Publications by authors named "David R Kelly"

71 Publications

Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.

J Pediatr Hematol Oncol 2021 Mar 31. Epub 2021 Mar 31.

Department of Pathology and Laboratory Medicine, Children's of Alabama Department of Pediatrics, Division of Hematology and Oncology Departments of Pathology Genetics, University of Alabama at Birmingham, Birmingham, AL.

Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1097/MPH.0000000000002097DOI Listing
March 2021

Pleuropulmonary blastoma in an adolescent.

J Pediatr Surg Case Rep 2020 Aug 23;59. Epub 2020 May 23.

Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA.

Primary pulmonary malignancies are rare in childhood. The most common, pleuropulmonary blastoma (PPB), has an incidence of 25-50 cases per year in the United States (Knight and et al., 2019) [1]. The majority of children are diagnosed with PPB before the age of four years. PPB is divided into subtypes I, Ir (type I-regressed), II, and III, which correlates to the age of diagnosis and patient prognosis [2,3]. Here we report an unusual presentation of PPB in a teen-aged female who presented with a one month history of a non-productive cough.
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http://dx.doi.org/10.1016/j.epsc.2020.101482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375461PMC
August 2020

Prevalence of chronic rhinosinusitis in bronchiectasis patients suspected of ciliary dyskinesia.

Int Forum Allergy Rhinol 2019 12 20;9(12):1430-1435. Epub 2019 Aug 20.

Department of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL.

Background: Mucociliary clearance is a main defense mechanism of the airway and is impaired in ciliary dyskinesia. The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia.

Methods: Bronchiectasis patients referred to a rhinology clinic for nasal brush biopsy (NBB) were included in this study. NBB was performed using a curettage technique whereby ciliated epithelial cells were obtained from the surface of the inferior nasal turbinate. Results of transmission electron microscopy findings, primary ciliary dyskinesia (PCD) gene (35 genes) analyses (Invitae), and sinus computed tomography (CT) scans were reviewed.

Results: Twenty-three patients (age, 54 ± 2.9 years) were referred for NBB between 2015 and 2018. Thirteen patients (56.5%) met the criteria for diagnosis of CRS. Nineteen patients had ciliary ultrastructural defects. The most common finding was compound cilia (n = 11, 47.8%). Five patients (21.7%) had central microtubule defects (CMD) with higher forced expiratory volume in 1 second (FEV ) at the time of referral than those without CMD (CMD , 91 ± 3.7%; CMD , 73.5 ± 5.7%; p = 0.023). Of 15 subjects with a PCD gene panel, 67% (9 of 15) carried at least 1 gene associated with PCD. Only 1 patient reached diagnosis of PCD. Approximately 50% of non-PCD carriers had a smoking history (p < 0.05). Lund-Mackay scores did not significantly differ between PCD and non-PCD carriers (p = 0.72).

Conclusion: Nearly half of bronchiectasis patients referred for NBB had concurrent CRS. The presence of ciliary abnormalities was not amplified in bronchiectasis patients with CRS compared to those without CRS. Extrinsic factors may be related to ciliary structural abnormalities in non-PCD gene carriers.
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http://dx.doi.org/10.1002/alr.22414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901752PMC
December 2019

Recurrent Skin Langerhan Cell Histiocytosis Successfully Treated With Indomethacin Monotherapy.

J Pediatr Hematol Oncol 2020 11;42(8):e795-e797

Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham.

Langerhans cell histiocytosis (LCH) often has a recurrent and refractory course despite multiagent treatment modalities. Common relapse treatments include intense or prolonged cytotoxic chemotherapy regimens. There are a few prior reports that the nonsteroidal anti-inflammatory drug indomethacin demonstrated activity against bone LCH. Here we report indomethacin as a successful treatment for a case of chronic skin LCH that failed multiple prior chemotherapy regimens. This experience supports the need for trials to investigate indomethacin as a treatment for LCH both in the relapsed or refractory setting as well as potential combination or maintenance therapy in newly diagnosed patients.
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http://dx.doi.org/10.1097/MPH.0000000000001474DOI Listing
November 2020

Clinicopathologic Features of a Series of Primary Renal CIC-rearranged Sarcomas With Comprehensive Molecular Analysis.

