Publications by authors named "Stephen P Dunn"

26 Publications

  • Page 1 of 1

The Right Child/Right Surgeon initiative: A position statement on pediatric surgical training, sub-specialization, and continuous certification from the American Pediatric Surgical Association.

J Pediatr Surg 2020 Dec 13;55(12):2566-2574. Epub 2020 Aug 13.

Department of Surgery, School of Medicine, Jefferson University, Philadelphia, PA.

The past 50 years have witnessed profound changes in the specialty of pediatric surgery in North America. There has been a marked increase in the number of both pediatric surgical training programs and practicing pediatric general and thoracic surgeons. Despite this trend, the population of children in the United States and the birth rate have recently remained relatively flat. Some pediatric surgeons have become "super specialists", concentrating their practices in oncology or colorectal surgery. This has the potential to result in a dilution of experience for both pediatric surgical trainees and practicing pediatric surgeons, thus limiting their ability to acquire and maintain expertise, respectively. Coincident with this, there has been a relative paradigm shift in recognition that "quality of life" is based more on maintaining a creative balance in lifestyle and is not "all about work". There has been a parallel growth in the number of practicing pediatric general and thoracic surgeons in urban settings, but we have not appreciated as much growth in rural and underserved areas, where access to pediatric surgical care remains limited and fewer pediatric general and thoracic surgeons practice. This is a complex issue, as some underserved areas are economically depressed and geographically sparse, but others are just underserved with adult providers taking care of children in settings that are often under resourced for pediatric surgical care. This problem may extend beyond the boundaries of pediatric general and thoracic surgery to other specialties. As the premier association representing all pediatric surgeons in the United States, the American Pediatric Surgical Association (APSA) has concluded that the quality of pediatric surgical care will likely decline should the status quo be allowed to continue. Therefore, APSA has initiated a Right Child/Right Surgeon initiative to consider these issues and propose some potential solutions. What follows is a brief statement of intent.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423589PMC
December 2020

Successful use of transarterial radioembolization with yttrium-90 (TARE-Y90) in two children with hepatoblastoma.

Pediatr Blood Cancer 2020 09 30;67(9):e28421. Epub 2020 Jun 30.

Division of Hematology/Oncology and Bone Marrow Transplantation, Nemours Children's, Specialty Care and Wolfson Children's Hospital, Jacksonville, Florida.

Primary malignant liver tumors are rare but all require surgical resection as part of therapy with curative intent. A minority of patients have resectable tumors at diagnosis. Chemotherapy has a therapeutic role in hepatoblastoma but only one-third of patients have resectable disease at diagnosis. Two children with hepatoblastoma and suboptimal responses to initial chemotherapy received therapy with transarterial radioembolization utilizing yttrium-90 (TARE-Y90) and had significant response leading to resection and remission. The role of TARE-Y90 needs to be studied further to define its use in primary pediatric liver neoplasms.
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http://dx.doi.org/10.1002/pbc.28421DOI Listing
September 2020

Evaluation of the diagnostic biopsy approach for children with hepatoblastoma: A report from the children's oncology group AHEP 0731 liver tumor committee.

J Pediatr Surg 2020 Apr 11;55(4):655-659. Epub 2019 May 11.

Division of Hematology/Oncology, Department of Pediatrics, Nemours Children's Specialty Care/Wolfson Children's Hospital, Jacksonville, FL.

Background: The histopathological assessment of pediatric liver tumors at presentation is critical to establish a diagnosis, guide treatment, and collect appropriate research samples. The purpose of this study was to evaluate complications associated with different approaches to liver biopsy for newly diagnosed hepatoblastoma.

Methods: Children with hepatoblastoma were enrolled on Children's Oncology Group study AHEP0731 (September 2009-March 2012). This analysis evaluated the study cohort of initially unresectable patients who therefore underwent a biopsy procedure at diagnosis. The primary endpoint was clinically significant postbiopsy hemorrhage, defined as requiring red blood cell transfusion.

Results: We identified 121 children who underwent open (n = 76, 63%), laparoscopic (n = 17, 14%), or percutaneous (n = 28, 23%) liver biopsies. All biopsy procedures yielded adequate tissue for diagnosis. Postbiopsy hemorrhage requiring transfusion occurred after 26% (n = 31) of biopsies. Need for blood product transfusion most frequently occurred following open (n = 27/76, 36%) and laparoscopic (n = 4/17, 24%) biopsies, compared with percutaneous (n = 0/28, 0%) biopsies (p < 0.01).

