES Gordon, R. D., Tzakis, A. G., Iwatsuki, S., Todo, S., Esquivel, C. O., Marsh, J. W., Stieber, A., Makowka, L., Starzl, T. E. 1988; 11 (2): 141-144


    Experience with the use of Orthoclone OKT3 monoclonal antibody for the treatment of acute cellular rejection in a series of 130 human orthotopic liver transplantations is reviewed. Treatment was highly effective in reversing rejection, in reducing the rate of retransplantation, and in lowering patient mortality. OKT3 was also useful for cyclosporine sparing in patients with poor renal function, hypertension, or CNS toxicity. There was a significant incidence of opportunistic infection associated with the use of OKT3.

    View details for Web of Science ID A1988M005600016

    View details for PubMedID 3124609

  • EXPERIENCE IN 1,000 LIVER-TRANSPLANTS UNDER CYCLOSPORINE-STEROID THERAPY - A SURVIVAL REPORT TRANSPLANTATION PROCEEDINGS Iwatsuki, S., Starzl, T. E., Todo, S., Gordon, R. D., Esquivel, C. O., Tzakis, A. G., Makowka, L., Marsh, J. W., Koneru, B., Stieber, A., Klintmalm, G., Husberg, B. 1988; 20 (1): 498-504

    View details for Web of Science ID A1988M463100152

    View details for PubMedID 3279643

  • ORTHOTOPIC LIVER-TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS ANNALS OF SURGERY Marsh, J. W., Iwatsuki, S., Makowka, L., Esquivel, C. O., Gordon, R. D., Todo, S., Tzakis, A., Miller, C., Vanthiel, D., Starzl, T. E. 1988; 207 (1): 21-25


    The incidence or diagnostic rate of sclerosing cholangitis is increasing. Because of the lack of effective medical or surgical therapy for patients with end-stage liver disease and sclerosing cholangitis, results with orthotopic liver transplantation were examined. The results of 55 consecutive liver replacements for this disease were reviewed. The 1- and 2-year actuarial survival rates are 71% and 57%, respectively. Orthotopic liver transplantation for end-stage liver disease from sclerosing cholangitis has emerged as the most effective therapy.

    View details for Web of Science ID A1988L633700005

    View details for PubMedID 2827593



    One of 55 patients transplanted for sclerosing cholangitis during the cyclosporin-steroid era (March 1980-June 1986) developed intrahepatic biliary strictures in the absence of allograft rejection within the 1st year posttransplantation. Although many causes underlie biliary pathology in the postoperative period (i.e., arterial injury, ischemia, chronic rejection, cholangitis), recurrent disease remains a possibility.

    View details for Web of Science ID A1988R067500002

    View details for PubMedID 3075471

  • EXPERIENCE WITH PRIMARY LIVER-TRANSPLANTATION ACROSS ABO BLOOD-GROUPS TRANSPLANTATION PROCEEDINGS Gordon, R. D., Iwatsuki, S., Esquivel, C. O., Todo, S., Makowka, L., Tzakis, A., Marsh, J. W., Starzl, T. E. 1987; 19 (6): 4575-4579

    View details for Web of Science ID A1987L305600042

    View details for PubMedID 3321622

  • ORTHOTOPIC LIVER-TRANSPLANTATION FOR ALPHA-1-ANTITRYPSIN DEFICIENCY - AN EXPERIENCE IN 29 CHILDREN AND 10 ADULTS TRANSPLANTATION PROCEEDINGS Esquivel, C. O., Vicente, E., Vanthiel, D., Gordon, R., Marsh, W., Makowka, L., Koneru, B., Iwatsuki, S., Madrigal, M., Millan, M. A., Todo, S., Tzakis, A., Starzl, T. E. 1987; 19 (5): 3798-3802
  • PROLONGATION OF PIG-TO-DOG RENAL XENOGRAFT SURVIVAL BY MODIFICATION OF THE INFLAMMATORY MEDIATOR RESPONSE ANNALS OF SURGERY Makowka, L., Miller, C., Chapchap, P., Podesta, L., Pan, C., Pressley, D., Mazzaferro, V., Esquivel, C. O., Todo, S., Banner, B., Jaffe, R., Saunders, R., Starzl, T. E. 1987; 206 (4): 482-495