Am J Surg Pathol 2018 10;42(10):1360-1369

Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI.

CIC-rearranged sarcomas rarely occur in visceral organs including the kidney. The most common fusion partner with CIC is the DUX4 gene, but variant fusion partners have also been reported. Herein, we describe the clinicopathologic features and comprehensive molecular profiling of 4 cases of primary renal CIC-rearranged sarcomas. All cases occurred in females, age range 13 to 82 years and included 3 resections and 1 needle biopsy specimen. There was a tendency for development of metastatic disease predominantly to the lungs and poor disease outcome despite different treatment strategies. Histologically, variable round cell (20% to 100%), spindle cell (0% to 80%), and rhabdoid morphologies (0% to 20%) were seen. By immunohistochemistry diffuse WT1 nuclear (2 to 3+, ∼90%) labeling was present in 1 case, with cytoplasmic staining in the others (3+, 40% to 75%). CD99 was focally positive in all 4 cases (≤10%); 1 case each was diffusely positive for c-myc (2 to 3+, ∼90%) and ETV4 (3+, ∼90%); 1 case was focally positive for c-myc (2+, ∼5%) and calretinin (2+, ∼5%); and all cases were negative for cytokeratin and NKX2.2. CIC rearrangement by fluorescence in situ hybridization was present in the 3 cases tested. Comprehensive genomic profiling (CGP) of 3 cases revealed a CIC-DUX4 fusion in 2 cases, and 1 CIC-NUTM1 fusion. All 4 CIC-rearranged renal sarcomas had low mutation burden, and except HLA-A and MLL mutations lacked genomic alterations in other oncogenic drivers. Material from the needle biopsy was insufficient for CGP but that case was positive with the DUX4 immunohistochemical stain as were the 2 CIC-DUX4 tumors. In conclusion, CIC-rearranged sarcomas rarely occur in the kidney with a tendency for poor outcome and in this series we illustrate an example with CIC-NUTM1 fusion, an emerging variant, at a visceral site. Testing by fluorescence in situ hybridization or CGP is optimal to avoid missing cases that harbor variant fusion partners.
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http://dx.doi.org/10.1097/PAS.0000000000001098DOI Listing
October 2018

Subclinical inflammation phenotypes and long-term outcomes after pediatric kidney transplantation.

Am J Transplant 2018 09 27;18(9):2189-2199. Epub 2018 Jun 27.

Department of Surgery, University of Alabama School of Medicine, Birmingham, Alabama.

The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single-center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies ≤6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell-mediated rejection without clinical dysfunction) is associated with a 5-year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation.
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http://dx.doi.org/10.1111/ajt.14933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436389PMC
September 2018

TLE1 Expression in Malignant Rhabdoid Tumor and Atypical Teratoid/Rhabdoid Tumor.

Pediatr Dev Pathol 2018 Nov-Dec;21(6):522-527. Epub 2018 Feb 28.