Conclusions: Pretreatment biopsy of pediatric liver tumors via a percutaneous approach yielded the lowest frequency of clinically significant hemorrhage requiring transfusion, without evidence of sacrificing diagnostic accuracy.

Level Of Evidence: Level I.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842675PMC
April 2020

Post-transplant lymphoproliferative disease of the larynx.

J Surg Case Rep 2019 Apr 6;2019(4):rjz111. Epub 2019 Apr 6.

Division of Pediatric Otolaryngology, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Laryngeal post-transplant lymphoproliferative disease (PTLD) is rare. Here, we describe two pediatric cases. The first, a 15-month-old who underwent liver transplantation at 5 weeks, presented with airway distress. Airway evaluation identified epiglottic and arytenoid infiltrate, and biopsy was consistent with polymorphic PTLD. The second, a 23-month-old who underwent liver transplantation at 13 months, presented with progressive stridor. Airway evaluation revealed sub-mucosal infiltrate of the epiglottis, arytenoids, post-cricoid region, and uvula. Biopsy was consistent with monomorphic PTLD. Airway findings and symptoms resolved for both after immunosuppression reduction. PTLD diagnosis requires a high index of suspicion in post-transplant patients with airway obstruction.
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http://dx.doi.org/10.1093/jscr/rjz111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451186PMC
April 2019

Acute and chronic rapamycin use in patients with Fibrodysplasia Ossificans Progressiva: A report of two cases.

Bone 2018 04 11;109:281-284. Epub 2017 Dec 11.

Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States. Electronic address:

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP.
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http://dx.doi.org/10.1016/j.bone.2017.12.011DOI Listing
April 2018

Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children's Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children's Oncology Group.

J Clin Oncol 2017 Oct 11;35(30):3465-3473. Epub 2017 Sep 11.

Allison F. O'Neill and Christopher B. Weldon, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA; Alexander J. Towbin and Greg M. Tiao, Cincinnati Children's Hospital, Cincinnati, OH; Mark D. Krailo, University of Southern California Keck School of Medicine, Los Angeles; Caihong Xia and Yun Gao, Children's Oncology Group, Monrovia; Marcio Malogolowkin, University of California Davis Comprehensive Cancer Center, Sacramento, CA; M. Beth McCarville, Wayne L. Furman, and Carlos Rodriguez-Galindo, St Jude Children's Research Hospital; Max R. Langham Jr, Le Bonheur Children's Hospital and University of Tennessee, Memphis; Howard M. Katzenstein, Vanderbilt University School of Medicine, Monroe Carell Jr Children's Hospital, Nashville, TN; Rebecka L. Meyers, Primary Children's Hospital and University of Utah, Salt Lake City, UT; Eugene D. McGahren, University of Virginia Children's Hospital and University of Virginia, Charlottesville, VA; Stephen P. Dunn, duPont Hospital for Children and Thomas Jefferson University, Philadelphia; Sarangarajan Ranganathan, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA; and Milton J. Finegold, Baylor College of Medicine, Houston, TX.

Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Children's Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis.
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http://dx.doi.org/10.1200/JCO.2017.73.5654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648177PMC
October 2017

Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee.

Cancer 2017 Jun 17;123(12):2360-2367. Epub 2017 Feb 17.

Department of Pediatric Surgery, Primary Children's Medical Center, Salt Lake City, Utah.

Background: The identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma.

Methods: Patients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level <100 ng/mL were eligible. Patients received 2 cycles of V at a dose of 1.5 mg/m /day intravenously on days 1 and 8 and I at a dose of 50 mg/m /day intravenously on days 1 to 5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to Response Evaluation Criteria In Solid Tumors (RECIST) or a 90% (>1 log ) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone.

Results: A total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively.

Conclusions: The VI combination appears to have substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR hepatoblastoma remains to be determined. Cancer 2017;123:2360-2367. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665173PMC
June 2017

Liver transplantation in the management of unresectable hepatoblastoma in children.

Front Biosci (Elite Ed) 2012 Jan 1;4:1293-302. Epub 2012 Jan 1.

University of Utah, Primary Children's Medical Center, Salt Lake City, UT 84113, USA.