    The pathogenesis of hyperacute renal rejection consists of a nonspecific effector cascade that invokes most of the components of a typical acute inflammatory response. Platelet-activating factor (PAF) represents the most recent and perhaps the most significant mediator and promoting agent of this phenomenon. These studies evaluated SRI 63-441, a novel, synthetic, and the most potent PAF receptor antagonist available, alone and in combination with other prostanoids, for their ability to influence this response and to prolong renal xenograft survival and function in a model of pig-to-dog heterotransplantation. Inhibition of PAF by SRI 63-441 alone, at the dosage and schedule used in these experiments, did not significantly prolong xenograft survival or function. However, the combination of SRI 63-441 with either prostacyclin (PGI2) or prostaglandin E1 (PGE1) infusion demonstrated significant synergism, and resulted in a 6-9-fold increase in kidney survival and a 3-20-fold increase in urine output. Neither PGI2 nor PGE1 infusions alone significantly influenced this xenograft model. Electromagnetic flow studies demonstrated significantly delayed diminution in renal artery blood flow in the combination-treated animals. Serial and end-stage histologic examination of kidneys receiving combination therapy demonstrated a delayed onset of the pathologic deterioration and an overall amelioration of the entire process. These studies demonstrate that significant abrogation of a rapid and violent form of hyperacute rejection can be achieved solely by the pharmacologic manipulation of the inflammatory mediator response.

    View details for Web of Science ID A1987K399900009

    View details for PubMedID 3310931

  • IS MULTIPLE ORGAN FAILURE A CONTRAINDICATION FOR LIVER-TRANSPLANTATION IN CHILDREN TRANSPLANTATION PROCEEDINGS Esquivel, C. O., Koneru, B., Todo, S., Iwatsuki, S., Gordon, R. D., Marsh, J. W., Makowka, L., Tzakis, A. G., Starzl, T. E. 1987; 19 (4): 47-48

    View details for Web of Science ID A1987J700500010

    View details for PubMedID 3303532

  • LIVER-TRANSPLANTATION IN PATIENTS WITH PATENT SPLENORENAL SHUNTS SURGERY Esquivel, C. O., Klintmalm, G., Iwatsuki, S., MAKOWSKA, L., Gordon, R. D., Tzakis, A., Starzl, T. E. 1987; 101 (4): 430-432


    Patent distal splenorenal shunts (Warren shunt) have been reported to cause decreases in the portal perfusion pressure and the total hepatic blood flow. Such hemodynamic alterations could have adverse effects on the transplanted liver. The experience with hepatic replacement in four patients with patent Warren shunts is reported. Operative findings were phlebosclerotic portal veins of small size and diminished portal blood flows. Hepatofugal collateral channels created by the construction of the Warren shunt were eliminated by division of the shunt and splenectomy in three patients and splenectomy alone in the other. All patients recovered; thus the presence of a patent Warren shunt should not be a contraindication for hepatic transplantation.

    View details for Web of Science ID A1987G781100008

    View details for PubMedID 3551166

  • HEPATIC-ARTERY IN LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Todo, S., Makowka, L., Tzakis, A. G., Marsh, J. W., Karrer, F. M., ARMANY, M., Miller, C., TALLENT, M. B., Esquivel, C. O., Gordon, R. D., Iwatsuki, S., Starzl, T. E. 1987; 19 (1): 2406-2411

    View details for Web of Science ID A1987G101500207

    View details for PubMedID 3547931

  • OKT3 IN THE REVERSAL OF ACUTE HEPATIC ALLOGRAFT-REJECTION TRANSPLANTATION PROCEEDINGS Esquivel, C. O., Fung, J. J., Markus, B., Iwatsuki, S., Gordon, R. D., Makowka, L., Marsh, J. W., Tzakis, A. G., Todo, S., Starzl, T. E. 1987; 19 (1): 2443-2446


    OKT3 was an effective immunosuppressant agent in patients with acute cell-mediated allograft rejection that had not responded to initial steroid therapy. OKT3 was also valuable for treating patients with early hepatic graft dysfunction caused by other factors than rejection. In such recipients, the doses of CyA can be greatly reduced, allowing recovery of frequently damaged kidneys while maintaining effective immunosuppression.

    View details for Web of Science ID A1987G101500220

    View details for PubMedID 3103297

  • ANALYSIS OF DONOR CRITERIA FOR THE PREDICTION OF OUTCOME IN CLINICAL LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Makowka, L., Gordon, R. D., Todo, S., Ohkohchi, N., Marsh, J. W., Tzakis, A. G., Yokoi, H., Ligush, J., Esquivel, C. O., Satake, M., Iwatsuki, S., Starzl, T. E. 1987; 19 (1): 2378-2382


    The results of 219 orthotopic human liver transplants performed during 1985 at the University of Pittsburgh were reviewed to determine whether donor parameters could be used to predict the quality of early graft function. Multivariate discriminant analysis demonstrated that traditional parameters of donor assessment are unreliable predictors of poor graft function. Furthermore, 56% of the donors considered poor by conservative selection criteria produced livers with good early posttransplant function. Survival of recipients of primary allografts from donors rated poor was no different than survival of recipients of allografts from donors rated good.

