William Berquist

All Publications

Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. Molecular genetics and metabolism Diaz, G. A., Schulze, A., Longo, N., Rhead, W., Feigenbaum, A., Wong, D., Merritt, J. L., Berquist, W., Gallagher, R. C., Bartholomew, D., McCandless, S. E., Smith, W. E., Harding, C. O., Zori, R., Lichter-Konecki, U., Vockley, J., Canavan, C., Vescio, T., Holt, R. J., Berry, S. A. 2019
Abstract

INTRODUCTION: Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB.METHODS: This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing.RESULTS: A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35 mol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure.CONCLUSION: Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.

View details for DOI 10.1016/j.ymgme.2019.07.004

View details for PubMedID 31326288
PEDIATRIC ENDOSCOPY PRACTICE PATTERNS IN THE UNITED STATES, CANADA AND MEXICO Barakat, M. T., Triadafilopoulos, G., Berquist, W. MOSBY-ELSEVIER. 2019: AB286
View details for Web of Science ID 000470094901185
LIVER TRANSPLANTATION IN MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALMYOPATHY (MNGIE) Kripps, K., Larson, A., Nakayuenyongsuk, W., Berquist, W., Ospina, N., Esquivel, C., Concepcion, W., Van Hove, J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 280–81
View details for Web of Science ID 000463310000038
Pediatric Endoscopy Practice Patterns in the United States, Canada and Mexico. Journal of pediatric gastroenterology and nutrition Barakat, M. T., Triadafilopoulos, G., Berquist, W. E. 2019
Abstract

BACKGROUND & AIMS: Endoscopic procedures are important for diagnosis and management of many gastrointestinal, liver and biliary conditions in children. Therapeutic endoscopy procedures, including ERCP, are performed less frequently in children relative to adults. However, a formal study to evaluate institutional volumes and practice patterns for advanced therapeutic pediatric endoscopy procedures has not been previously undertaken.METHODS: A self-administered 16-question (5-minute) online survey assessing practice patterns for performance of pediatric endoscopy procedures was distributed to all registered North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) programs. Results were analyzed using descriptive statistics and thematic analysis of free-text comments.RESULTS: Respondents from 82.9% of NASPGHAN centers completed this survey. Responses revealed that EGD/colonoscopy are performed at the vast majority of centers (>90%), with most performing >50/year. Therapeutic endoscopy procedures are performed less frequently in the pediatric population, with 18.97% reporting that ERCP is not performed at their institution. Where ERCP is performed, 91.38% reported <25/year. EUS is not performed at over half (53.33%) of institutions. 71.67% of respondents do not believe their institution's current arrangement for performing pediatric therapeutic endoscopy procedures is adequate.CONCLUSIONS: Although the range of endoscopic procedures performed in children parallels that performed in adults, there are notable differences in pediatric and adult gastroenterologists' endoscopy training and procedure volumes. Our results and respondent comments suggest that pediatric patients would benefit from a partnership between pediatric and adult gastroenterologists, with adult gastroenterologists performing more complex therapeutic endoscopic procedures.

View details for PubMedID 30789864
Initial experience with peroral endoscopic myotomy for treatment of achalasia in children JOURNAL OF PEDIATRIC SURGERY Kethman, W. C., Thorson, C. M., Sinclair, T. J., Berquist, W. E., Chao, S. D., Wall, J. K. 2018; 53 (8): 1532–36
View details for DOI 10.1016/j.jpedsurg.2017.07.023

View details for Web of Science ID 000439577000014
"Blueberry Muffin" Rash and Neonatal Cholestatic Liver Failure. Digestive diseases and sciences Mudambi, K., Berquist, W. 2018; 63 (7): 1747–50
View details for PubMedID 29071487
"Blueberry Muffin" Rash and Neonatal Cholestatic Liver Failure DIGESTIVE DISEASES AND SCIENCES Mudambi, K., Berquist, W. 2018; 63 (7): 1747–50
View details for DOI 10.1007/s10620-017-4810-9

View details for Web of Science ID 000435949100011
Growing Concerns: A 3-Year-Old Girl with Multiple Hepatic Masses and Gastrointestinal Bleeding DIGESTIVE DISEASES AND SCIENCES Yang, C., Gomez, A., Haldipur, A., Berquist, W., Bass, D. 2018; 63 (2): 329–33
View details for PubMedID 28646285
Prenatal treatment of ornithine transcarbamylase deficiency. Molecular genetics and metabolism Wilnai, Y., Blumenfeld, Y. J., Cusmano, K., Hintz, S. R., Alcorn, D., Benitz, W. E., Berquist, W. E., Bernstein, J. A., Castillo, R. O., Concepcion, W., Cowan, T. M., Cox, K. L., Lyell, D. J., Esquivel, C. O., Homeyer, M., Hudgins, L., Hurwitz, M., Palma, J. P., Schelley, S., Akula, V. P., Summar, M. L., Enns, G. M. 2018
Abstract

Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery.Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years.Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

View details for PubMedID 29396029
Dilation of Esophageal Stricture in a Pediatric Patient Using Functional Lumen Imaging Probe Technology Without the Use of Fluoroscopy. Journal of pediatric gastroenterology and nutrition Taylor, J. S., Danzer, E., Berquist, W. E., Wall, J. K. 2018
View details for DOI 10.1097/MPG.0000000000001936

View details for PubMedID 29470294
Initial experience with peroral endoscopic myotomy for treatment of achalasia in children. Journal of pediatric surgery Kethman, W. C., Thorson, C. M., Sinclair, T. J., Berquist, W. E., Chao, S. D., Wall, J. K. 2017
Abstract

Achalasia is a primary esophageal motility disorder characterized by aperistalsis of the esophagus and failed relaxation of the lower esophageal sphincter that presents rarely in childhood. The peroral endoscopic myotomy (POEM) procedure is an emerging treatment for achalasia in adults that has recently been introduced into pediatric surgical practice.This is a prospective case series of all children referred to Stanford University Lucile Packard Children's Hospital with manometry-confirmed achalasia who underwent a POEM procedure from 2014 to 2016.We enrolled 10 subjects ranging in age from 7 to 17years (M=13.4). The mean pre- and 1-month post-procedure Eckardt scores were 7 (SD=2.5) and 2.4 (SD=2) (p<0.001), respectively. The median procedure time for the entire cohort was 142min (range 60-259min) with ongoing improvement with increased experience (R2=0.6, p=0.008). There were no major adverse events.The POEM procedure can be successfully completed in children for the treatment of achalasia with demonstrated short-term post-operative improvement in symptoms. The adoption of advanced endoscopic techniques by pediatric surgeons may enable development of unique intraluminal approaches to congenital anomalies and other childhood diseases.Treatment Study - Level IV.

View details for PubMedID 28827050
Mass cytometry reveals a distinct immunoprofile of operational tolerance in pediatric liver transplantation. Pediatric transplantation Lau, A. H., Vitalone, M. J., Haas, K., Shawler, T., Esquivel, C. O., Berquist, W. E., Martinez, O. M., Castillo, R. O., Krams, S. M. 2016
Abstract

Long-term IS in transplant patients has significant morbidity, poorer quality of life, and substantial economic costs. TOL, defined as graft acceptance without functional impairment in the absence of IS, has been achieved in some pediatric LT recipients. Using mass cytometry, peripheral blood immunotyping was performed to characterize differences between tolerant patients and patients who are stable on single-agent IS. Single-cell mass cytometry was performed using blood samples from a single-center pediatric LT population of operationally tolerant patients to comprehensively characterize the immune cell populations in the tolerant state compared with patients on chronic low-dose IS. Specific T-cell populations of interest were confirmed by flow cytometry. This high-dimensional phenotypic analysis revealed distinct immunoprofiles between transplant populations as well as a CD4(+) TOT (CD4(+) CD5(+) CD25(+) CD38(-/lo) CD45RA) that correlates with tolerance in pediatric LT recipients. In TOL patients, the TOT was significantly increased as compared to patients stable on low levels of IS. This TOT cell was confirmed by flow cytometry and is distinct from classic Treg cells. These results demonstrate the power of mass cytometry to discover significant immune cell signatures that have diagnostic potential.