Complete surgical resection is essential to long-term survival in children with hepatoblastoma. We present the guidelines from the Children's Oncology Group (COG), liver tumor study group of the Societe Internationale Oncologie Pediatrique (SIOPEL), and German Pediatric Oncology Group (GPOH) for early referral of children with potentially unresectable hepatoblastoma to a specialty center with expertise in extreme resection and liver transplantation. Patients who will become candidates for liver transplantation should receive chemotherapy following the same protocols as for children undergoing a partial hepatectomy. The Pediatric Liver Unresectable Tumor Observatory (PLUTO) is an international prospective database established to collect data and make future recommendations on controversial issues regarding the use of transplant in hepatoblastoma including: 1) What is the optimal treatment of multifocal tumors. 2) What is the role of extreme resection vs. liver transplant in patients with major venous involvement. 3) What is the role of transplant in patients who present with lung metastasis. 3) Should patients with tumor relapse be offered a rescue transplant. 4) What is the role of pre- and post- transplant chemotherapy.
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http://dx.doi.org/10.2741/460DOI Listing
January 2012

Pilot study using an Internet-based program in informed consent.

J Pediatr Surg 2010 Jun;45(6):1137-41

Department of Surgery, Christiana Care Health System, Newark, DE 19713, USA.

Purpose: To examine the effect of an internet-based aid to informed consent on parent recall of potential surgical complications.

Methods: Parents of children scheduled for elective inguinal hernia repair were assigned to a control group or were enrolled in an internet-based program designed to aid in the consent process. Nine potential surgical complications were presented to the parent(s) in the consent discussion and in the Internet program. Parent recall of potential surgical complications was assessed immediately after the consent discussion and on the day of surgery.

Results: Overall recall of complications was poor in both groups, both immediately and on the day of surgery. Parents in the control group (n = 13) recalled a mean of 2.9 complications immediately and 1.5 on the day of surgery, approaching statistical significance (P = .056). The parents in the internet program group (n = 17) recalled a mean of 2.6 complications immediately and 2.9 on the day of surgery (P = NS). There was no significant difference in immediate recall between the two groups, but there was a trend towards statistically significant improvement in recall in the study group the day of surgery vs. controls (P = .06).

Conclusion: Although overall recall of potential surgical complications was poor in both groups, there was a trend towards a significant improvement in recall in the study group after viewing the Internet-based program.
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http://dx.doi.org/10.1016/j.jpedsurg.2010.02.071DOI Listing
June 2010

Selection of live-related liver transplantation candidates.

J Pediatr Surg 2009 Jun;44(6):1096-100; discussion 1100-1

Department of General Surgery, Alfred I duPont Hospital for Children, Wilmington, DE 19803, USA.

Purpose: Living donor liver transplantation (LR) is an important alternative for children. We compared our outcomes of LR and cadaveric (CAD) graft recipients, with attention to the pediatric end-stage liver disease (PELD) score and perioperative morbidity and mortality to identify appropriate candidates for LR.

Methods: Our transplant database and electronic medical records were searched for demographics and outcome measures.

Results: From 2000 to 2008, 81 children underwent liver transplantation from 37 LR and 44 CAD donors. There were no significant differences in graft or overall survival at 3 months or 1 year. The LR group was significantly younger (4.46 +/- 5.2 years vs 7.41 +/- 6.6 years; P = .03) and had a significantly lower PELD score (12.7 +/- 13 vs 22 +/- 12; P = .001) at the time of transplantation. Ten patients were transplanted for unresectable tumor in the LR group vs 4 CAD (P = .03). Significantly fewer LR recipients required return to the operating room in the first 30 days posttransplant (13.9% vs 34.1%; P = .03). The LR recipients had a higher rate of biliary stricture requiring reoperation (22.2% vs 2.3%; P = .005).

Conclusions: The LR liver transplantation is highly selected for patients with a parent donor who will need transplant but do not yet have a high PELD score. A lower PELD score at operation may have contributed to the lower incidence of postoperative complications requiring reoperation.
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http://dx.doi.org/10.1016/j.jpedsurg.2009.02.012DOI Listing
June 2009

Failure of immunosuppressive drug levels to predict T-cell reactivity in pediatric transplant patients.

J Pediatr Surg 2008 Jun;43(6):1134-41

Nemours Biomedical Research, Molecular Genetics, Cellular and Tissue Transplantation, Wilmington, DE 19803, USA.

Purpose: In children, therapeutic management of immunosuppression relies on allograft function, drug levels, and clinical insight. Using a Food and Drug Administration-approved test for T-cell response, T-cell activation in vitro can be measured to monitor the immune response.