    View details for Web of Science ID A1987G101500197

    View details for PubMedID 3103296

  • LATE MORTALITY AND MORBIDITY AFTER LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Iwatsuki, S., Starzl, T. E., Gordon, R. D., Esquivel, C. O., Todo, S., Tzakis, A. G., Makowka, L., Marsh, J. W., Miller, C. M. 1987; 19 (1): 2373-2377

    View details for Web of Science ID A1987G101500196

    View details for PubMedID 3547930

  • USE OF OKT3 WITH CICLOSPORIN AND STEROIDS FOR REVERSAL OF ACUTE KIDNEY AND LIVER ALLOGRAFT-REJECTION NEPHRON Fung, J. J., Demetris, A. J., Porter, K. A., Iwatsuki, S., Gordon, R. D., Esquivel, C. O., Jaffe, R., Tzakis, A., Shaw, B. W., Starzl, T. E. 1987; 46: 19-33


    OKT3 monoclonal antibody therapy was added to preexisting baseline immunosuppressive treatment with ciclosporin and steroids to treat rejection in 52 recipients of cadaveric livers and 10 recipients of cadaveric kidneys. Rejection was controlled in 75% of patients treated, often after high-dose steroid therapy had failed. Rejection recurred during the 17-month follow-up period, after completion of OKT3, in only 25% of the patients who had responded. The safety and effectiveness of this monoclonal therapy, added to ciclosporin and steroids, has been established in this study.

    View details for Web of Science ID A1987J437000004

    View details for PubMedID 3306422

  • EXCRETION OF CYCLOSPORINE AND ITS METABOLITES IN HUMAN BILE TRANSPLANTATION PROCEEDINGS Burckart, G. J., Starzl, T. E., Venkataramanan, R., Hashim, H., Wong, L., Wang, P., Makowka, L., Zeevi, A., Ptachcinski, R. J., Knapp, J. E., Iwatsuki, S., Esquivel, C., Sanghvi, A., VANTHIEL, D. H. 1986; 18 (6): 46-49


    Quantitative and qualitative studies of cyclosporine and its metabolites were performed on human bile from liver transplant and liver disease patients. The concentration of CsA in bile is higher in patients with normal liver function than in those with poor liver function but in neither case could account for more than 2% of an absorbed dose of CsA. Although concentrations of CsA plus metabolites in bile measured by RIA were 18 to 36 times higher than HPLC concentrations, they accounted for less than 50% of an absorbed CsA dose. By means of mass spectrometry and HPLC retention times of known metabolites, peaks equivalent to the previously isolated CsA M8, M13, M17, M1, M18, and M21 of Maurer et al were found in the ether extracts of bile. Future studies should not only concentrate on the pharmacologic and toxicologic effects of the metabolites but should also accurately quantitate these compounds in blood, plasma, urine, and bile.

    View details for Web of Science ID A1986F245100008

    View details for PubMedID 3538573

  • INDICATIONS FOR LIVER-TRANSPLANTATION IN THE CYCLOSPORINE ERA SURGICAL CLINICS OF NORTH AMERICA Gordon, R. D., Shaw, B. W., Iwatsuki, S., Esquivel, C. O., Starzl, T. E. 1986; 66 (3): 541-556


    One hundred seventy orthotopic liver transplants were performed under conventional immunosuppression with azathioprine and steroids with 1- and 5-year survivals of 32.9 per cent and 20.0 per cent, respectively. Since the introduction of cyclosporine-prednisone therapy in March 1980, 313 primary orthotopic liver transplants have been performed. Actuarial survivals at 1 and 5 years have improved to 69.7 per cent and 62.8 per cent, respectively. Biliary atresia is now the most common indication for liver replacement. In adults, primary biliary cirrhosis and sclerosing cholangitis have become more common indications for transplantation, and alcoholic cirrhosis and primary liver malignancy as indications have declined. Early enthusiasm for liver transplantation in patients with hepatic cancer has been tempered by the finding that recurrence is both common and rapid. An increasing number of patients with inborn errors of metabolism originating in the liver are receiving transplants, including patients with Wilson's disease, tyrosinemia, alpha-1-antitrypsin deficiency, glycogen storage disease, familial hypercholesterolemia, and hemochromatosis. Survival in this group of patients has been excellent (74.4 per cent at 1 and 5 years). A hemophiliac who received a transplant for postnecrotic cirrhosis has survived and may have been cured of his hemophilia. About 20 per cent of patients require retransplantation for rejection, technical failure, or primary graft failure. Only four of the patients receiving retransplants under conventional immunosuppression survived beyond 6 months, and all died within 14 months of retransplantation. Sixty-eight patients have received retransplants under cyclosporine-prednisone. Thirty-one patients are surviving, all for at least 1 year. Six of the twelve patients requiring a third transplant are alive 2 to 3 years after the primary operation. An aggressive approach to retransplantation in the patient with a failed graft is justified.

