Kenneth L. Cox

All Publications

• Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis. Scandinavian journal of gastroenterology Ali, A. H., Damman, J., Shah, S. B., Davies, Y., Hurwitz, M., Stephen, M., Lemos, L. M., Carey, E. J., Lindor, K. D., Buness, C. W., Alrabadi, L., Berquist, W. E., Cox, K. L. 2020: 1–10

  Abstract

  BACKGROUND: Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV.METHODS: Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50mg/kg/day in 3 divided doses if weight <30kg, and 500mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline.RESULTS: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n=59; median age was 13.5years [range, 1.5-44years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7years (range, 0.2-14years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6months of OV treatment. One patient underwent liver transplantation 8years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events.CONCLUSION: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

  View details for DOI 10.1080/00365521.2020.1787501

  View details for PubMedID 32633158

• Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series. American journal of therapeutics Buness, J. G., Ali, A. H., Tabibian, J. H., Buness, C. W., Cox, K. L., Lindor, K. D. 2019

  Abstract

  Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD.The etiopathogenesis of PSC remains an enigma.We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed.We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months.We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.

  View details for DOI 10.1097/MJT.0000000000001065

  View details for PubMedID 31567143

• Long-Term Treatment with Oral Vancomycin for the Treatment of Primary Sclerosing Cholangitis and Inflammatory Bowel Disease Damman, J., Hurwitz, M., Shah, S., Davies, Y., Ali, A., Stephan, M., Lemos, L., Cox, K. L. WILEY. 2018: 1091A–1092A

  View details for Web of Science ID 000446020503144

• Prenatal treatment of ornithine transcarbamylase deficiency. Molecular genetics and metabolism Wilnai, Y. n., Blumenfeld, Y. J., Cusmano, K. n., Hintz, S. R., Alcorn, D. n., Benitz, W. E., Berquist, W. E., Bernstein, J. A., Castillo, R. O., Concepcion, W. n., Cowan, T. M., Cox, K. L., Lyell, D. J., Esquivel, C. O., Homeyer, M. n., Hudgins, L. n., Hurwitz, M. n., Palma, J. P., Schelley, S. n., 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

• Plasmapheresis for Hypertriglyceridemia-Induced Acute Pancreatitis in a Child A Case Report and Brief Review of the Literature PANCREAS Zhang, K., Cox, K. L., Sellers, Z. M. 2017; 46 (7): E58–E59

  View details for PubMedID 28697142

• Response to strict and liberalized specific carbohydrate diet in pediatric Crohn's disease WORLD JOURNAL OF GASTROENTEROLOGY Burgis, J. C., Nguyen, K., Park, K. T., Cox, K. 2016; 22 (6): 2111-2117

  Abstract

  To investigate the specific carbohydrate diet (SCD) as nutritional therapy for maintenance of remission in pediatric Crohn's disease (CD).Retrospective chart review was conducted in 11 pediatric patients with CD who initiated the SCD as therapy at time of diagnosis or flare. Two groups defined as SCD simple (diet alone, antibiotics or 5-ASA) or SCD with immunomodulators (corticosteroids and/or stable thiopurine dosing) were followed for one year and compared on disease characteristics, laboratory values and anthropometrics.The mean age at start of the SCD was 11.8 ± 3.0 years (range 6.6-17.6 years) with five patients starting the SCD within 5 wk of diagnosis. Three patients maintained a strict SCD diet for the study period and the mean time for liberalization was 7.7 ± 4.0 mo (range 1-12) for the remaining patients. In both groups, hematocrit, albumin and ESR values improved while on strict SCD and appeared stable after liberalization (P-value 0.006, 0.002, 0.002 respectively). The majority of children gained in weight and height percentile while on strict SCD, with small loss in weight percentile documented with liberalization.Disease control may be attainable with the SCD in pediatric CD. Further studies are needed to assess adherence, impact on mucosal healing and growth.