View details for DOI 10.1111/petr.12795

View details for PubMedID 27781378
Protein and calorie intakes in adult and pediatric subjects with urea cycle disorders participating in clinical trials of glycerol phenylbutyrate. Molecular genetics and metabolism reports Hook, D., Diaz, G. A., Lee, B., Bartley, J., Longo, N., Berquist, W., Le Mons, C., Rudolph-Angelich, I., Porter, M., Scharschmidt, B. F., Mokhtarani, M. 2016; 6: 34-40
Abstract

Little prospectively collected data are available comparing the dietary intake of urea cycle disorder (UCD) patients to UCD treatment guidelines or to healthy individuals.To examine the protein and calorie intakes of UCD subjects who participated in clinical trials of glycerol phenylbutyrate (GPB) and compare these data to published UCD dietary guidelines and nutritional surveys.Dietary data were recorded for 45 adult and 49 pediatric UCD subjects in metabolic control during participation in clinical trials of GPB. Protein and calorie intakes were compared to UCD treatment guidelines, average nutrient intakes of a healthy US population based on the National Health and Nutrition Examination Survey (NHANES) and Recommended Daily Allowances (RDA).In adults, mean protein intake was higher than UCD recommendations but lower than RDA and NHANES values, while calorie intake was lower than UCD recommendations, RDA and NHANES. In pediatric subjects, prescribed protein intake was higher than UCD guidelines, similar to RDA, and lower than NHANES data for all age groups, while calorie intake was at the lower end of the recommended UCD range and close to RDA and NHANES data. In pediatric subjects height, weight, and body mass index (BMI) Z-scores were within normal range (- 2 to 2).Pediatric patients treated with phenylbutyrate derivatives exhibited normal height and weight. Protein and calorie intakes in adult and pediatric UCD subjects differed from UCD dietary guidelines, suggesting that these guidelines may need to be reconsidered.

View details for DOI 10.1016/j.ymgmr.2015.11.002

View details for PubMedID 27014577

View details for PubMedCentralID PMC4789342
Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis NATURE COMMUNICATIONS Gomez-Ospina, N., Potter, C. J., Xiao, R., Manickam, K., Kim, M., Kim, K., Shneider, B. L., Picarsic, J. L., Jacobson, T. A., Zhang, J., He, W., Liu, P., Knisely, A. S., Finegold, M. J., Muzny, D. M., Boerwinkle, E., Lupski, J. R., Plon, S. E., Gibbs, R. A., Eng, C. M., Yang, Y., Washington, G. C., Porteus, M. H., Berquist, W. E., Kambham, N., Singh, R. J., Xia, F., Enns, G. M., Moore, D. D. 2016; 7
View details for DOI 10.1038/ncomms10713

View details for Web of Science ID 000371035200014
Glutamine and hyperammonemic crises in patients with urea cycle disorders MOLECULAR GENETICS AND METABOLISM Lee, B., DIAZ, G. A., Rhead, W., Lichter-Konecki, U., Feigenbaum, A., Berry, S. A., Le Mons, C., Bartley, J., Longo, N., Nagamani, S. C., Berquist, W., Gallagher, R. C., Harding, C. O., McCandless, S. E., Smith, W., Schulze, A., Marino, M., Rowell, R., Coakley, D. F., Mokhtarani, M., Scharschmidt, B. F. 2016; 117 (1): 27-32
Abstract

Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients.The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate.The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 μmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]μmol/L) than patients with baseline glutamine ≤ 900 μmol/L (26.6 [18.0]μmol/L). Glutamine values >900 μmol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia ≥ 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 μmol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia ≥ 1.0 ULN (HR=4.62; p=0.0011).The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels.

View details for DOI 10.1016/j.ymgme.2015.11.005

View details for Web of Science ID 000368220400005

View details for PubMedCentralID PMC4915945
Endoscopic Submucosal Dissection of a Large Hamartoma in a Young Child. Journal of pediatric gastroenterology and nutrition Wall, J., Esquivel, M., Bruzoni, M., Wright, R., Berquist, W., Albanese, C. 2016; 62 (1): e5-7
View details for DOI 10.1097/MPG.0000000000000376

View details for PubMedID 26709909
Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nature communications Gomez-Ospina, N., Potter, C. J., Xiao, R., Manickam, K., Kim, M., Kim, K. H., Shneider, B. L., Picarsic, J. L., Jacobson, T. A., Zhang, J., He, W., Liu, P., Knisely, A. S., Finegold, M. J., Muzny, D. M., Boerwinkle, E., Lupski, J. R., Plon, S. E., Gibbs, R. A., Eng, C. M., Yang, Y., Washington, G. C., Porteus, M. H., Berquist, W. E., Kambham, N., Singh, R. J., Xia, F., Enns, G. M., Moore, D. D. 2016; 7: 10713-?
Abstract

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

View details for DOI 10.1038/ncomms10713

View details for PubMedID 26888176
Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials. Molecular genetics and metabolism Nagamani, S. C., Diaz, G. A., Rhead, W., Berry, S. A., Le Mons, C., Lichter-Konecki, U., Bartley, J., Feigenbaum, A., Schulze, A., Longo, N., Berquist, W., Gallagher, R., Bartholomew, D., Harding, C. O., Korson, M. S., McCandless, S. E., Smith, W., Vockley, J., Kronn, D., Zori, R., Cederbaum, S., Lawrence Merritt, J., Wong, D., Coakley, D. F., Scharschmidt, B. F., Dickinson, K., Marino, M., Lee, B. H., Mokhtarani, M. 2015; 116 (1-2): 29-34
Abstract

Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes.Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB).After 3months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1; p<0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose.The reduction in symptoms following 3months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.

View details for DOI 10.1016/j.ymgme.2015.08.002

View details for PubMedID 26296711
Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder GENETICS IN MEDICINE Lee, B., Diaz, G. A., Rhead, W., Lichter-Konecki, U., Feigenbaum, A., Berry, S. A., Le Mons, C., Bartley, J. A., Longo, N., Nagamani, S. C., Berquist, W., Gallagher, R., Bartholomew, D., Harding, C. O., Korson, M. S., McCandless, S. E., Smith, W., Cederbaum, S., Wong, D., Merritt, J. L., Schulze, A., Vockley, G., Kronn, D., Zori, R., Summar, M., Milikien, D. A., Marino, M., Coakley, D. F., Mokhtarani, M., Scharschmidt, B. F. 2015; 17 (7): 561-568
Abstract

The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and ≥1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced ≥1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5×; P = 0.011) and rate (~5×, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia ≥1.0 ULN vs. <0.5ULN; relative risk was even greater (20×; P = 0.009) in patients ≥6 years old. A 10- or 25-µmol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis.Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.Genet Med 17 7, 561-568.