    View details for Web of Science ID A1986C707400012

    View details for PubMedID 3520895

  • LIVER-TRANSPLANTATION IN THE CICLOSPORIN ERA PROGRESS IN ALLERGY Starzl, T. E., Iwatsuki, S., Shaw, B. W., Gordon, R. D., Esquivel, C. 1986; 38: 366-394

    View details for Web of Science ID A1986D111900021

    View details for PubMedID 3088582

  • REFINEMENTS IN THE SURGICAL TECHNIQUE OF LIVER-TRANSPLANTATION SEMINARS IN LIVER DISEASE Starzl, T. E., Iwatsuki, S., Esquivel, C. O., Todo, S., Kam, I., Lynch, S., Gordon, R. D., Shaw, B. W. 1985; 5 (4): 349-356

    View details for Web of Science ID A1985AVM4600008

    View details for PubMedID 3909429



    During the last 5 years, liver transplantation has become a service as opposed to an experimental operation. The most important factor in making this possible has been the introduction of cyclosporine-steroid therapy. At the same time, liver transplantation has been made more practical by improvements in diagnosing and managing other causes of postoperative hepatic dysfunction. Tissue typing and matching have played no role in improving the results of liver transplantation. With the demonstration that performed antibody states are irrelevant, even avoidance of positive cross-matches caused by cytotoxic antibodies and observance of ABO blood group barriers have become unnecessary if the recipient's needs are great. With the exceptions of malignancy and cirrhosis, the nature of the underlying hepatic disease has not profoundly influenced the results. Retransplantation has played an important role in improving survival, although the costs of retransplantation have been extremely high.

    View details for Web of Science ID A1985AVM4600006

    View details for PubMedID 3909427

  • FACTORS IN THE DEVELOPMENT OF LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Starzl, T. E., Iwatsuki, S., Shaw, B. W., Gordon, R. D., Esquivel, C., Todo, S., Kam, I., Lynch, S. 1985; 17: 107-119
  • LIVER REJECTION AND ITS DIFFERENTIATION FROM OTHER CAUSES OF GRAFT DYSFUNCTION SEMINARS IN LIVER DISEASE Esquivel, C. O., Jaffe, R., Gordon, R. D., Iwatsuki, S., Shaw, B. W., Starzl, T. E. 1985; 5 (4): 369-374


    Numerous causes can lead to hepatic dysfunction following orthotopic liver transplantation. The most common cause is rejection, which is usually nonpreventable. The clinical presentation, time of onset, and even treatment are variable. Other causes, such as perioperative ischemic injury, vascular thrombosis, and complications of bile duct reconstruction may be preventable with good surgical technique. Infections can also be minimized by careful adjustment of immunotherapy, avoidance overimmunosuppression, and the judicious use of antibiotics. Hepatic dysfunction following orthotopic liver transplantation requires rapid assessment and proper treatment in order to prevent serious and possibly fatal complications.

    View details for Web of Science ID A1985AVM4600010

    View details for PubMedID 3001943

  • LIVER-TRANSPLANTATION FOR FULMINANT HEPATIC-FAILURE SEMINARS IN LIVER DISEASE Iwatsuki, S., Esquivel, C. O., Gordon, R. D., Shaw, B. W., Starzl, T. E., SHADE, R. R., VANTHIEL, D. H. 1985; 5 (4): 325-328

    View details for Web of Science ID A1985AVM4600004

    View details for PubMedID 3909425

  • POSTOPERATIVE SMALL BOWEL INTUSSUSCEPTION WESTERN JOURNAL OF MEDICINE Esquivel, C. O., Bishop, P. J., Marr, C., Schwartz, M. Z. 1985; 143 (1): 108-110

    View details for Web of Science ID A1985AMK8500031

    View details for PubMedID 4036108

  • NEPHROTOXICITY OF CYCLOSPORINE IN LIVER-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Iwatsuki, S., Esquivel, C. O., Klintmalm, G. B., Gordon, R. D., Shaw, B. W., Starzl, T. E. 1984; 17 (4): 191-195

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