  View details for DOI 10.3748/wjg.v22.i6.2111

  View details for Web of Science ID 000368559400016

  View details for PubMedCentralID PMC4726683

• Response to strict and liberalized specific carbohydrate diet in pediatric Crohn's disease. World journal of gastroenterology Burgis, J. C., Nguyen, K., Park, K. T., Cox, K. 2016; 22 (6): 2111-7

  Abstract

  To investigate the specific carbohydrate diet (SCD) as nutritional therapy for maintenance of remission in pediatric Crohn's disease (CD).Retrospective chart review was conducted in 11 pediatric patients with CD who initiated the SCD as therapy at time of diagnosis or flare. Two groups defined as SCD simple (diet alone, antibiotics or 5-ASA) or SCD with immunomodulators (corticosteroids and/or stable thiopurine dosing) were followed for one year and compared on disease characteristics, laboratory values and anthropometrics.The mean age at start of the SCD was 11.8 ± 3.0 years (range 6.6-17.6 years) with five patients starting the SCD within 5 wk of diagnosis. Three patients maintained a strict SCD diet for the study period and the mean time for liberalization was 7.7 ± 4.0 mo (range 1-12) for the remaining patients. In both groups, hematocrit, albumin and ESR values improved while on strict SCD and appeared stable after liberalization (P-value 0.006, 0.002, 0.002 respectively). The majority of children gained in weight and height percentile while on strict SCD, with small loss in weight percentile documented with liberalization.Disease control may be attainable with the SCD in pediatric CD. Further studies are needed to assess adherence, impact on mucosal healing and growth.

  View details for DOI 10.3748/wjg.v22.i6.2111

  View details for PubMedID 26877615

  View details for PubMedCentralID PMC4726683

• Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations. PloS one Chao, C. S., McKnight, K. D., Cox, K. L., Chang, A. L., Kim, S. K., Feldman, B. J. 2015; 10 (2)

  Abstract

  Patients with pancreatic agenesis are born without a pancreas, causing permanent neonatal diabetes and pancreatic enzyme insufficiency. These patients require insulin and enzyme replacement therapy to survive, grow, and maintain normal blood glucose levels. Pancreatic agenesis is an uncommon condition but high-throughput sequencing methods provide a rare opportunity to identify critical genes that are necessary for human pancreas development. Here we present the clinical history, evaluation, and the genetic and molecular analysis from two patients with pancreatic agenesis. Both patients were born with intrauterine growth restriction, minor heart defects and neonatal diabetes. In both cases, pancreatic agenesis was confirmed by imaging studies. The patients are clinically stable with pancreatic enzymes and insulin therapy. In order identify the etiology for their disease, we performed whole exome sequencing on both patients. For each proband we identified a de novo heterozygous mutation in the GATA6 gene. GATA6 is a homeobox containing transcription factor involved in both early development of the pancreas and heart. In vitro functional analysis of one of the variants revealed that the mutation creates a premature stop codon in the coding sequence resulting in the production of a truncated protein with loss of activity. These results show how genetic mutations in GATA6 may lead to functional inactivity and pancreatic agenesis in humans.

  View details for DOI 10.1371/journal.pone.0118449

  View details for PubMedID 25706805

• Novel GATA6 Mutations in Patients with Pancreatic Agenesis and Congenital Heart Malformations. PloS one Chao, C. S., McKnight, K. D., Cox, K. L., Chang, A. L., Kim, S. K., Feldman, B. J. 2015; 10 (2): e0118449

  Abstract

  Patients with pancreatic agenesis are born without a pancreas, causing permanent neonatal diabetes and pancreatic enzyme insufficiency. These patients require insulin and enzyme replacement therapy to survive, grow, and maintain normal blood glucose levels. Pancreatic agenesis is an uncommon condition but high-throughput sequencing methods provide a rare opportunity to identify critical genes that are necessary for human pancreas development. Here we present the clinical history, evaluation, and the genetic and molecular analysis from two patients with pancreatic agenesis. Both patients were born with intrauterine growth restriction, minor heart defects and neonatal diabetes. In both cases, pancreatic agenesis was confirmed by imaging studies. The patients are clinically stable with pancreatic enzymes and insulin therapy. In order identify the etiology for their disease, we performed whole exome sequencing on both patients. For each proband we identified a de novo heterozygous mutation in the GATA6 gene. GATA6 is a homeobox containing transcription factor involved in both early development of the pancreas and heart. In vitro functional analysis of one of the variants revealed that the mutation creates a premature stop codon in the coding sequence resulting in the production of a truncated protein with loss of activity. These results show how genetic mutations in GATA6 may lead to functional inactivity and pancreatic agenesis in humans.