View details for DOI 10.1038/gim.2014.148

View details for PubMedID 25503497
Gastric Outlet Obstruction Caused by Heterotopic Pancreas in an Adolescent DIGESTIVE DISEASES AND SCIENCES Rodriguez, A. A., Berquist, W., Bingham, D. 2015; 60 (4): 835-837
View details for DOI 10.1007/s10620-014-3314-0

View details for Web of Science ID 000354464900010

View details for PubMedID 25107445
Text Messaging Improves Participation in Laboratory Testing in Adolescent Liver Transplant Patients. Journal of participatory medicine McKenzie, R. B., Berquist, W. E., Foley, M. A., Park, K. T., Windsheimer, J. E., Litt, I. F. 2015; 7
Abstract

In solid organ transplant patients, non-participation in all aspects of the medical regimen is a prevalent problem associated with adverse consequences particularly in the adolescent and young adult (AYA) age group. This study is the first to evaluate the feasibility, utility and impact of a text messaging (TM) intervention to improve participation in laboratory testing in adolescent liver transplant patients.AYA patients, aged 12 to 21 years, were recruited for a prospective pilot trial evaluating a TM intervention delivered over a 1-year period. The intervention involved automated TM reminders with feedback administered according to a prescribed laboratory testing frequency. Participation rate in laboratory testing after the intervention was compared to the year prior. Patient responses and feedback by text and survey were used to assess feasibility, acceptability and use of the intervention.Forty-two patients were recruited and 33 patients remained enrolled for the study duration. Recipients of the TM intervention demonstrated a significant improvement in participation rate in laboratory testing from 58% to 78% (P<.001). This rate was also significantly higher than in non-intervention controls (P=.003). There was a high acceptability, response rate and a significant correlation with reported versus actual completion of laboratory tests by TM.TM reminders significantly improved participation in laboratory testing in AYA liver transplant patients. The intervention demonstrated feasibility, acceptability, and use with a high proportion of patients who engaged in and perceived a benefit from using this technology.

View details for PubMedID 26213633

View details for PubMedCentralID PMC4511378
Misdiagnosis of Alpha-1 Antitrypsin Phenotype in an Infant with CMV Infection and Liver Failure DIGESTIVE DISEASES AND SCIENCES Arias, P., Kerner, J., Christofferson, M., Berquist, W., Park, K. T. 2014; 59 (8): 1710-1713
View details for DOI 10.1007/s10620-014-3094-6

View details for Web of Science ID 000340051200075

View details for PubMedID 24633574
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
Abstract

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
Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio MOLECULAR GENETICS AND METABOLISM Mokhtarani, M., DIAZ, G. A., Rhead, W., Berry, S. A., Lichter-Konecki, U., Feigenbaum, A., Schulze, A., Longo, N., Bartley, J., Berquist, W., Gallagher, R., Smith, W., McCandless, S. E., Harding, C., Rockey, D. C., Vierling, J. M., Mantry, P., Ghabril, M., Brown, R. S., Dickinson, K., Moors, T., Norris, C., Coakley, D., Milikien, D. A., Nagamani, S. C., LeMons, C., Lee, B., Scharschmidt, B. F. 2013; 110 (4): 446-453
Abstract

Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels.The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values.Only 0.2% (11) of 4683 samples exceeded 500 μg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels>500 μg/ml.The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

View details for DOI 10.1016/j.ymgme.2013.09.017

View details for Web of Science ID 000328094500006

View details for PubMedID 24144944

View details for PubMedCentralID PMC4108288
USE OF A NOVEL PROTOCOL TO SUCCESSFULLY CHARACTERIZE AND TREAT IMMUNE-MEDIATED ACUTE HEPATITIS AND LIVER FAILURE IN CHILDREN McKenzie, R. B., Berquist, W., Esquivel, C., Nadeau, K., Chen, S., Sibley, R., Cox, K. WILEY-BLACKWELL. 2013: 52
View details for Web of Science ID 000321439600042
IMPACT OF AN ADOLESCENT LIVER TRANSPLANT CLINIC ON CLINICAL OUTCOMES Algaze, S. D., McKenzie, R. B., Park, K. T., Castillo, M., Berquist, W. E. WILEY-BLACKWELL. 2013: 67
View details for Web of Science ID 000321439600101
Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate HEPATOLOGY Diaz, G. A., Krivitzky, L. S., Mokhtarani, M., Rhead, W., Bartley, J., Feigenbaum, A., Longo, N., Berquist, W., Berry, S. A., Gallagher, R., Lichter-Konecki, U., Bartholomew, D., Harding, C. O., Cederbaum, S., McCandless, S. E., Smith, W., Vockley, G., Bart, S. A., Korson, M. S., Kronn, D., Zori, R., Merritt, J. L., Nagamani, S. C., Mauney, J., LeMons, C., Dickinson, K., Moors, T. L., Coakley, D. F., Scharschmidt, B. F., Lee, B. 2013; 57 (6): 2171-2179
Abstract

Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short-term comparisons of glycerol phenylbutyrate versus NaPBA, NH3 -AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with the slow-release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open-label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self-monitoring, was significantly improved. Conclusion: Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric UCD patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012).

View details for DOI 10.1002/hep.26058

View details for Web of Science ID 000320276400013

View details for PubMedID 22961727

View details for PubMedCentralID PMC3557606
Evaluation of ethanol lock therapy in pediatric patients on long-term parenteral nutrition. Nutrition in clinical practice Pieroni, K. P., Nespor, C., Ng, M., Garcia, M., Hurwitz, M., Berquist, W. E., Kerner, J. A. 2013; 28 (2): 226-231
Abstract

Pediatric home parenteral nutrition (PN) patients present a unique challenge with risks of catheter-associated bloodstream infections (CABSIs), sometimes requiring subsequent catheter removal. Recurrent infections can lead to line removal and potential loss of venous access in the future.Demonstrate that weekly ethanol lock therapy decreases CABSIs in long-term home PN patients and decreases line removals due to infections.Beginning August 2007, patients receiving PN with a history of multiple previous CABSIs were started on ethanol lock therapy. Seventy percent ethanol solution was instilled into the central venous catheter (CVC) for 2 hours weekly. Episodes of CABSIs and catheter removal due to infection were documented in patients prior to and after ethanol lock therapy.Fourteen patients were followed for an average of 690 days after ethanol lock therapy was initiated. These patients were found to average 9.8 CABSIs per 1000 catheter days prior to starting ethanol lock therapy and only 2.7 CABSIs per 1000 catheter days after ethanol lock therapy (P < .001). Prior to ethanol lock therapy, the group averaged 4.3 catheter removals per 1000 catheter days but only 1.0 catheter removal per 1000 catheter days after ethanol lock therapy.Our group of patients showed a 73% reduction in CABSIs and a 77% reduction in catheter removal due to infection after ethanol lock therapy. In our patient population, weekly ethanol lock therapy for 2 hours is an effective technique to reduce CABSIs and catheter removal in long-term home PN patients.

View details for DOI 10.1177/0884533612468009

View details for PubMedID 23232749
Use of a Novel Protocol to Successfully Characterize and Treat Immune-Mediated Acute Hepatitis and Liver Failure in Children 13th American Transplant Congress (ATC) McKenzie, R., Berquist, W., Nadeau, K., Chen, S., Sibley, R., Cox, K. WILEY-BLACKWELL. 2013: 49–49
View details for Web of Science ID 000318240300061
ECHINOCANDIN AND ETHANOL LOCK THERAPY TREATMENT OF FUNGAL CATHETER INFECTIONS PEDIATRIC INFECTIOUS DISEASE JOURNAL Pieroni, K. P., Nespor, C., Poole, R. L., Kerner, J. A., Berquist, W. E. 2013; 32 (3): 289-291
Abstract

Ethanol lock therapy has been implemented to prevent infections of central venous catheters as well as to treat infections. Fungal catheter-associated blood stream infections are historically more difficult to treat and have required removal of central venous catheters. We report the largest case series to date, successfully treating 5 of 7 fungal catheter-associated blood stream infections with ethanol lock therapy and systemic echinocandin administration.