Methods: In a retrospective study, 92 posttransplant children who received either a liver and/or kidney transplant and were followed by routine screening had their T-cell response tested by the Cylex ImmuKnow assay (Columbia, MD). After phytohemagglutinin-L stimulation of T-cells, adenosine triphosphate (ATP) concentrations were measured. In this assay, light emission at lambda = 562 nm is proportional to the ATP concentration (ng/mL). Immunosuppressive drug trough levels were also measured. Quantitative real-time polymerase chain reaction Epstein-Barr virus (EBV) viral titers were determined for 2 patients.

Results: Separating the results into younger than 12 years and 12-year or older populations, we found that for the younger than 12 years, 28% of patients were in the low immune function category, 47% in the moderate, and 25% in the high category. For the 12 years or older, 25% of patients were in the low immune function category, 47% in the moderate, and 28% in the high category. The immune function distribution was not different (P = not significant) between the younger than 12 years and 12-year or older groups. Tacrolimus trough levels were 6.3 +/- 2.4 ng/mL for younger than 12 years and 5.6 +/- 3.3 ng/mL for 12 years or older (P = not significant), and rapamycin was similar, but both showed no correlation to immune function. We observed increased ATP values with decreased EBV viral loads.

Conclusions: These results suggest that tacrolimus and/or rapamycin levels do not adequately determine the biologic effect of immunosuppression. We expect that future T-cell activation monitoring will allow us to diminish rejection and infection events posttransplantation and lead to a healthier pediatric transplant population.
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http://dx.doi.org/10.1016/j.jpedsurg.2008.02.044DOI Listing
June 2008

Health-related quality of life and family function following pediatric liver transplantation.

Liver Transpl 2008 Apr;14(4):460-8

Children's Memorial Hospital, Chicago, IL 60614, USA.

This multicenter study compared health-related quality of life (HRQOL) and family function of pediatric liver transplant recipients to those of healthy children to determine if this population differed from a healthy population and to distinguish which pretransplant and posttransplant factors impact HRQOL and family function. HRQOL data from 102 patients achieving 2-year survival were collected with the Infant Toddler Quality of Life Instrument or the Child Health Questionnaire Parent Form 50 parent surveys. Family functioning was assessed with the Family Assessment Device (FAD) completed by each participant's family members. Demographic and clinical information were retrieved from the Studies of Pediatric Liver Transplant database. Recipients 5 years of age and older scored lower than a normative sample in physical health (P < 0.001), general health (P < 0.001), parental emotional impact (P < 0.001), and disruption of family activities (P < 0.001). Younger children, 2 to 5 years of age, scored lower than controls in global health (P = 0.004) and general health perceptions (P < 0.001) but did not differ in subscales measuring physical and psychosocial outcomes. Univariate analysis among the subscales identified demographic but not clinical variables as significant predictors of HRQOL. Mean scores of FAD scales were below published thresholds indicating healthy family functioning. As reported in previous studies, parents of older recipients reported higher levels of stress, although their level of family function appears normal. Significant associations were also observed between FAD scores and demographic variables, suggesting that further investigation of the impact of race, parental marital status, and socio-economic status on the patient rehabilitation process is needed.
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http://dx.doi.org/10.1002/lt.21352DOI Listing
April 2008

MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells.

Cancer Res 2007 Oct;67(20):9762-70

Department of Molecular Genetics, Cellular and Tissue Transplantation, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, and Center for Applied Genomics, Public Health Research Institute, UMDNJ-New Jersey Medical School, Newark, USA.

Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-F4 increased levels of members of the let-7 family. In inhibited cells at 24 h, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-F4, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to down-regulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-2462DOI Listing
October 2007

Successful liver transplant for unresectable hepatoblastoma.

J Pediatr Surg 2007 Jan;42(1):184-7

Division of Solid Organ Transplant, AI duPont Hospital for Children, PO Box 269, Wilmington, DE 19899, USA.

Background: Treatment of children with stage III and IV hepatoblastoma has shown little improvement with 5-year survival rates of 64% and 25%, respectively (J Clin Oncol 2000;18:2665-75). A timely and organized treatment program including preoperative chemotherapy combined with living donor liver transplantation and postoperative chemotherapy has been used seeking improved long-term survival in stage III and IV cases.

Methods: A retrospective review of 8 patients with stage III and IV hepatoblastoma unresectable by conventional resection were treated with complete hepatectomy and transplantation. Approval was obtained from our institutional review board.