  View details for DOI 10.1371/journal.pone.0118449

  View details for PubMedID 25706805

• 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

• Characteristics and Direct Costs of Academic Pediatric Subspecialty Outpatient No-Show Events JOURNAL FOR HEALTHCARE QUALITY Perez, F. D., Xie, J., Sin, A., Tsai, R., Sanders, L., Cox, K., Haberland, C. A., Park, K. T. 2014; 36 (4): 32-42

  Abstract

  BACKGROUND: Clinic no shows (NS) create a lost opportunity for provider-patient interaction and impose a financial burden to the healthcare system and on society. We aimed to: (1) to determine the clinical and demographic factors associated with increased NS rates at a children's hospital's subsubspecialty clinics and (2) to estimate the direct institutional financial costs associated with NS events. METHODS: A comprehensive database was generated from all clinic encounters for 15 subspecialty outpatient clinics (five surgical and 10 medical) between September 12, 2005 and December 30, 2010. Multivariate logistic regressions were performed to identify the variables associated with NS events. Direct costs of NS events were estimated using annual revenue for each clinic. RESULTS: A total of 284,275 encounters and 17,024 NS events were available for analysis. Public insurance coverage (Medicaid and Title V), compared to private insurance or self-pay status, was associated with an increased likelihood NS (OR 2.19, 95% CI 2.10-2.28, p < 0.0005 for Medicaid; OR 1.56, 95% CI 1.50-1.62, p < 0.0005 for Title V). Compared to patients 21-30 years of age, patients <12 years (OR 2.08, 95% CI 1.77-2.45, p < 0.0005) had increased likelihood of NS. Scheduled visits with medical subspecialists were more likely than surgical subspecialty visits to result in a NS (OR 1.69, 95% CI 1.63-1.75, p < 0.0005). The predicted annualized lost revenue associated with NS visits was estimated at $730,000 from the 15 clinics analyzed, approximately $210 per NS event. CONCLUSION: Pediatric subspecialty NS events are common, costly, and potentially preventable.

  View details for Web of Science ID 000348450800003

  View details for PubMedID 23551280

• PRENATAL TREATMENT OF ORNITHINE TRANSCARBAMYLASE DEFICIENCY Wilnai, Y., Alcorn, D., Benitz, W., Berquist, W., Bernstein, J., Blumenfeld, Y. J., Castillo, R., Concepcion, W., Cowan, T., Cox, K. L., Cusmano, K., Deirdre, L., Esquival, C., Hintz, S. R., Homeyer, M., Hudgins, L., Palma, J., Summar, M. L., Schelley, S., Vishnu, P., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 248

  View details for Web of Science ID 000332500200048

• 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

• Markers of Antigen Presentation and Activation on Eosinophils and T Cells in the Esophageal Tissue of Patients With Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Le-Carlson, M., Seki, S., Abarbanel, D., Quiros, A., Cox, K., Nadeau, K. C. 2013; 56 (3): 257-262

  Abstract

  Evidence suggests eosinophils may be acting as antigen-presenting cells (APCs) by presenting antigen to T cells. We investigated the surface proteins of eosinophils and T cells in the esophageal biopsies of patients with eosinophilic esophagitis (EoE), patients with gastroesophageal reflux disease (GERD), and healthy controls (HCs).: Subjects were categorized as EoE, GERD, or HC. In esophageal tissue, EG2+ eosinophils were stained for the APC markers, CD40 or CD80, via immunohistochemistry. CD3+ T cells were stained for costimulatory markers, CD40L or CD28, and for activation markers, CD69 or CD134, via immunofluorescence or immunohistochemistry.Eosinophils stained with CD40 and CD80. The number of EG2+CD40+ cells was increased in EoE (mean 19.1±14.8 cells/high-power field [HPF], n=11), compared with GERD (mean 0.13±0.19 cells/HPF, n=5, P<0.01) and HC (mean 0.3±0.7 cells/HPF, n=5, P<0.01). There was an elevation in EG2+CD80+ cells in EoE (mean 18.1±16.2 cells/HPF, n=10), GERD (mean 1.7±2.8 cells/HPF, n=6, P<0.01), or HC (mean 0.8±1.3 cells/HPF, n=6, P<0.01). CD3+ T cells stained with CD40L (not quantified). CD3+ T cells stained with CD28 at elevated levels in EoE (mean 14±8.7 cells/HPF, n=9) versus GERD (mean 3.3±1.2 cells/HPF, n=6, P<0.05) or HC (mean 3.0±3.2 cells/HPF, n=7, P<0.01). The number of CD3+CD69+ cells was highest in EoE (mean 14.8±7.5 cells/HPF, n=6) versus GERD (mean 0.8±0.9 cells/HPF, n=6, P<0.001) or HC (mean 2.7±2.5 cells/HPF, n=6, P<0.001).We show that esophageal eosinophils express CD40 and CD80, and T cells with CD40L, CD28, and CD69. The number of double-stained cells was higher in EoE in comparison to control groups. These data support the hypothesis that eosinophils in EoE may act as APCs, activating T cells.