View details for DOI 10.1097/INF.0b013e3182784867

View details for Web of Science ID 000314932700027

View details for PubMedID 23076381
Impact of Immunosuppression on the Development of Epstein-Barr Virus (EBV) Viremia After Pediatric Liver Transplantation TRANSPLANTATION PROCEEDINGS Lu, B. R., Park, K. T., Hurwitz, M., Cox, K. L., Berquist, W. E. 2013; 45 (1): 301-304
Abstract

Pediatric liver transplant (OLT) patients are at risk of posttransplant lymphoproliferative disease (PTLD) from Epstein-Barr virus (EBV). This study examined the impact of induction and immunosuppression on EBV viremia.A retrospective chart review was performed on 197 pediatric patients and induction regimen, immunosuppression levels, and EBV viremia were documented for 1 year post-OLT. Logistic regression models determined associations between induction, immunosuppression, and EBV.Fifty six percent of patients developed EBV viremia. Incidence of EBV viremia was 73% with antithymocyte globulin (ATG), 63% with daclizumab, and 39% for neither, though the trend was not significant [ATG: odds ratio (OR) 0.19; 95% confidence interval (CI) 0.024-1.58; P = .125; daclizumab OR; 1.07; 95% CI 0.270-4.23; P = .925]. Tacrolimus immunosuppression levels were supratherapeutic 28.7% of the time; however, only supratherapeutic tacrolimus levels between 0 and 2 weeks increased EBV viremia at 2 to 4 weeks post-OLT (OR 1.80; 95% CI 1.10-2.94; P = .02). Three patients developed PTLD.The use of ATG and daclizumab induction likely does not play a role in the development of EBV viremia. Supratherapeutic tacrolimus levels 0 to 2 weeks post-OLT impact the development of EBV viremia at 2 to 4 weeks. The incidence of PTLD was low, suggesting better EBV and immunosuppression monitoring plays an important role in reducing PTLD.

View details for DOI 10.1016/j.transproceed.2012.04.035

View details for Web of Science ID 000315007200060

View details for PubMedID 23267800
Endoscopy in the management of pancreaticobiliary complications after liver, intestine, or composite visceral transplantation in children PEDIATRIC TRANSPLANTATION Berquist, W. E. 2012; 16 (8): 815-817
View details for DOI 10.1111/petr.12000

View details for Web of Science ID 000310804300016

View details for PubMedID 23131054
Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders MOLECULAR GENETICS AND METABOLISM Mokhtarani, M., DIAZ, G. A., Rhead, W., Lichter-Konecki, U., Bartley, J., Feigenbaum, A., Longo, N., Berquist, W., Berry, S. A., Gallagher, R., Bartholomew, D., Harding, C. O., Korson, M. S., McCandless, S. E., Smith, W., Vockley, J., Bart, P. S., Kronn, D., Zori, R., Cederbaum, S., Dorrani, N., Merritt, J. L., Sreenath-Nagamani, S., Summar, M., LeMons, C., Dickinson, K., Coakley, D. F., Moors, T. L., Lee, B., Scharschmidt, B. F. 2012; 107 (3): 308-314
Abstract

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control.The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.

View details for DOI 10.1016/j.ymgme.2012.08.006

View details for Web of Science ID 000310720200010

View details for PubMedID 22958974

View details for PubMedCentralID PMC3608516
THE USE OF DACLIZUMAB OR ANTITHYMOCYTE GLOBULIN (ATG) FOR INDUCTION IN PEDIATRIC LIVER TRANSPLANTATION DOES NOT INCREASE THE RISK OF EPSTEIN-BARR VIRUS (EBV) VIREMIA POST TRANSPLANTATION BUT DOES SHORTEN THE TIME INTERVAL TO THE DEVELOPMENT Lu, B., Park, K. T., Balise, R. R., Hurwitz, M., Cox, K., Berquist, W. WILEY-BLACKWELL. 2011: 706A–707A
View details for Web of Science ID 000295578002715
HIGH DOSES OF CALCINEURIN INHIBITORS ARE ASSOCIATED WITH LOW LEVELS OF T REGULATORY CELLS IN PEDIATRIC LIVER TRANSPLANT RECIPIENTS. Piard-Ruster, K. S., Silva, R., Berquist, W., Pham, B., Gallo, A., Krams, S. M., Esquivel, C. O., Martinez, O. M. WILEY-BLACKWELL. 2011: 57–57
View details for Web of Science ID 000293251100066
A 15-Year-Old Girl with Dysphagia, Failure to Thrive PEDIATRIC ANNALS Ryan, C., Khan, M., Delgado, E., Berquist, W., Longhurst, C. 2011; 40 (8): 397-400
View details for DOI 10.3928/00904481-20110708-05

View details for Web of Science ID 000305740900005

View details for PubMedID 21815600
Immunophenotyping of Peripheral Eosinophils Demonstrates Activation in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Tammie Nguyen, T., Gernez, Y., Fuentebella, J., Patel, A., Tirouvanziam, R., Reshamwala, N., Bass, D., Berquist, W. E., Cox, K. L., Kerner, J. A., Nadeau, K. C. 2011; 53 (1): 40-47
Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE.Eosinophils and CD3+ lymphocytes were identified directly from 50 μL of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset.Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05).Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.

View details for DOI 10.1097/MPG.0b013e318212647a

View details for Web of Science ID 000291925500006

View details for PubMedID 21694534
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
Abstract

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
Exfoliative Rejection in Intestinal Transplantation DIGESTIVE DISEASES AND SCIENCES Park, K. T., Berquist, W. L., Pai, R., Triadafilopoulos, G. 2010; 55 (12): 3336-3338
View details for DOI 10.1007/s10620-010-1354-7

View details for Web of Science ID 000284066200006

View details for PubMedID 20683662
Increased HLA-DR Expression on Tissue Eosinophils in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Patel, A. J., Fuentebella, J., Gernez, Y., Nguyen, T., Bass, D., Berquist, W., Cox, K., Sibley, E., Kerner, J., Nadeau, K. 2010; 51 (3): 290-294
Abstract

The aim of the study was to investigate whether eosinophils have increased human leukocyte antigen (HLA)-DR expression in subjects with eosinophilic esophagitis (EoE) compared with controls.Patients who were undergoing an upper endoscopy with biopsies for suspected gastroesophageal reflux disease (GERD) or EoE at Lucile Packard Children's Hospital were enrolled. In total, the blood and tissue samples of 10 healthy controls (HC), 11 subjects with GERD, and 10 with EoE were studied. Multiple tissue staining to identify eosinophils (via eosinophil cationic protein-clone EG2) and major histocompatibility complex class II cell surface receptors (via HLA-DR) was performed via immunohistochemistry. The peripheral blood was analyzed using flow cytometry to detect eosinophil HLA-DR expression among these subjects.In the tissue, a greater proportion of eosinophils expressed HLA-DR among the subjects with EoE (mean 0.83 +/- 0.14, n = 9) relative to those with GERD (mean 0.18 +/- 0.19, n = 8, P < 0.01) and HC (mean 0.18 +/- 0.13, n = 6, P < 0.01). In total, 6 participants (4 HC subjects and 2 subjects with GERD) did not have any eosinophils identified on tissue staining and were unable to be included in the present statistical analysis. In the blood, there was no statistically significant difference in eosinophil HLA-DR expression among HC subjects (mean 415 +/- 217, n = 6), subjects with GERD (mean 507 +/- 429, n = 2), and those with EoE (mean 334 +/- 181, n = 6).These data demonstrate that the eosinophils from the esophagus of subjects with EoE have increased HLA-DR expression within this tissue.