2 Department of Pathology, Children's of Alabama, Birmingham, Alabama.

Malignant rhabdoid tumors (MRT; atypical teratoid/rhabdoid tumor [ATRT] in the central nervous system) are aggressive tumors in infants and children which can overlap with other sarcomas, such as synovial sarcoma (SS). The gold standard for SS diagnosis is characterization of the t(X;18) chromosomal translocation. However, stratification of cases for molecular analysis is not always straightforward or feasible. Recent literature suggests transducer-like enhancer of split 1 (TLE1) protein expression may distinguish SS from certain histologic mimics; however, this has not been investigated in MRT and ATRT. We stained whole-tissue sections of 18 archived cases of MRT and ATRT with TLE1. Nuclear expression was scored using a 4-tiered (0, 1+, 2+, and 3+) scale describing staining intensity, extent, or combination of both. The majority of MRT and ATRT cases showed some TLE1 immunoreactivity (n = 16; 89% for ≥1 + staining); 14 (78%) of total cases showed ≥2 + positivity using any of the 3 scoring systems. Over half (n = 10; 56%) of cases showed ≥2 + staining; 4 (22%) cases showed 3 + strong and diffuse TLE1 staining measured by all scoring systems in agreement. Although still of potential use, we urge caution in the interpretation of TLE1 when the differential diagnosis includes both SS and MRT or ATRT.
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http://dx.doi.org/10.1177/1093526618761720DOI Listing
December 2018

Pediatric Anaplastic Embryonal Rhabdomyosarcoma: Targeted Therapy Guided by Genetic Analysis and a Patient-Derived Xenograft Study.

Front Oncol 2017 11;7:327. Epub 2018 Jan 11.

Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, United States.

Therapy for rhabdomyosarcoma (RMS) has generally been limited to combinations of conventional cytotoxic agents similar to regimens originally developed in the late 1960s. Recently, identification of molecular alterations through next-generation sequencing of individual tumor specimens has facilitated the use of more targeted therapeutic approaches for various malignancies. Such targeted therapies have revolutionized treatment for some cancer types. However, malignancies common in children, thus far, have been less amenable to such targeted therapies. This report describes the clinical course of an 8-year-old female with embryonal RMS having anaplastic features. This patient experienced multiple relapses after receiving various established and experimental therapies. Genomic testing of this RMS subtype revealed mutations in , and genes, each of which contributes to epigenetic regulation and interacts with or modifies the activity of histone deacetylases (HDAC). Based on these findings, the patient was treated with the HDAC inhibitor vorinostat as a single agent. The tumor responded transiently followed by subsequent disease progression. We also examined the efficacy of vorinostat in a patient-derived xenograft (PDX) model developed using tumor tissue obtained from the patient's most recent tumor resection. The antitumor activity of vorinostat observed with the PDX model reflected clinical observations in that obvious areas of tumor necrosis were evident following exposure to vorinostat. Histologic sections of tumors harvested from PDX tumor-bearing mice treated with vorinostat demonstrated induction of necrosis by this agent. We propose that the evaluation of clinical efficacy in this type of preclinical model merits further evaluation to determine if PDX models predict tumor sensitivity to specific agents and/or combination therapies.
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http://dx.doi.org/10.3389/fonc.2017.00327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768639PMC
January 2018

Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors.

Sci Rep 2017 12 19;7(1):17787. Epub 2017 Dec 19.

Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.

Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores ≥20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with >99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty-three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis.
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http://dx.doi.org/10.1038/s41598-017-17162-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736554PMC
December 2017

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Hum Genet 2016 May 12;135(5):569-586. Epub 2016 Apr 12.

Division of Medical Genetics, Department of Pediatrics, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
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http://dx.doi.org/10.1007/s00439-016-1655-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518754PMC
May 2016

Regulation of alveolar septation by microRNA-489.

Am J Physiol Lung Cell Mol Physiol 2016 Mar 30;310(5):L476-87. Epub 2015 Dec 30.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama;

MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.
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http://dx.doi.org/10.1152/ajplung.00145.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773841PMC
March 2016

Surgical and Anesthetic Management of a Mediastinal Fatty Tumor: Lipoblastoma.

Ann Thorac Surg 2015 Nov;100(5):e97-8

Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, Alabama.

