Publications by authors named "Donald Coulter"

15 Publications

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Fusion genes as biomarkers in pediatric cancers: A review of the current state and applicability in diagnostics and personalized therapy.

Cancer Lett 2021 Feb 25;499:24-38. Epub 2020 Nov 25.

Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address:

The incidence of pediatric cancers is rising steadily across the world, along with the challenges in understanding the molecular mechanisms and devising effective therapeutic strategies. Pediatric cancers are presented with diverse molecular characteristics and more distinct subtypes when compared to adult cancers. Recent studies on the genomic landscape of pediatric cancers using next-generation sequencing (NGS) approaches have redefined this field by providing better subtype characterization and novel actionable targets. Since early identification and personalized treatment strategies influence therapeutic outcomes, survival, and quality of life in pediatric cancer patients, the quest for actionable biomarkers is of great value in this field. Fusion genes that are prevalent and recurrent in several pediatric cancers are ideally suited in this context due to their disease-specific occurrence. In this review, we explore the current status of fusion genes in pediatric cancer subtypes and their use as biomarkers for diagnosis and personalized therapy. We discuss the technological advancements made in recent years in NGS sequencing and their impact on fusion detection algorithms that have revolutionized this field. Finally, we also discuss the advantages of pairing liquid biopsy protocols for fusion detection and their eventual use in diagnosis and treatment monitoring.
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http://dx.doi.org/10.1016/j.canlet.2020.11.015DOI Listing
February 2021

Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth.

BMC Cancer 2020 Oct 1;20(1):941. Epub 2020 Oct 1.

Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA.

Background: Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized.

Methods: To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27.

Results: Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27.

Conclusions: Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.
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http://dx.doi.org/10.1186/s12885-020-07370-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528478PMC
October 2020

Nanoformulation of CCL21 greatly increases its effectiveness as an immunotherapy for neuroblastoma.

J Control Release 2020 11 22;327:266-283. Epub 2020 Jul 22.

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, United States of America; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States of America; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States of America; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States of America. Electronic address:

Neuroblastoma is the most commonly diagnosed extracranial solid tumor in children. The patients with aggressive metastatic disease or refractory/relapsed neuroblastoma currently face a dismally low chance of survival. Thus, there is a great need for more effective therapies for this illness. In previous studies, we, as well as others, showed that the immune cell chemoattractant C-C motif chemokine ligand 21 (CCL21) is effective as an intratumoral therapy able to slow the growth of cancers. In this current study, we developed and tested an injectable, slow-release, uniform, and optimally loaded alginate nanoformulation of CCL21 as a means to provide prolonged intratumoral treatment. The alginate-nanoformulated CCL21, when injected intratumorally into mice bearing neuroblastoma lesions, significantly prolonged survival and decreased the tumor growth rate compared to CCL21 alone, empty nanoparticles, or buffer. Notably, we also observed complete tumor clearance and subsequent full protection against tumor rechallenge in 33% of nanoformulated CCL21-treated mice. Greater intratumoral presence of nanoformulated CCL21, compared to free CCL21, at days 1 and 2 after treatment ended was confirmed through fluorescent labeling and tracking. Nanoformulated CCL21-treated tumors exhibited a general pattern of prolonged increases in anti-tumor cytokines and relatively lower levels of pro-tumor cytokines in comparison to tumors treated with CCL21 alone or buffer only. Thus, this novel nanoformulation of CCL21 is an effective treatment for neuroblastoma, and may have potential for the delivery of CCL21 to other types of solid tumors in the future and as a slow-release delivery modality for other immunotherapies.
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http://dx.doi.org/10.1016/j.jconrel.2020.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606783PMC
November 2020

ApoE mimetic peptide targeted nanoparticles carrying a BRD4 inhibitor for treating Medulloblastoma in mice.

J Control Release 2020 07 5;323:463-474. Epub 2020 May 5.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:

Treatment of medulloblastoma (MB) is challenging due to diverse genetic make-up, chemoresistance and inefficient drug transport across the blood brain barrier (BBB). Since hedgehog (Hh) signaling regulates cancer cell proliferation and tumorigenicity, Hh inhibitors have the potential to treat sonic Hh driven MB (SHH-MB), but their repeated use develops chemoresistance due to mutations in smoothened (SMO). Herein, we aimed to overcome these problems by modulating GLI transcription using JQ1, which is a small molecule BRD4 inhibitor. JQ1 inhibited HD-MB03 and DAOY cell proliferation, with the IC of 402 and 4220 nM, respectively. JQ1 inhibited colony formation, but increased apoptosis in HD-MB03 and DAOY cells. Western blot analysis confirmed significant inhibition of GLI1 and c-MYC protein expression in DAOY and HD-MB03 cells, respectively. JQ1 was encapsulated into apolipoprotein (ApoE) mimetic peptide decorated nanoparticles (ApoE-NPs), with the mean particle size of 64 nm and drug loading of 10% (w/w). ApoE-NPs increased JQ1 concentration in the tumor by 5 and 8 folds at 6 and 24 h after systemic administration into orthotopic MB tumor bearing NSG mice compared to non-targeted JQ1 loaded NPs. Although there was also modest increase in JQ1 delivery to the liver, there was no hepatotoxicity as evidenced by H&E staining and little increase in serum ALT and AST after treatment with JQ1 loaded ApoE-NPs. There was also significant decrease in the orthotopic MB tumor burden after systemic administration of JQ1 loaded ApoE- NPs at the dose of 10 mg/kg every 3rd day for a total of 8 injections. In conclusion, JQ1 loaded NPs have the potential to treat Group 3 and SHH driven MB in mice.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.053DOI Listing
July 2020

MiR-1253 exerts tumor-suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7-H3).