View details for DOI 10.1097/MPG.0b013e3181e083e7

View details for Web of Science ID 000281453500008

View details for PubMedID 20639774
Increased Number of Regulatory T Cells in Children With Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Fuentebella, J., Patel, A., Nguyen, T., Sanjanwala, B., Berquist, W., Kerner, J. A., Bass, D., Cox, K., Hurwitz, M., Huang, J., Nguyen, C., Quiros, J. a., Nadeau, K. 2010; 51 (3): 283-289
Abstract

There are limited data on the role of regulatory T cells (Treg) in the disease pathology of eosinophilic esophagitis (EoE). We tested the differences in Treg in subjects with EoE compared with those with gastroesophageal reflux disease (GERD) and healthy controls (HC).Pediatric patients evaluated by endoscopy were recruited for our study. Participants were categorized into 3 groups: EoE, GERD, and HC. RNA purified from esophageal biopsies were used for real-time quantitative polymerase chain reaction assays and tested for forkhead box P3 (FoxP3) mRNA expression. Treg were identified as CD4+CD25hiCD127lo cells in peripheral blood and as CD3+/FoxP3+cells in esophageal tissue.Forty-eight subjects were analyzed by real-time quantitative polymerase chain reaction: EoE (n = 33), GERD (n = 7), and HC (n = 8). FoxP3 expression was higher by up to 1.5-fold in the EoE group compared with the GERD and HC groups (P < 0.05). Protein levels of FoxP3 in blood and tissue were then investigated in 21 subjects: EoE (n = 10), GERD (n = 6), and HC (n = 5). The percentage of Treg and their subsets in peripheral blood were not significant between groups (P > 0.05). The amount of Treg in esophageal tissue was significantly greater in the EoE group (mean 10.7 CD3+/FoxP3+cells/high power field [HPF]) compared with the other groups (GERD, mean 1.7 CD3+/FoxP3+cells/HPF and HC, mean 1.6 CD3+/FoxP3+cells/HPF) (P < 0.05).We show that Treg are increased in esophageal tissue of EoE subjects compared with GERD and HC subjects. The present study illustrates another possible mechanism involved in EoE that implicates impairment of immune homeostasis.

View details for DOI 10.1097/MPG.0b013e3181e0817b

View details for PubMedID 20639775
The Effect of Calcineurin Inhibitor Dose on T Regulatory Cell Levels in Pediatric Liver Transplant Recipients. Piard-Ruster, K., Silva, R., Berquist, W., Pham, B., Gallo, A., Krams, S. M., Esquivel, C. O., Martinez, O. M. WILEY-BLACKWELL PUBLISHING, INC. 2010: 486
View details for Web of Science ID 000275921703268
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
Abstract

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 PubMedID 19671092
Eotaxin and FGF enhance signaling through an extracellular signal-related kinase (ERK)-dependent pathway in the pathogenesis of Eosinophilic esophagitis. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Huang, J. J., Joh, J. W., Fuentebella, J., Patel, A., Nguyen, T., Seki, S., Hoyte, L., Reshamwala, N., Nguyen, C., Quiros, A., Bass, D., Sibley, E., Berquist, W., Cox, K., Kerner, J., Nadeau, K. C. 2010; 6 (1): 25-?
Abstract

Eosinophilic esophagitis (EoE) is characterized by the inflammation of the esophagus and the infiltration of eosinophils into the esophagus, leading to symptoms such as dysphagia and stricture formation. Systemic immune indicators like eotaxin and fibroblast growth factor were evaluated for possible synergistic pathological effects. Moreover, blood cells, local tissue, and plasma from EoE and control subjects were studied to determine if the localized disease was associated with a systemic effect that correlated with presence of EoE disease.Real-time polymerase chain reaction from peripheral blood mononuclear cells (PBMC), immunohistochemistry from local esophageal biopsies, fluid assays on plasma, and fluorescence-activated cell sorting on peripheral blood cells from subjects were used to study the systemic immune indicators in newly diagnosed EoE (n = 35), treated EoE (n = 9), Gastroesophageal reflux disease (GERD) (n = 8), ulcerative colitis (n = 5), Crohn's disease (n = 5), and healthy controls (n = 8).Of the transcripts tested for possible immune indicators, we found extracellular signal-regulated kinase (ERK), Bcl-2, bFGF (basic fibroblast growth factor), and eotaxin levels were highly upregulated in PBMC and associated with disease presence of EoE. Increased FGF detected by immunohistochemistry in esophageal tissues and in PBMC was correlated with low levels of pro-apoptotic factors (Fas, Caspase 8) in PBMC from EoE subjects. Plasma-derived bFGF was shown to be the most elevated and most specific in EoE subjects in comparison to healthy controls and disease control subjects.We describe for the first time a possible mechanism by which increased FGF is associated with inhibiting apoptosis in local esophageal tissues of EoE subjects as compared to controls. Eotaxin and FGF signaling pathways share activation through the ERK pathway; together, they could act to increase eosinophil activation and prolong the half-life of eosinophils in local tissues of the esophagus in EoE subjects.

View details for DOI 10.1186/1710-1492-6-25

View details for PubMedID 20815913

View details for PubMedCentralID PMC2976489
Transcription Factors as Disease Indicators in Eosinophilic Esophagitis 10th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Nguyen, T., Gernez, Y., Fuentella, J., Patel, A., Tirouvanziam, R., Reshamwala, N., Saper, V., Bass, D., Berquist, W., Kerner, J., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S81–S82
View details for DOI 10.1016/j.clim.2010.03.246

View details for Web of Science ID 000277953700230
Novel Deoxyguanosine Kinase Gene Mutations and Viral Infection Predispose Apparently Healthy Children to Fulminant Liver Failure JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Shieh, J. T., Berquist, W. E., Zhang, Q., Chou, P., Wong, L. C., Enns, G. M. 2009; 49 (1): 130-132
View details for PubMedID 19502998
Identifying Eosinophilic Esophagitis through Evaluation of Plasma Biomarkers 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Joh, J., Huang, J., Nguyen, T., Vishwaanath, N., Patel, A., Fuentebella, J., Saper, V., Kerner, J., Cox, K., Berquist, W., Nadeau, K. MOSBY-ELSEVIER. 2009: S169–S169
View details for Web of Science ID 000263596301118
Combined liver-kidney transplantation in children: Indications and outcome PEDIATRIC TRANSPLANTATION Sutherland, S. M., Alexander, S. R., Sarwal, M. M., Berquist, W. E., Concepcion, W. 2008; 12 (8): 835-846
Abstract

Although it remains a relatively infrequent procedure in children, CLKT has become a viable option for a select group of pediatric patients with severe liver and kidney disease. Most are performed for rare primary diseases such as PH1, but a selected few are performed in the setting of concomitant hepatic and renal failure of uncertain etiology and prognosis. This article reviews the indications for and outcomes following CLKT in children. While it focuses on the specific primary diseases which impact liver and kidney function simultaneously, it addresses the indications based on concomitant hepatic and renal failure, such as seen in the hepatorenal syndrome, as well.