Lipoblastoma is a rare fatty tumor that is diagnosed almost exclusively in children. Presentation often consists of respiratory symptoms; chest computed tomography shows a hypodense, low, attenuated mediastinal mass. Surgical approach and anesthetic management are dependent on the location of the tumor and the degree of airway compression; in most cases, a thoracotomy is performed, although a sternotomy is used in selected cases. Final diagnosis can be confirmed using molecular genetic analysis; a genetic hallmark of lipoblastoma is the rearrangement of chromosomal region 8q12 and the PLAG1 gene. Tumor recurrence is rare when a complete resection is performed.
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http://dx.doi.org/10.1016/j.athoracsur.2015.04.103DOI Listing
November 2015

Shone variant with large eustachian valve: implication for repair and heart transplantation.

Cardiovasc Pathol 2015 Mar-Apr;24(2):124-7. Epub 2014 Oct 16.

UAB Pediatric Cardiology.

We present a case of a neonate with Shone complex in addition to the underdevelopment of the right ventricle associated with dysplasia and stenosis of the tricuspid valve. Because of lack of effective surgical options, the patient was transplanted at the age of 8days. A gradient was noted in the postoperative period across the inferior vena cava anastomosis. At reoperation, a prominent myxomatous Eustachian valve was resected. We believe the large Eustachian valve was likely responsible for the right-sided pathology.
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http://dx.doi.org/10.1016/j.carpath.2014.10.002DOI Listing
November 2015

Multiple native flavin reductases in camphor-metabolizing Pseudomonas putida NCIMB 10007: functional interaction with two-component diketocamphane monooxygenase isoenzymes.

Microbiology (Reading) 2014 Aug 16;160(Pt 8):1783-1794. Epub 2014 May 16.

Department of Chemistry, University of Wales College of Cardiff, Cardiff CF1 3TB, UK.

Although they have been studied for nearly 50 years, the source of the FMNH2 needed for effective biooxidation by the 2,5- and 3,6-diketocamphane monooxygenase (DKCMO) isoenzymes induced by the growth of Pseudomonas putida NCIMB 10007 (ATCC 17453) on camphor remains incompletely characterized. Prior studies have focussed exclusively on enzymes present in cells harvested during late-exponential-phase growth despite considerable circumstantial evidence that the flavin reductase (FR) component of these multicomponent monooxygenases is subject to growth-phase-dependent variation. In this study, a number of alternative FMNH2-generating activities, including both conventional FRs and enzymes also able to serve as ferric reductases, were isolated from camphor-grown cells, and the relative level, and hence potential contribution, of these various proteins shown to vary considerably depending on the point of harvest of NCIMB 10007 within exponential-phase growth. While two constitutive monomeric ferric reductases (molecular masses 27.0 and 28.5 kDa) were found to be the major relevant sources of FMNH2 during the initial stages of growth on camphor-based media, a significant subsequent contribution throughout the mid- to late-exponential phases of growth was also made by the camphor-induced homodimeric 37.0 kDa FR Fred, recently reported to serve such a role exclusively. The possible involvement of camphor-induced putidaredoxin reductase (51.0 kDa) as a contributory activity was also investigated and considered. Studies with highly purified preparations of the isofunctional DKCMOs confirmed the potential of the various reductases to function effectively as sources of the requisite FMNH2 to both monooxygenases at different times throughout growth on camphor.
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http://dx.doi.org/10.1099/mic.0.079913-0DOI Listing
August 2014

Intestinal epithelial apoptosis initiates gut mucosal injury during extracorporeal membrane oxygenation in the newborn piglet.

Lab Invest 2014 Feb 23;94(2):150-60. Epub 2013 Dec 23.

1] Division of Neonatology, Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA [2] Department of Pediatrics, Center for Neonatal and Pediatric Gastrointestinal Disease, University of Illinois at Chicago, Chicago, IL, USA [3] Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.