Brain Pathol 2020 07 30;30(4):732-745. Epub 2020 Mar 30.

Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.

Of the four primary subgroups of medulloblastoma, the most frequent cytogenetic abnormality, i17q, distinguishes Groups 3 and 4 which carry the highest mortality; haploinsufficiency of 17p13.3 is a marker for particularly poor prognosis. At the terminal end of this locus lies miR-1253, a brain-enriched microRNA that regulates bone morphogenic proteins during cerebellar development. We hypothesized miR-1253 confers novel tumor-suppressive properties in medulloblastoma. Using two different cohorts of medulloblastoma samples, we first studied the expression and methylation profiles of miR-1253. We then explored the anti-tumorigenic properties of miR-1253, in parallel with a biochemical analysis of apoptosis and proliferation, and isolated oncogenic targets using high-throughput screening. Deregulation of miR-1253 expression was noted, both in medulloblastoma clinical samples and cell lines, by epigenetic silencing via hypermethylation; specific de-methylation of miR-1253 not only resulted in rapid recovery of expression but also a sharp decline in tumor cell proliferation and target gene expression. Expression restoration also led to a reduction in tumor cell virulence, concomitant with activation of apoptotic pathways, cell cycle arrest and reduction of markers of proliferation. We identified two oncogenic targets of miR-1253, CDK6 and CD276, whose silencing replicated the negative trophic effects of miR-1253. These data reveal novel tumor-suppressive properties for miR-1253, i.e., (i) loss of expression via epigenetic silencing; (ii) negative trophic effects on tumor aggressiveness; and (iii) downregulation of oncogenic targets.
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http://dx.doi.org/10.1111/bpa.12829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383594PMC
July 2020

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Blood 2020 04;135(15):1287-1298

CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.
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http://dx.doi.org/10.1182/blood.2019003186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146024PMC
April 2020

Targeting cyclin-dependent kinase 9 sensitizes medulloblastoma cells to chemotherapy.

Biochem Biophys Res Commun 2019 12 5;520(2):250-256. Epub 2019 Oct 5.

Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.

Medulloblastoma (MB) is a highly aggressive, malignant brain tumor in children with poor prognosis. Cyclin-dependent kinase 9 (CDK9), a serine-threonine kinase, is widely implicated in the control of basal gene expression by phosphorylating Serine 2 (Ser2) of the heptad repeat in the RNA Polymerase II (RNA Pol II) C-terminal domain (CTD). Although CDK9 plays a pathogenic role in various cancers, its function in MB remains unknown. Here, we show that CDK9 is highly expressed in MB tumors and increased CDK9 expression is correlated with high risk MB patients. CDK9 expression along with phospho-Ser2 RNA Pol II (pRNA Pol II ser2) and bromodomain-binding protein 4 (BRD4), which recruits CDK9, were elevated in multiple MB cell lines and in MB tumors originated spontaneously from Ptch1p53 mice. Inhibition of CDK9 with LDC067 suppressed MB cell growth, reduced pRNA Pol II ser2 level and expression of oncogenic markers, including MYC. Moreover, LDC067 treatment synergistically sensitizes MB cells to chemotherapeutic agent cisplatin. Further, LDC067 in combination with BRD4 inhibitor decreased MB cells growth, delayed cell migration and attenuated pRNA Pol II ser2 occupancy to CCND1 and BCL2 gene promoters as revealed by chromatin immunoprecipitation assay (ChIP). Together, these findings highlight the importance of CDK9 in MB pathogenesis and suggest that it may serve as a promising therapeutic target for the treatment of MB.
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http://dx.doi.org/10.1016/j.bbrc.2019.09.118DOI Listing
December 2019

Norepinephrine-Transporter-Targeted and DNA-Co-Targeted Theranostic Guanidines.

J Med Chem 2020 03 3;63(5):2051-2073. Epub 2019 Jul 3.

Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, Nebraska 68132-6850, United States.