Results: Since August of 2001, we have treated 6 patients with stage III hepatoblastoma and 2 patients with initial stage IV hepatoblastoma. These patients (age, 23 months-9 years) had all received extensive chemotherapy or prior resections. After chemotherapy, none had gross tumor documented outside of the liver at time of transplantation. All underwent hepatectomy including vena cava resection, in selected cases, with living donor orthotopic liver transplantation. All patients had at least 2 cycles of postoperative chemotherapy. Of 8 patients, 6 are alive and well with normalized alpha-fetoprotein levels. There were 2 late deaths from recurrent disease. Length of follow-up ranged from 7 to 53 months.

Conclusion: Complete hepatectomy with living donor liver transplantation provides optimal surgical treatment in unresectable stage III and initial stage IV disease confined to the liver at resection. This series indicates that children tolerate complete hepatectomy, transplantation, and postoperative chemotherapy well. Referral to a transplant center during the first 3 cycles of chemotherapy appears to offers the best opportunity for long-term survival.
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http://dx.doi.org/10.1016/j.jpedsurg.2006.09.017DOI Listing
January 2007

Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR.

Breast Cancer Res 2006 ;8(6):R70

Molecular Genetics, Cellular and Tissue Transplantation, Nemours Biomedical Research, Rockland Road, Wilmington, DE 19803, USA.

Introduction: Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients.

Methods: Peripheral blood and breast carcinoma specimens from 24 patients were collected. DNA was extracted and then amplified by MGB-TaqMan real time PCR.

Results: Of 24 breast tumor specimens, 11 (46%) were positive for EBV DNA. Of these 11 breast tumor specimens, 7 (64%) were also positive for EBV DNA in the peripheral blood, while 4 (36%) were positive for EBV DNA in the tumor, but negative in the blood.

Conclusion: EBV was found at extremely low levels, with a mean of 0.00004 EBV genomes per cell (range 0.00014 to 0.00001 EBV genomes per cell). Furthermore, our finding of the presence of EBV in the tumor specimens coupled to the absence of detection of EBV genomic DNA in the peripheral blood is consistent with the epithelial nature of the virus. Because of the low levels of viral DNA in tumor tissue, further studies are needed to assess the biological input of EBV in breast cancer.
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http://dx.doi.org/10.1186/bcr1627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797024PMC
February 2007

Intussusception in a child with respiratory syncytial virus: a new association.

Del Med J 2006 May;78(5):185-7

Division of Trauma and Critical Care, East Texas Medical Center, Tyler, USA.

Intussusception is known to be associated with childhood viral illnesses. Respiratory syncytial virus (RSV) has not, to our knowledge, been previously reported in association with intussusception. We report a case of a 4-month-old boy admitted with RSV bronchiolitis, who subsequently developed an intussusception during the hospital course, necessitating laparotomy and resection.
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May 2006

c-Myc inhibition negatively impacts lymphoma growth.

J Pediatr Surg 2006 Jan;41(1):207-11; discussion 207-11

Nemours Biomedical Research, Molecular Genetics, Cellular and Tissue Transplantation, Wilmington, DE 19803, USA.

Background: Proto-oncogene c-Myc dysregulation is commonly found in aggressive tumors. Dysregulation is central to lymphomagenesis in Burkitt lymphoma and other non-Hodgkin's lymphomas. This suggests targeting c-Myc as a treatment for myc-associated malignancies.

Methods: Microarrays showed c-Myc dysregulation in a B-lymphoblastoid line, TIB-215. This was confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and extended to 3 additional Burkitt lymphoma lines. Growth effects of a c-Myc inhibitor, compound 10058-F4, were determined in these 4 lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses and direct cell counts. Drug effects on c-Myc gene expression levels were measured using minor groove binding-TaqMan real-time reverse transcriptase-polymerase chain reaction. Drug specificity was analyzed in rat c-Myc knockout (-/-) and Myc-transfected cells.

Results: c-Myc dysregulation was shown to be cell-cycle independent without rapid decay of c-Myc mRNA levels in all 4 lines. Using a c-Myc inhibitor, we found that growth inhibition was time- and dose-dependent. This inhibition caused unexpected downregulation (> or =65%) of c-Myc mRNAs.

Conclusions: The inhibition of c-Myc decreased growth in aggressive lymphoma cells. This mechanism included c-Myc mRNA downregulation and dissociation of c-Myc/Max protein heterodimer. These results support targeting c-Myc in tumors with high morbidity and mortality.
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http://dx.doi.org/10.1016/j.jpedsurg.2005.10.025DOI Listing
January 2006

Liver transplantation as definitive treatment for a factor V Leiden mutation.