Neonates and young infants exposed to extracorporeal circulation during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass are at risk of developing a systemic inflammatory response syndrome with multi-organ dysfunction. We used a piglet model of ECMO to investigate the hypothesis that epithelial apoptosis is an early event that precedes villous damage during ECMO-related bowel injury. Healthy 3-week-old piglets were subjected to ECMO for up to 8 h. Epithelial apoptosis was measured in histopathological analysis, nuclear imaging, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Plasma intestinal fatty acid-binding protein (I-FABP) levels were measured by enzyme immunoassay. Intestinal mast cells were isolated by fluorescence-assisted cell sorting. Cleaved caspase-8, caspase-9, phospho-p38 MAPK, and fas ligand expression were investigated by immunohistochemistry, western blots, and reverse transcriptase-quantitative PCR. Piglet ECMO was associated with increased gut epithelial apoptosis. Extensive apoptotic changes were noted on villus tips and in scattered crypt cells after 2 h of ECMO. After 8 h, the villi were denuded and apoptotic changes were evident in a majority of crypt cells. Increased circulating I-FABP levels, a marker of gut epithelial injury, showed that epithelial injury occurred during ECMO. We detected increased cleaved caspase-8, but not cleaved caspase-9, in epithelial cells indicating that the extrinsic apoptotic pathway was active. ECMO was associated with increased fas ligand expression in intestinal mast cells, which was induced through activation of the p38 mitogen-activated protein kinase. We conclude that epithelial apoptosis is an early event that initiates gut mucosal injury in a piglet model of ECMO.
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http://dx.doi.org/10.1038/labinvest.2013.149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946757PMC
February 2014

Eosinophilic Appendicitis Attributable to Strongyloides Infection in a Pediatric Renal Transplant Patient.

J Pediatric Infect Dis Soc 2013 Sep 11;2(3):274-7. Epub 2012 Oct 11.

Division of Infectious Diseases, Department of Pediatrics.

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http://dx.doi.org/10.1093/jpids/pis090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761319PMC
September 2013

Myofibroblast differentiation and enhanced TGF-B signaling in cystic fibrosis lung disease.

PLoS One 2013 12;8(8):e70196. Epub 2013 Aug 12.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Rationale: TGF-β, a mediator of pulmonary fibrosis, is a genetic modifier of CF respiratory deterioration. The mechanistic relationship between TGF-β signaling and CF lung disease has not been determined.

Objective: To investigate myofibroblast differentiation in CF lung tissue as a novel pathway by which TGF-β signaling may contribute to pulmonary decline, airway remodeling and tissue fibrosis.

Methods: Lung samples from CF and non-CF subjects were analyzed morphometrically for total TGF-β1, TGF-β signaling (Smad2 phosphorylation), myofibroblast differentiation (α-smooth muscle actin), and collagen deposition (Masson trichrome stain).

Results: TGF-β signaling and fibrosis are markedly increased in CF (p<0.01), and the presence of myofibroblasts is four-fold higher in CF vs. normal lung tissue (p<0.005). In lung tissue with prominent TGF-β signaling, both myofibroblast differentiation and tissue fibrosis are significantly augmented (p<0.005).

Conclusions: These studies establish for the first time that a pathogenic mechanism described previously in pulmonary fibrosis is also prominent in cystic fibrosis lung disease. The presence of TGF-β dependent signaling in areas of prominent myofibroblast proliferation and fibrosis in CF suggests that strategies under development for other pro-fibrotic lung conditions may also be evaluated for use in CF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741283PMC
March 2014

Polyarteritis nodosa in childhood: recognition of early dermatologic signs may prevent morbidity.

Pediatr Dermatol 2014 Jan-Feb;31(1):e6-9. Epub 2013 Aug 13.

Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.

Systemic polyarteritis nodosa (PAN) is a vasculitis that affects small to medium-size arteries. Onset in childhood is rare and can cause significant morbidity. Often, cutaneous manifestations can provide early clues toward diagnosis. This article describes a case of childhood systemic PAN that presented with fever, a necrotic skin lesion, and oral ulceration. Intestinal perforation complicated this case. Prompt recognition of childhood PAN is important to prevent serious complications.
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http://dx.doi.org/10.1111/pde.12207DOI Listing
September 2014

Successful treatment of preadolescents with small cell carcinoma of the ovary hypercalcemic type.