  View details for DOI 10.1097/MPG.0b013e3182758d49

  View details for Web of Science ID 000315461400010

  View details for PubMedID 23059644

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

  Abstract

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

  View details for DOI 10.1016/j.jpeds.2012.07.015

  View details for Web of Science ID 000313579900021

  View details for PubMedID 22914224

• Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. Journal of clinical immunology Abarbanel, D. N., Seki, S. M., Davies, Y., Marlen, N., Benavides, J. A., Cox, K., Nadeau, K. C., Cox, K. L. 2013; 33 (2): 397-406

  Abstract

  Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin's therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-β) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4 + CD25hiCD127lo and CD4 + FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC + IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC + IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.

  View details for DOI 10.1007/s10875-012-9801-1

  View details for PubMedID 23054338

  View details for PubMedCentralID PMC3565076

• Successful treatment of recurrent primary sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin. Case reports in transplantation Davies, Y. K., Tsay, C. J., Caccamo, D. V., Cox, K. M., Castillo, R. O., Cox, K. L. 2013; 2013: 314292-?

  Abstract

  Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disease of the liver that is marked by inflammation of the bile ducts and damage to the hepatic biliary tree. Approximately 60-70% of patients also have inflammatory bowel disease and progression of PSC can lead to ulcerative colitis and cirrhosis of the liver. Due to limited understanding of the etiology and mechanism of PSC, the only existing treatment option is orthotopic liver transplantation (OLT); however, recurrence of PSC, after OLT is estimated to be between 5% and 35%. We discuss the successful treatment of a pediatric patient, with recurrent PSC, after OLT with oral Vancomycin.

  View details for DOI 10.1155/2013/314292

  View details for PubMedID 23509657

  View details for PubMedCentralID PMC3595721

• Characteristics and Direct Costs of Academic Pediatric Subspecialty Outpatient No-Show Events J Healthc Qual Perez, F., Xie, J., Sin, A., Tsai, R., Sanders, L., Cox, K., Haberland, C., Park, K. 2013; Mar 29
• A Common Peripheral Blood Gene Set for Diagnosis of Operational Tolerance in Pediatric and Adult Liver Transplantation AMERICAN JOURNAL OF TRANSPLANTATION Li, L., Wozniak, L. J., RODDER, S., Heish, S., Talisetti, A., Wang, Q., Esquivel, C., Cox, K., Chen, R., McDiarmid, S. V., Sarwal, M. M. 2012; 12 (5): 1218-1228

  Abstract

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

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

  View details for Web of Science ID 000303235100020

  View details for PubMedID 22300520

• 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

• RURALITY AND HEALTH OUTCOMES IN PEDIATRIC LIVER TRANSPLANTATION Park, K. T., Bensen, R., Nanda, P., Esquivel, C., Cox, K. WILEY-BLACKWELL. 2011: 135–135

  View details for Web of Science ID 000293251100393

• 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

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

  Abstract

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

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

  View details for Web of Science ID 000289628100018

  View details for PubMedID 21450010

• 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

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

  Abstract

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

  View details for DOI 10.1097/TP.0b013e3181f546af

  View details for Web of Science ID 000283650200011

  View details for PubMedID 20814356

• 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

• HLA-G: A Novel Serological Marker for Liver Transplant Tolerance Zarkhin, V., Talisetti, A., Cox, K., Hurwitz, M., Esquivel, C., Sarwal, M. WILEY-BLACKWELL PUBLISHING, INC. 2010: 178