View details for DOI 10.1111/j.1399-3046.2008.01041.x

View details for Web of Science ID 000260341600004

View details for PubMedID 19000066
SIR 2008 annual meeting film panel case: Abernethy malformation JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Sze, D. Y., Berquist, W. E. 2008; 19 (9): 1274-1277
View details for DOI 10.1016/j.jvir.2008.04.017

View details for Web of Science ID 000259054900002

View details for PubMedID 18725088
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
Abstract

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
Cold agglutinin syndrome in pediatric liver transplant recipients PEDIATRIC TRANSPLANTATION Wong, W., Merker, J. D., Nguyen, C., Berquist, W., Jeng, M., Viele, M., Glader, B., Fontaine, M. J. 2007; 11 (8): 931-936
Abstract

Anemia is a common finding in post-liver transplant patients. Causes for the anemia include nutritional deficiencies, red cell aplasia as well as immune-mediated hemolysis. One of the immunologic causes of hemolytic anemia is drug-induced hemolysis. Tacrolimus is a common immunosuppressant used in post-liver transplant patients to prevent graft rejection. There have been reports of tacrolimus-associated hemolytic anemia secondary to hemolytic uremic syndrome as well as autoimmune hemolysis. There are also case-reports of severe hemolytic anemia related to cold agglutinin production in post-liver transplant patients. We described in this paper three cases of severe cold agglutinin hemolytic anemia in three pediatric liver transplant patients. Steroid therapy, plasmapheresis and withdrawal of tacrolimus led to resolution of the severe hemolytic process in each case. Whether the immune-mediated hemolysis is related to tacrolimus is not clear and needs to be characterized further.

View details for DOI 10.1111/j.1399-3046.2007.00795.x

View details for PubMedID 17976131
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
Abstract

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
Ileoscopic biopsies may be inadequate for rejection surveillance after isolated intestinal transplantation. Talisetti, A. K., Berquist, W. E., Cox, K. L., Castillo, R. O. WILEY-BLACKWELL. 2007: 97–97
View details for Web of Science ID 000246659800269
Transition from pediatric to adult care in liver transplant recipients. Berquist, R. K., Berquist, W. E., Litt, I. F. BLACKWELL PUBLISHING. 2007: 63
View details for Web of Science ID 000246659800124
High prevalence of non-adherence in adolescent liver transplant recipients: Associated with demographic risk factors and significant adverse outcomes. Berquist, R. K., Berquist, W. E., Litt, I. F. BLACKWELL PUBLISHING. 2007: 73
View details for Web of Science ID 000246659800163
Cold agglutinin syndrome in post-liver transplant patients on tacrolimus. 48th Annual Meeting of the American-Society-of-Hematology Wong, W., Merker, J., Nguyen, C., Berquist, W., Glader, B., Fontaine, M. J. AMER SOC HEMATOLOGY. 2006: 288A–289A
View details for Web of Science ID 000242440001227
Optimizing care for GI disorders in children after hematopoietic stem cell transplantation GASTROINTESTINAL ENDOSCOPY Berquist, W., Dvorak, C. C. 2006; 64 (3): 386–88
View details for DOI 10.1016/j.gie.2006.04.006

View details for Web of Science ID 000240304200015

View details for PubMedID 16923487
Pediatric intestinal transplantation at Packard children's hospital/Stanford University medical center: Report of a four-year experience 9th International Symposium on Small Bowel Transplantation Castillo, R. O., Zarge, R., Cox, K., Strichartz, D., Berquist, W., Bonham, C. A., Esquivel, C. O. ELSEVIER SCIENCE INC. 2006: 1716–17
Abstract

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
Parenteral nutrition-associated cholestasis related to parental care. Nutrition in clinical practice Wu, P. A., Kerner, J. A., Berquist, W. E. 2006; 21 (3): 291-295
Abstract

Parenteral nutrition-associated cholestasis (PNAC) is a complication not uncommon in the pediatric population. In severe cases, patients require a liver transplant. To our knowledge, we report the only case of PNAC with end-stage liver failure in a child with short bowel syndrome that resolved with a change in caretaker. Until his care was transferred from his abusive parents, he was frequently admitted for infection and sepsis. His liver function vastly improved from aspartate aminotransferase (AST) 3139 units/L, conjugated bilirubin 25.9 mg/dL to AST 47 units/L, direct bilirubin 0.3 mg/dL under the care of his attentive foster mother, and a liver transplant was no longer necessary. Bacterial infection and sepsis are risk factors correlated with patients with PNAC requiring liver transplant. Prevention of infection by a good caregiver may be a means to reduce the incidence of PNAC.

View details for PubMedID 16772546
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
Abstract

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
Hepatic infantile hemangioendothelioma with unusual manifestations 16th Annual Meeting of the North-American-Society-of-Pediatric-Gastroenterology-Hepatology-and-Nutrition Burtelow, M., Garcia, T., Lucile, S., Cox, K., Berquist, W., Kemer, J. LIPPINCOTT WILLIAMS & WILKINS. 2006: 109–13
View details for PubMedID 16385264
Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: Case report and review of the literature PEDIATRIC BLOOD & CANCER George, T. I., Jeng, M., Berquist, W., Cherry, A. M., Link, M. P., Arber, D. A. 2005; 44 (3): 270-276
Abstract

Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplantation. The vast majority of PTLD are Epstein-Barr virus (EBV)-related infections that manifest as B-cell malignancies. We report an unusual case of an EBV-associated T-cell lymphoma in a 10-year-old boy who had previously undergone liver transplantation at age 4 years. He presented with hemophagocytic syndrome (HPS) and active EBV infection, with positive serum titers and polymerase chain reaction (PCR) for EBV in blood, colon, and antral samples.

View details for DOI 10.1002/pbc.20231

View details for PubMedID 15468305
Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation 4th Annual Meeting of the American-Transplant-Congress Hurwitz, M., Desai, D. M., Cox, K. L., Berquist, W. E., Esquivel, C. O., Millan, M. T. WILEY-BLACKWELL PUBLISHING, INC. 2004: 267–72
Abstract

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
The value of the PRISM scores in comparing pediatric liver transplant outcomes PEDIATRIC TRANSPLANTATION Berquist, W. E., Andrus, J. P. 2004; 8 (3): 208–9
View details for DOI 10.1111/j.1399-3046.2004.00143.x

View details for Web of Science ID 000221693200003

View details for PubMedID 15176954
Failure to diagnose obesity and screen for fatty liver disease in general pediatric practice Riley, M. R., Berquist, W. E., Merriman, R. B., Bass, N. M., Rosenthal, P. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2004: 262A
View details for Web of Science ID 000220591101538
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
Abstract

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
Thirteen years' experience in pediatric liver transplantation: Differences between tacrolimus and cyclosporine 2nd International Congress on Immunosuppression Zajicek, A., Esquivel, C., MILLAN, M., Cox, K., Berquist, R., Berquist, W. ELSEVIER SCIENCE INC. 2002: 1976–78
View details for Web of Science ID 000177369700254

View details for PubMedID 12176653
Paediatric liver transplantation: Indications, timing and medical complications 1st University-of-California-San-Francisco/Stanford Asia Liver Symposium Cox, K. L., Berquist, W. E., Castillo, R. O. WILEY-BLACKWELL PUBLISHING, INC. 1999: S61–S66
Abstract

Newer surgical techniques and immunosuppressive therapies have resulted in paediatric liver transplantation being available for most children with end-stage liver disease and has resulted in a greater than 80% 5-year survival rate. The most common indications for paediatric liver transplantation are biliary atresia (43%), metabolic disease (13%) and acute hepatic necrosis (11%). For approximately 75% of children with acute hepatic failure, the cause is unknown. Timing of liver transplantation not only affects survival rate, but may influence neurodevelopmental outcome. Fortunately, numerous types of donors, such as reduced-sized, living related or unrelated and blood-type mismatched, have reduced the mortality of children who are waiting for liver transplantation. However, the mortality and morbidity before and after liver transplantation remain high for children who have fulminant hepatic failure or are less than 5 months of age at the time of transplantation. The principle medical complications after liver transplantation are rejection and infection. Although use of newer immunosuppressive regimens has reduced the rate of rejection, Epstein-Barr virus infection with associated lymphoproliferative disorder remains the principle cause for morbidity and mortality after the initial 3 months post-liver transplant.