J Pediatr Hematol Oncol 2013 Oct;35(7):566-9

Departments of *Pediatrics, Division of Hematology-Oncology †Pathology and Laboratory Medicine, Children's Hospital of Alabama, University of Alabama at Birmingham, Birmingham, AL.

Background: Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare tumor with a peak incidence in young adulthood that historically has carried a poor prognosis.

Observations: We present 2 advanced stage cases of SCCOHT in preadolescents successfully treated with a combination of cisplatin-based chemotherapy and surgical resection. The more recent patient also underwent consolidative high-dose chemotherapy with stem cell rescue and external beam radiotherapy. Her therapy was concluded with a maintenance course of bevacizumab. The patients are now disease-free 7 years and 30 months, respectively, after diagnosis.

Conclusions: With aggressive multimodal therapy SCCOHT is curable in children.
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http://dx.doi.org/10.1097/MPH.0b013e318282cca8DOI Listing
October 2013

Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall.

Am J Dermatopathol 2013 Feb;35(1):e16-21

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-0009, USA.

Proliferative (cellular) nodules (PN) which mimic malignant melanoma clinically and histologically are described in congenital melanocytic nevi (CMN) and may pose significant diagnostic challenges. We report the case of a 10-day-old male with a giant congenital nevus involving the neck, upper chest, back, and left shoulder containing several nodular lesions, some crusted. Biopsy of a nodule revealed densely packed nevus cells with hyperchromatic round to oval and occasionally irregularly shaped nuclei. There was no necrosis or pushing border, and the nodule blended with the adjacent nevus; however, the lesion demonstrated a significant number of mitoses (27 per mm2) and a 60% labeling index with Ki-67. Further analysis by fluorescence in situ hybridization (FISH) with a 4-color probe set targeting 6p25, 6q23, 11q13, and centromere 6 revealed increased chromosomal copy numbers of all 4 probes, which was interpreted as evidence of polyploidy. In addition, analysis of DNA copy number changes using a single nucleotide polymorphism microarray (Affymetrix, Santa Clara, CA) showed no chromosomal aberrations. The diagnosis of PN in a giant congenital nevus was eventually rendered. At 13-month follow-up, the nodules showed no evidence of growth. Our case illustrates that PNs in the neonatal period might demonstrate extreme mitotic activity. This feature is worrisome when encountered in melanocytic lesions; however, it should not trigger by itself a diagnosis of melanoma in the absence of other histologic criteria of malignancy. In addition, we document polyploidy by FISH in PN, which can potentially be misinterpreted as a FISH-positive result.
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http://dx.doi.org/10.1097/DAD.0b013e318265fe12DOI Listing
February 2013

Angiodysplasia (vascular malformations) of the colon presenting as an acute abdomen.

J Pediatr Surg 2012 Oct;47(10):e37-40

Pediatric Surgery Division, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

Angiodysplasia (vascular malformations) of the colon is extremely rare in children, and, as in adults, present with lower gastrointestinal hemorrhage. Here we report an unusual pediatric case of angiodysplasia of the terminal ileum and cecum presenting as an acute abdomen with radiological features suggestive of lymphoma.
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http://dx.doi.org/10.1016/j.jpedsurg.2012.06.020DOI Listing
October 2012

Sarcoidosis in a young child with Alagille syndrome: a case report.

Pediatr Rheumatol Online J 2012 Aug 31;10(1):32. Epub 2012 Aug 31.

Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.