J Pediatr 2005 Mar;146(3):418-22

Division of Solid Organ Transplantation, Nemours Biomedical Research, Nemours Children's Clinic-Wilmington, Alfred I. duPont Hospital for Children, Delaware, USA.

Liver transplantation (LT) was achieved for factor V Leiden-induced thrombophilia in a neonate with hepatic veno-occlusive disease. Initial LT was performed with a liver segment removed from a child with primary oxalosis. Four months later, a second, definitive LT was performed. The child remains well without recurrent thrombosis.
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http://dx.doi.org/10.1016/j.jpeds.2004.10.036DOI Listing
March 2005

Improvement in renal function and rejection control in pediatric liver transplant recipients with the introduction of sirolimus.

Pediatr Transplant 2004 Aug;8(4):362-6

Division of Solid Organ Transplantation, Nemours Children's Clinic-Wilmington, Alfred I. duPont Hospital for Children, Wilmington, DE 19899, USA.

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated.
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http://dx.doi.org/10.1111/j.1399-3046.2004.00193.xDOI Listing
August 2004

Finance. Stars and gripes.

Authors:
Stephen P Dunn

Health Serv J 2004 Apr;114(5902):41-2

Institute of Health Policy Studies, California University, San Francisco, USA.

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April 2004

Pediatric transplantation.

Am J Transplant 2003 ;3 Suppl 4:53-63

The Johns Hopkins Hospital, Baltimore, MD, USA.

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http://dx.doi.org/10.1034/j.1600-6143.3.s4.6.xDOI Listing
January 2004

Neoral monitoring 2 hours post-dose and the pediatric transplant patient.

Authors:
Stephen P Dunn

Pediatr Transplant 2003 Feb;7(1):25-30

Alfred I. duPont Hospital for Children, Wilmington, Delaware 19899, USA.

Cyclosporin A therapy has evolved greatly over the past 25 years of clinical experience. Sophisticated studies of CsA pharmacokinetics and pharmacodynamics have led to a better understanding of the relationship between dose response and biological effect. It has become apparent that achieving target drug exposure is necessary for optimal clinical outcomes. Monitoring dose response has become a key aspect of immunosuppressive management. This review presents the information available supporting cyclosporin drug concentration drawn two hours post dose (C-2) in children who have been transplanted as the best single indicator of CsA exposure. Further studies evaluating the clinical benefit of achieving C-2 targets in children are indicated.
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http://dx.doi.org/10.1034/j.1399-3046.2003.02040.xDOI Listing
February 2003

Domino as a bridge to definitive liver transplantation in a neonate.

Pediatr Transplant 2002 Jun;6(3):249-54

Division of Solid Organ Transplantation, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19899, USA.

An interim liver transplant was used to extend survival in a neonate. This was accomplished by the initial transplant of a left-lateral segment of a metabolically abnormal liver obtained from a 7-yr-old patient with primary oxalosis. This bridging strategy was required because our neonatal patient was dying of fulminant hepatic failure caused by hepatic vein thrombosis and a small liver or liver segment could not be found. Although problems with hyperoxaluria were encountered in the neonate post-transplant, the interim liver transplant enabled the baby to survive and grow until the age of 4 months. At that time, a definitive transplant was performed using the left-lateral segment of his mother's liver. This case represents the first reported use of a pediatric domino transplant where a metabolically abnormal liver was used to allow sufficient growth to permit a definitive liver transplantation.
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http://dx.doi.org/10.1034/j.1399-3046.2002.01083.xDOI Listing
June 2002

Basiliximab in pediatric liver transplantation: a pharmacokinetic-derived dosing algorithm.

Pediatr Transplant 2002 Jun;6(3):224-30

Novartis Pharmaceuticals, Basel, Switzerland.

The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age-group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed-dose approach for part two of the study in which infants and children received two 10-mg doses of basiliximab and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for screening for anti-idiotype antibodies and analysis of basiliximab and soluble interleukin-2 receptor (IL-2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by approximately 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9-14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25-saturating basiliximab concentrations were maintained for 27 +/- 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 +/- 11 days in part two of the study, based on the fixed-dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age-related bias observed in part one of the study. Anti-idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent-to-treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post-transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12-month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine-release syndrome or other infusion-related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10-mg doses and those > or = 35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.
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http://dx.doi.org/10.1034/j.1399-3046.2002.01086.xDOI Listing
June 2002