View details for Web of Science ID 000081033600013

View details for PubMedID 10382641
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
Abstract

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
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
Outcome of nissen fundoplication using intraoperative manometry in children 31st Annual Meeting of the Pacific-Association-of-Pediatric-Surgeons Inge, T. H., Carmeci, C., Ohara, L. J., Berquist, W. B., Cahill, J. L. W B SAUNDERS CO-ELSEVIER INC. 1998: 1614–17
Abstract

Intraoperative manometry is useful in performing Nissen fundoplication (NF) in children. Long-term clinical outcome information after use of this method is lacking.A retrospective review of the outcomes of 62 consecutive NFs using intraoperative manometry was performed. The follow-up period was 3.4 years. Approximately half of the patients were neurologically normal (NN) and half were neurologically impaired (NI). All patients with gastroesophageal reflux disease (GERD) did not respond to an adequate trial of medical treatment.The NF was tailored to result in a twofold increase in the lower esophageal sphincter pressure (LESP) and a 75% increase in the LES length (LESL). An accelerated growth rate in 40% of "failure to thrive" (FTT) patients was demonstrated. Eighty-four percent of caregivers reported improved quality of life after NF. There was a twofold reduction in the number of hospital admissions and a sixfold reduction in total inpatient days for both NI and NN children. The early and late mortality rate was 13%, and the complication rate was similar to other series reported in the literature, with more complications occurring in NI patients. There was a 2% incidence of wrap herniation. An improvement in long-term outcomes after NF was seen in 89% of NN children and over half of NI patients.Intraoperative manometry is useful in standardizing the tightness of the wrap in NF. There was a low incidence of complications, dysphagia, recurrent emesis, and GERD in this series. Long-term outcomes using this technique were deemed very good based on caregivers' responses.

View details for Web of Science ID 000077131500007

View details for PubMedID 9856878
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
Abstract

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
New, improved Helicobacter pylori eradication therapy in children. Journal of pediatric gastroenterology and nutrition Berquist, W. E. 1998; 26 (3): 360-361
View details for PubMedID 9523877
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
Abstract

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
Wernicke encephalopathy and Beriberi during total parenteral nutrition attributable to multivitamin infusion shortage PEDIATRICS Hahn, J. S., Berquist, W., Alcorn, D. M., Chamberlain, L., Bass, D. 1998; 101 (1)
Abstract

Wernicke encephalopathy (WE) is an acute neurologic disorder characterized by a triad of ophthalmoplegia, ataxia, and mental confusion. WE is attributable to thiamine (vitamin B1) deficiency. Beriberi is the systemic counterpart of thiamine deficiency and often manifests in cardiovascular collapse. WE is usually associated with alcoholism and malnutrition. It has also been seen in people with gastrointestinal diseases with malabsorption. Patients who have received total parenteral nutrition (TPN) without proper replacement of thiamine have also developed WE. Since November 1996, there has been a shortage of multivitamin infusion (MVI). Many patients who were on chronic TPN with MVI ceased to receive the MVI and were converted to an oral form of the multivitamin. As a result, there have been several reports of children and adults on TPN who have developed WE as a result of thiamine deficiency. With this case report, we bring to attention the association of the MVI shortage and WE. Early diagnosis of WE is important, because if it is treated with thiamine in the acute stages, the neurologic and cardiovascular abnormalities can be reversed.We report a 20-year-old female patient with Crohn's disease who developed WE as a result of thiamine deficiency. She had Crohn's disease since age 9 years and was on chronic TPN. Two months before admission, MVI was discontinued in the TPN because of the shortage of its supply. An oral multivitamin tablet was substituted instead. She was admitted to the hospital for persistent vomiting. In the hospital, she continued to receive TPN without MVI, but continued taking an oral multivitamin preparation. Two weeks after admission, she developed signs of WE including diplopia, ophthalmoplegia, nystagmus, and memory disturbance. She also developed hypotension that was thought to be caused by beriberi. She was treated with 50 mg of intravenous thiamine. Within hours of the intravenous thiamine, her hypotension resolved. The day after the infusion, she no longer complained of diplopia, and her ophthalmoplegia had improved dramatically. Magnetic resonance imaging showed several areas of abnormally high signal on T2-weighted images in the brainstem, thalamus, and mamillary bodies. The topographic distribution of these changes was typical of WE. After 2 months, her mental status and neurologic status had recovered completely.WE and thiamine deficiency should be considered in all patients with malabsorption, malnutrition, and malignancies. WE from thiamine deficiency can occur as a result of cessation of MVI in the TPN infusion. Even if an oral multivitamin preparation is given instead of MVI, patients with malabsorption may not absorb thiamine adequately. Prompt diagnosis of WE is important because it is potentially fatal and readily treatable with thiamine supplementation. Early recognition of WE may be more difficult in children, because the classic triad of symptoms may not develop fully. Magnetic resonance imaging may be useful in these cases to confirm the diagnosis of WE. Because the shortage of MVI is expected to be a long-term, there are likely to be more cases of WE in the pediatric population of TPN-dependent children. Because there is no shortage of intravenous thiamine, it should be administered with TPN even if MVI is not available.

View details for Web of Science ID 000071331400026

View details for PubMedID 9417174
Cholic acid synthesis is reduced in pediatric liver recipients during graft dysfunction due to ischemic injury and allograft rejection Annual Meeting of the American-Society-of-Pediatrics / Society-of-Pediatric-Research Lang, T., Sendl, A. F., Esquivel, C. O., Berquist, W. E., Cox, K. L. LIPPINCOTT WILLIAMS & WILKINS. 1997: 1585–90
Abstract

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
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
Abstract

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 PubMedID 9256181
Potential effect of cyclosporin A in formation of cholesterol gallstones in pediatric liver transplant recipients DIGESTIVE DISEASES AND SCIENCES Cao, S., Cox, K., So, S. S., Berquist, W., Lee, S. P., Haigh, W. G., Concepcion, W., Monge, H., Esquivel, C. O. 1997; 42 (7): 1409-1415
Abstract

Recent advancements in liver transplantation have resulted in extended survival both for grafts and recipients. Such improvement, together with the shortage of donor organs has prompted expansion of the donor pool to include less than ideal donors, especially in life-threatening situations. The use of older liver donors has been associated with lower long-term survival. However, potential morbidity such as gallstone formation has not been explored. We analyzed bile composition in a child who developed cholesterol gallstones in the proximal bile duct two years after undergoing emergency liver transplantation with a liver from a 78-year-old donor. Oral administration of ursodeoxycholic acid (ursodiol) shifted the cholesterol composition of the bile from a supersaturated, potentially crystallized state to a liquid (micellar) state. Unlike cyclosporin A, FK506 showed an increase in the proportion of chenodeoxycholic acid and a decrease in the proportion of cholic acid, and thus may exhibit minimal or no hepatotoxic effect. Thus, in donor livers with factors known to be associated with cholesterol gallstone formation (such as age, sex, or obesity), one may consider analyzing the bile composition at the time of procurement. Depending on cholesterol and bile acid composition the use of FK506 with or without addition of ursodeoxycholic acid may be warranted.