We report a now 6-year-old African-American male with both Alagille syndrome and pediatric sarcoidosis. With a prior JAG1 mutation positive diagnosis of Alagille syndrome, he presented to the hospital with a subacute, predominantly respiratory febrile condition, eventually diagnosed as sarcoidosis. A liver biopsy revealed paucity of bile ducts and scattered epithelioid granulomas, while a skin biopsy showed granulomatous angiitis, a manifestation of sarcoidosis not yet reported in a pediatric patient. He has subsequently been treated with corticosteroids, mycophenolate mofetil, and infliximab with clinical response. Alagille syndrome and sarcoidosis have not yet been reported in the medical literature in the same patient to the best of our knowledge. We briefly review these two seemingly unrelated conditions and propose a possible common pathogenic mechanism.
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http://dx.doi.org/10.1186/1546-0096-10-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599400PMC
August 2012

Crohn's disease with pulmonary manifestations in children: 2 case reports and review of the literature.

J Crohns Colitis 2013 Apr 14;7(3):e85-92. Epub 2012 Jun 14.

Division of Pediatric Gastroenterology and Nutrition, Children's of Alabama, Birmingham, AL 35233, USA.

Crohn's disease (CD) is a chronic granulomatous disease of unknown etiology that affects primarily the gastrointestinal system but can be associated with extraintestinal manifestations. Latent pulmonary involvement in children with CD has been described, but symptomatic pulmonary disease has rarely been reported in children. In this review, we report two pediatric cases, one with pleural effusion at the time of CD diagnosis and the other with bilateral cavitary lesions in a previously diagnosed CD patient. We review the current literature and summarize the diagnosis and management of pulmonary involvement in CD. Awareness of these pulmonary complications of CD in children may lead to more prompt diagnosis, guide appropriate therapy, and decrease morbidity.
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http://dx.doi.org/10.1016/j.crohns.2012.05.007DOI Listing
April 2013

Type 1 hyperlipoproteinemia and recurrent acute pancreatitis due to lipoprotein lipase antibody in a young girl with Sjogren's syndrome.

J Clin Endocrinol Metab 2011 Nov 31;96(11):3302-7. Epub 2011 Aug 31.

Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

Context: Type 1 hyperlipoproteinemia (T1HLP) in childhood is most often due to genetic deficiency of lipoprotein lipase (LPL) or other related proteins.

Objective: The aim was to report a case of marked hypertriglyceridemia and recurrent acute pancreatitis due to the presence of LPL autoantibody in a young girl who was subsequently diagnosed with Sjögren's syndrome.

Subject And Methods: A 9-yr-old African-American girl presented with acute pancreatitis and serum triglycerides of 4784 mg/dl. Strict restriction of dietary fat reduced serum triglycerides, but she continued to experience recurrent pancreatitis. Approximately 18 months thereafter, she developed transient pauciarticular arthritis with elevated serum antinuclear antibody (>1:1280). Minor salivary gland biopsy revealed chronic sialadenitis with a dense periductal lymphocytic aggregate suggestive of Sjögren's syndrome. Genomic DNA was analyzed for LPL, GPIHBP1, APOA5, APOC2, and LMF1. Immunoblotting was performed to detect serum LPL autoantibody.

Results: The patient had no disease-causing variants in LPL, GPIHBP1, APOA5, APOC2, or LMF1. Immunoblotting revealed serum LPL antibody. The patient responded to immunosuppressive therapy for Sjögren's syndrome with resolution of hypertriglyceridemia.

Conclusions: Unexplained T1HLP in childhood could be secondary to LPL deficiency induced by autoantibodies. Therefore, diagnosis of autoimmune T1HLP should be entertained if clinical features are suggestive of an autoimmune process.
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http://dx.doi.org/10.1210/jc.2011-1113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205898PMC
November 2011

Involvement of the brachial plexus and its branches by cystic hygromas.

J Neurosurg Pediatr 2011 Mar;7(3):282-5

Pediatric Neurosurgery, Children's Hospital, Birmingham, Alabama 35233, USA.