  View details for Web of Science ID 000275921701469

• 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

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

  Abstract

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

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

  View details for PubMedID 18331536

• Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: An immunomodulating antibiotic JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Davies, Y. K., Cox, K. M., Abdullah, B. A., Safta, A., Terry, A. B., Cox, K. L. 2008; 47 (1): 61-67

  Abstract

  Primary sclerosing cholangitis is a rare chronic cholestatic condition of unknown etiology, frequently associated with inflammatory bowel disease and characterized by diffuse fibrosing and inflammatory destruction of the intra- and/or extrahepatic biliary duct system.The study involved 14 children with primary sclerosing cholangitis confirmed by either liver biopsy, endoscopic retrograde cholangiopancreatography, and/or magnetic resonance cholangiogram. In each of the 14 cases, liver histology showed characteristic features consistent with primary sclerosing cholangitis. Eleven children had intrahepatic biliary beading and strictures (6 by endoscopic retrograde cholangiopancreatography; 5 by magnetic resonance cholangiogram). Biochemical tests of liver function including alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase and the erythrocyte sedimentation rate were elevated for a mean 17 +/- 22 months before vancomycin treatment was initiated. All of the patients were shown to have inflammatory bowel disease histologically; 13 of those patients had clinical evidence of colitis. Oral vancomycin was given to all 14 patients.All 14 patients showed improvement in their alanine aminotransferase (P = 0.007), gamma-glutamyl transpeptidase (P = 0.005), erythrocyte sedimentation rate (P = 0.008), and clinical symptoms with oral vancomycin treatment. There was less improvement noted in the patients with cirrhosis when compared with the patients without cirrhosis.Before this study, there has not been an effective long-term treatment for sclerosing cholangitis to prevent the usual progression of this disease to cirrhosis. This study showed that oral vancomycin could be an effective long-term treatment of sclerosing cholangitis in children, especially those without cirrhosis.

  View details for Web of Science ID 000257179500010

  View details for PubMedID 18607270

• 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

• 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

• Should Milan criteria be applied to children with hepatocellular carcinom (HCC)? Beaunoyer, M., Vanatta, J., Ogihara, M., Strichartz, D., Cox, K., Esquivel, C. BLACKWELL PUBLISHING. 2007: 65–66

  View details for Web of Science ID 000246659800134

• Sirolimus as maintenance immunosuppression in pediatric intestinal transplantation. Safta, A. M., Castillo, R. O., Cox, K., Esquivel, C. O. WILEY-BLACKWELL. 2007: 78–78

  View details for Web of Science ID 000246659800187

• Risk factors for small bowel bacterial overgrowth in cystic fibrosis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Fridge, J. L., Conrad, C., Gerson, L., Castillo, R. O., Cox, K. 2007; 44 (2): 212-218

  Abstract

  The purpose of this study was to determine the prevalence of small bowel bacterial overgrowth in patients with pancreatic-insufficient cystic fibrosis (CF) compared with age-matched controls and to identify potential risk factors for small bowel bacterial overgrowth.Fifty patients, 25 pancreatic-insufficient CF study patients (mean age, 17 y) and 25 gastrointestinal clinic control patients (mean age, 15 y), completed a glucose-hydrogen breath test after an overnight fast. Study patients completed a quality-of-life questionnaire modified from the Cystic Fibrosis Questionnaire. The medical history of each patient was compared with breath test results. A positive breath test was defined as a fasting hydrogen > or =15 ppm or a rise of > or =10 ppm hydrogen over baseline during the test.The prevalence of positive breath tests was higher in the CF study group (56%) than in the control group (20%) (P = 0.02). The mean fasting hydrogen levels of patients in the study and control groups were 22 and 5 ppm (P = 0.0001). The mean questionnaire scores were not significantly different between breath test-positive and -negative study patients. The use of azithromycin was associated with an increased risk of a positive breath test. Use of laxatives and inhaled ipratropium was associated with a decreased risk of a positive breath test.Patients with CF were more likely to have elevated fasting hydrogen levels compared with controls. This suggests a high prevalence of small bowel bacterial overgrowth in CF patients. Medications commonly used by CF patients may influence intestinal health.