View details for PubMedID 9246038
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
Abstract

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
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
Abstract

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
Orthotopic liver transplantation for hepatocellular carcinoma - Factors affecting long-term patient survival 67th Annual Session of the Pacific-Coast-Surgical-Association Ojogho, O. N., So, S. K., Keeffe, E. B., Berquist, W., Concepcion, W., GARCIAKENNEDY, R., Imperial, J., Esquivel, C. O. AMER MEDICAL ASSOC. 1996: 935–39
Abstract

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
Abstract

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 PubMedID 8693530
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
Abstract

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
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
Abstract

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
FULMINANT HEPATIC-FAILURE FOLLOWING VARICELLA-ZOSTER INFECTION IN A CHILD - A CASE-REPORT OF SUCCESSFUL TREATMENT WITH LIVER-TRANSPLANTATION AND PERIOPERATIVE ACYCLOVIR TRANSPLANTATION Tojimbara, T., So, S. K., Cox, K. L., Berquist, W. E., Egawa, H., GARCIAKENNEDY, R., Esquivel, C. O. 1995; 60 (9): 1052-1053
View details for Web of Science ID A1995TE94600031

View details for PubMedID 7491682
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
ISOLATED ALKALINE PHOSPHATEMIA FOLLOWING PEDIATRIC LIVER-TRANSPLANTATION IN THE FK506 ERA TRANSPLANTATION Egawa, H., Berquist, W., So, S. K., Cox, K., Menegaux, F., Esquivel, C. O. 1995; 59 (5): 791-793
View details for Web of Science ID A1995QM65600028

View details for PubMedID 7533958
AN INCREASED INCIDENCE OF EPSTEIN-BARR-VIRUS INFECTION AND LYMPHOPROLIFERATIVE DISORDER IN YOUNG-CHILDREN ON FK506 AFTER LIVER-TRANSPLANTATION 13th Annual Meeting of the American-Society-of-Transplant-Physicians Cox, K. L., LAWRENCEMIYASAKI, L. S., GARCIAKENNEDY, R., Lennette, E. T., Martinez, O. M., Krams, S. M., Berquist, W. E., So, S. K., Esquivel, C. O. WILLIAMS & WILKINS. 1995: 524–29
Abstract

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
Biofeedback therapy for anorectal disorders in children. Seminars in pediatric surgery Berquist, W. E. 1995; 4 (1): 48-53
Abstract

The physiological rationale, methodology, and results of biofeedback therapy in the management of anorectal disorders in children are presented. Balloon manometry and surface electromyography (EMG) are current biofeedback methods used to teach improved recognition of rectal distension and coordination of muscle function to either maintain fecal continence or to allow proper defecation. These techniques have permitted a success rate of over 70% in the management of children with functional or organic anorectal disease refractory to conventional medical and behavioral therapy. Biofeedback therapy is recommended to assist in the successful rehabilitation of these patients.

View details for PubMedID 7728508
CIRCULATING INTERCELLULAR-ADHESION MOLECULE-1 AND VASCULAR CELL-ADHESION MOLECULE-1 IN PEDIATRIC LIVER RECIPIENTS XVth World Congress of the Transplantation-Society Lang, T., Krams, S. M., Villanueva, J. C., So, S. K., Berquist, W. E., Cox, K. L., Esquivel, C. O., Martinez, O. M. ELSEVIER SCIENCE INC. 1995: 1148–49
View details for Web of Science ID A1995QJ19900457

View details for PubMedID 7533368
HEPATOCELLULAR-CARCINOMA AND LIVER-CELL DYSPLASIA IN CHILDREN WITH CHRONIC LIVER-DISEASE JOURNAL OF PEDIATRIC SURGERY Esquivel, C. O., Gutierrez, C., Cox, K. L., GARCIAKENNEDY, R., Berquist, W., Concepcion, W. 1994; 29 (11): 1465-1469
Abstract

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
REVASCULARIZATION TECHNIQUE FOR REDUCED-SIZE LIVER-TRANSPLANTATION FOR INFANTS WEIGHING LESS-THAN 10-KG JOURNAL OF PEDIATRIC SURGERY Nakazato, P. Z., Cox, K. L., Concepcion, W., Berquist, W. E., Esquivel, C. O. 1993; 28 (7): 923-926
Abstract

Reduced-size liver transplantation has been recognized as a powerful modality in alleviating the global donor shortage in pediatric liver transplantation. We describe, for the first time, a technique for revascularizing reduced-size grafts which has not been patterned after adult revascularization techniques. This revascularization method for reduced-size liver transplantation is particularly suitable for infants weighing < 10 kg. This technique differs from adult revascularization techniques in that the supraceliac aorta is always used as the origin for graft arterialization, and that the anastomoses are always performed in the following order: end-to-side donor celiac artery to supraceliac aorta anastomoses first, followed by the suprahepatic vena caval anastomoses, infrahepatic vena caval anastomoses, and then portal vein anastomoses. Hepatic artery thrombosis in infants weighing < 10 kg has occurred in 4 of 32 nonreduced versus 0 of 21 reduced transplantations (P = .05616, Z test, one tail). Adult revascularization was primarily used in the nonreduced group, whereas our proposed revascularization method was primarily used in the reduced group. We conclude that, for infants weighing < 10 kg receiving reduced grafts, this proposed technique should be used to decrease hepatic artery thrombosis.

View details for Web of Science ID A1993LN64600014

View details for PubMedID 8229570
THE INFLUENCE OF PORTOENTEROSTOMY WITH STOMA ON MORBIDITY IN PEDIATRIC-PATIENTS WITH BILIARY ATRESIA UNDERGOING ORTHOTOPIC LIVER-TRANSPLANTATION 23RD ANNUAL MEETING OF THE AMERICAN PEDIATRIC SURGICAL ASSOC Meister, R. K., Esquivel, C. O., Cox, K. L., Concepcion, W., Berquist, W., Nakazato, P., deVries, P. A. W B SAUNDERS CO-ELSEVIER INC. 1993: 387–90
Abstract

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
GRAFT INVOLVEMENT BY LEGIONELLA IN A LIVER-TRANSPLANT RECIPIENT ARCHIVES OF SURGERY Tokunaga, Y., Concepcion, W., Berquist, W. E., Cox, K. L., WIVIOTT, L. D., GARCIAKENNEDY, R., Itasaka, H., Nakazato, P., Esquivel, C. O. 1992; 127 (4): 475-477
Abstract

Legionella pneumophila, serogroup 1, was identified by direct immunofluorescence in the lung and liver graft from a 2 1/2-month-old infant who underwent orthotopic liver transplantation because of fulminant hepatic failure secondary to neonatal hepatitis. The patient died of respiratory failure owing to this infection 22 days after transplantation despite treatment with erythromycin lactobionate. To our knowledge, this represents the first reported case of hepatic infection with Legionella in liver transplant recipients.

View details for Web of Science ID A1992HM46400020

View details for PubMedID 1558502
EARLY EXPERIENCE WITH FK-506 INDUCTION IMMUNOSUPPRESSION - SUGGESTION FOR USING ORAL FK-506 INTERNATIONAL CONGRESS ON FK 506 Nakazato, P., Cox, K., Concepcion, W., Gish, R., Berquist, W., Imperial, J., Esquivel, C. ELSEVIER SCIENCE INC. 1991: 3019–20
View details for Web of Science ID A1991GV17500096

View details for PubMedID 1721345
THE IMPACT OF LIVER REDUCTIONS IN PEDIATRIC LIVER-TRANSPLANTATION 62ND ANNUAL SCIENTIFIC SESSION OF THE PACIFIC COAST SURGICAL ASSOC Esquivel, C. O., Nakazato, P., Cox, K., Concepcion, W., Berquist, W., Russell, T. R. AMER MEDICAL ASSOC. 1991: 1278–86
Abstract

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
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

Professor of Pediatrics (Gastroenterology) at the Lucile Salter Packard Children's Hospital

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