Lymphatic malformations that involve the nervous system are uncommon. The authors review their experience with involvement of the brachial plexus and its branches by cystic hygromas. A retrospective review of the authors' experience with pathology of the pediatric brachial plexus revealed 4 cases involving patients with compression of this structure and its branches due to cystic hygroma. Although such cases are apparently rare, the neurosurgeon should consider malformations of the lymphatic system in the differential diagnosis of masses involving the brachial plexus and its branches.
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http://dx.doi.org/10.3171/2010.12.PEDS10282DOI Listing
March 2011

2D-difference gel electrophoretic proteomic analysis of a cell culture model of alveolar rhabdomyosarcoma.

J Proteome Res 2011 Feb 10;10(2):624-36. Epub 2011 Jan 10.

Department of Pediatrics, Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

To evaluate the consequences of expression of the protein encoded by PAX3-FOXO1 (P3F) in the pediatric malignancy alveolar rhabdomyosarcoma (A-RMS), we developed and evaluated a genetically defined in vitro model of A-RMS tumorigenesis. The expression of P3F in cooperation with simian virus 40 (SV40) Large-T (LT) antigen in murine C3H10T1/2 fibroblasts led to robust malignant transformation. Using 2-dimensional-difference gel electrophoresis (2D-DIGE), we compared proteomes from lysates from cells that express P3F + LT versus from cells that express LT alone. Analysis of 2D gel spot patterns by DeCyder image analysis software indicated 93 spots that were different in abundance. Peptide mass fingerprint analysis of the 93 spots by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis identified 37 nonredundant proteins. 2D-DIGE analysis of cell culture media conditioned by cells transduced by P3F + LT versus by LT alone found 29 spots in the P3F + LT cells leading to the identification of 11 nonredundant proteins. A substantial number of proteins with potential roles in tumorigenesis and myogenesis were detected, most of which have not been identified in previous wide-scale expression studies of RMS experimental models or tumors. We validated the 2D gel image analysis findings by Western blot analysis and immunohistochemistry (IHC). Thus, the 2D-DIGE proteomics methodology described here provided an important discovery approach to the study of RMS biology and complements the findings of previous mRNA expression studies.
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http://dx.doi.org/10.1021/pr1008493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071502PMC
February 2011

Three sequential malignancies in a child.

Clin Pediatr (Phila) 2011 Sep 22;50(9):879-81. Epub 2010 Nov 22.

University of Alabama at Birmingham, Birmingham, AL 35233, USA.

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http://dx.doi.org/10.1177/0009922810384850DOI Listing
September 2011

Complete response to carboplatin, gemcitabine, and paclitaxel in a patient with advanced metastatic renal medullary carcinoma.

Pediatr Blood Cancer 2010 Dec;55(6):1217-20

Division of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Renal medullary carcinoma (RMC) is a rare and aggressive malignancy seen primarily in patients with sickle-cell trait. We report a complete response to carboplatin, paclitaxel, and gemcitabine in a patient with advanced metastatic RMC.
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http://dx.doi.org/10.1002/pbc.22611DOI Listing
December 2010

Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent pediatric patients.

Pediatr Blood Cancer 2010 Dec;55(6):1227-30

Department of Pediatrics, Children's Hospital of Philadelphia, Pennsylvania, Philadelphia, USA.

We report two cases of primary CNS lymphoma (PCNSL) treated with high-dose methotrexate. Though standard adult treatment of PCNSL incorporates whole-brain radiotherapy, the literature suggests it may be possible to delay or avoid radiotherapy and the associated increased risk of neurologic sequelae in pediatric patients. Studies in adults indicate methotrexate therapy can be effective against PCNSL and has advantages over the current standard of treatment. Both patients have no evidence of disease 9 and 7 years after treatment, suggesting high-dose methotrexate may lead to disease control in pediatric patients with PCNSL while avoiding the effects of radiotherapy.
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http://dx.doi.org/10.1002/pbc.22752DOI Listing
December 2010
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