  View details for Web of Science ID 000243851900011

  View details for PubMedID 17255834

• 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

• 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

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

  Abstract

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

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

  View details for PubMedID 16573603

• 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

• 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

• Microvascular abnormalities in Alagille Syndrome: A computer-assisted intravital microscopy study Annual Meeting of the Pediatric-Academic-Societies Cheung, A. T., Ramanujam, S., Chan, M. S., Cox, K. M., Chin, C., Cox, K. L. NATURE PUBLISHING GROUP. 2004: 184A–185A

  View details for Web of Science ID 000220591101073

• 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

• Outcomes associated with a comprehensive pain management intervention on children receiving liver transplants Sharek, P. J., Lin, E. N., Cox, K., Wayman, K. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2003: 178A

  View details for Web of Science ID 000181897901012

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

  Abstract

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

  View details for PubMedID 12352909

• 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

• Mortality rate correlated with the number of pediatric liver transplants performed at a center 18th World Congress of the Transplantation-Society Cox, K., Rodriguez-Baez, N., Nasr, A., Esquivel, C. ELSEVIER SCIENCE INC. 2001: 1512–13

  View details for Web of Science ID 000167629900707

  View details for PubMedID 11267400

• Gastrointestinal dysfunction associated with syringomyelia and hydromyelia JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Garcia-Careaga, M., Cox, K. M., Blankenberg, F., Cox, K. L. 2000; 31 (1): 71-75

  View details for Web of Science ID 000087924200016

  View details for PubMedID 10896075

• Significance of detecting Epstein-Barr-Specific sequences in the peripheral blood of asymptomatic pediatric liver transplant recipients 3rd International Congress on Pediatric Transplantation Krieger, N. R., Martinez, O. M., Krams, S. M., Cox, K., So, S., Esquivel, C. O. JOHN WILEY & SONS INC. 2000: 62–66

  Abstract

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

  View details for Web of Science ID 000085673100008

  View details for PubMedID 10648579

• 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

• Oral vancomycin: Treatment of primary sclerosing cholangitis in children with inflammatory bowel disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Cox, K. L., Cox, K. M. 1998; 27 (5): 580-583

  View details for Web of Science ID 000076693500015

  View details for PubMedID 9822326

• 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

• 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

• Epstein-Barr virus lymphoproliferative disorders after liver transplantation. Clinics in liver disease Cao, S., Cox, K. L. 1997; 1 (2): 453-?

  Abstract

  Post-transplant lymphoproliferative disorders (PTLD) represent a spectrum of histological and immunological abnormalities, ranging from benign polyclonal B-cell hyperplasia to monoclonal malignant lymphoma. The important role of Epstein-Barr virus (EBV) in PTLD in liver transplant patients, particularly in pediatric recipients, is reviewed. Understanding the risks of EBV infection, the clinical presentations and diagnosis of PTLD, and its pathophysiology are crucial to the management of these disorders. Current treatment methods have resulted in better outcomes of these disorders, which in the past were uniformly fatal.

  View details for PubMedID 15562578

• 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

• 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

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

  Abstract

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

  View details for Web of Science ID A1994NJ20800005

  View details for PubMedID 7513911

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

  Abstract

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

  View details for PubMedID 7547535

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

  Abstract

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

  View details for Web of Science ID A1993MF75400013

  View details for PubMedID 8236019

• 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

• CHARACTERIZATION OF CHOLECYSTOKININ RECEPTORS ON THE HUMAN GALLBLADDER SURGERY Tokunaga, Y., Cox, K. L., Coleman, R., Concepcion, W., Nakazato, P., Esquivel, C. O. 1993; 113 (2): 155-162

  Abstract

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

  View details for Web of Science ID A1993KL37600007

  View details for PubMedID 7679224

• 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

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

  Abstract

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

  View details for Web of Science ID A1991GP12600003

  View details for PubMedID 1815388

  View details for PubMedCentralID PMC1003060

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

  Abstract

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

  View details for Web of Science ID A1991EX24100005

  View details for PubMedID 1992520

• 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