High risk neuroblastoma often recurs, even with aggressive treatments. Clinical evidence suggests that proliferative activities are predictive of poor outcomes. This report describes syntheses, characterization, and biological properties of theranostic guanidines that target norepinephrine transporter and undergo intracellular processing, and subsequently their catabolites are efficiently incorporated into DNA of proliferating neuroblastoma cells. Radioactive guanidines are synthesized from 5-radioiodo-2'-deoxyuridine, a molecular radiotherapy platform with clinically proven minimal toxicities and DNA-targeting properties. The transport of radioactive guanidines into neuroblastoma cells is active as indicated by the competitive suppression of cellular uptake by -iodobenzylguanidine. The rate of intracellular processing and DNA uptake is influenced by the agent's catabolic stability and cell population doubling times. The radiotoxicity is directly proportional to DNA uptake and duration of exposure. Biodistribution of 5-[I]iodo-3'--(ε-guanidinohexanoyl)-2'-deoxyuridine in a mouse neuroblastoma model shows significant tumor retention of radioactivity. Neuroblastoma xenografts regress in response to the clinically achievable doses of this agent.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00437DOI Listing
March 2020

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.

Blood 2019 07 1;134(3):304-316. Epub 2019 May 1.

British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.
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http://dx.doi.org/10.1182/blood.2019000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911839PMC
July 2019

Impact of miRNA-mRNA Profiling and Their Correlation on Medulloblastoma Tumorigenesis.

Mol Ther Nucleic Acids 2018 Sep 19;12:490-503. Epub 2018 Jun 19.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:

Medulloblastoma (MB) is a clinically challenging, childhood brain tumor with a diverse genetic makeup and differential miRNA profile. Aiming to identify deregulated miRNAs in MB, the miRNA expression profile of human MB samples was compared to that of normal cerebellar tissues. As a result, 8 upregulated and 64 downregulated miRNAs were identified in MB samples. Although various algorithms have been developed to predict the interaction between miRNA-mRNA pairs, the complexity and fidelity of miRNA-mRNA remain a concern. Therefore, to identify the signatures of miRNA-mRNA interactions essential for MB pathogenesis, miRNA profiling, RNA sequencing, and ingenuity pathway analysis (IPA) were performed in the same primary human MB samples. Further, when miR-217 was inhibited, a significant upregulation of predicted target genes SIRT1, ROBO1, FOXO3, and SMAD7 in HDMB03 cells was observed, confirming the validity of our approach. Functional analysis revealed that the inhibition of miR-217 in HDMB03 cells suppresses colony formation, migration, invasion, promoted apoptosis, and arrested cell population in S phase, indicating that manipulation of miR-217 may have a therapeutic potential for MB patients. Therefore, our study provides an essential platform for future investigations of specific miRNAs responsible for MB pathogenesis.
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http://dx.doi.org/10.1016/j.omtn.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070673PMC
September 2018

Using Watershed Boundaries to Map Adverse Health Outcomes: Examples From Nebraska, USA.

Environ Health Insights 2018 24;12:1178630217751906. Epub 2018 Jan 24.

Department of Environmental, Agricultural & Occupational Health, University of Nebraska Medical Center, Omaha, NE, USA.

In 2009, a paper was published suggesting that watersheds provide a geospatial platform for establishing linkages between aquatic contaminants, the health of the environment, and human health. This article is a follow-up to that original article. From an environmental perspective, watersheds segregate landscapes into geospatial units that may be relevant to human health outcomes. From an epidemiologic perspective, the watershed concept places anthropogenic health data into a geospatial framework that has environmental relevance. Research discussed in this article includes information gathered from the literature, as well as recent data collected and analyzed by this research group. It is our contention that the use of watersheds to stratify geospatial information may be both environmentally and epidemiologically valuable.
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http://dx.doi.org/10.1177/1178630217751906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788116PMC
January 2018

Challenges and Recent Advances in Medulloblastoma Therapy.

Trends Pharmacol Sci 2017 12 20;38(12):1061-1084. Epub 2017 Oct 20.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:

Medulloblastoma (MB) is the most common childhood brain tumor, which occurs in the posterior fossa. MB tumors are highly heterogeneous and have diverse genetic make-ups, with differential microRNA (miRNA) expression profiles and variable prognoses. MB can be classified into four subgroups, each with different origins, pathogenesis, and potential therapeutic targets. miRNA and small-molecule targeted therapies have emerged as a potential new therapeutic paradigm in MB treatment. However, the development of chemoresistance due to surviving cancer stem cells and dysregulation of miRNAs remains a challenge. Combination therapies using multiple drugs and miRNAs could be effective approaches. In this review we discuss various MB subtypes, barriers, and novel therapeutic options which may be less toxic than current standard treatments.
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http://dx.doi.org/10.1016/j.tips.2017.09.002DOI Listing
December 2017

Amyloid precursor protein and amyloid precursor-like protein 2 in cancer.

Oncotarget 2016 Apr;7(15):19430-44

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.

Amyloid precursor protein (APP) and its family members amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) are type 1 transmembrane glycoproteins that are highly conserved across species. The transcriptional regulation of APP and APLP2 is similar but not identical, and the cleavage of both proteins is regulated by phosphorylation. APP has been implicated in Alzheimer's disease causation, and in addition to its importance in neurology, APP is deregulated in cancer cells. APLP2 is likewise overexpressed in cancer cells, and APLP2 and APP are linked to increased tumor cell proliferation, migration, and invasion. In this present review, we discuss the unfolding account of these APP family members' roles in cancer progression and metastasis.
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http://dx.doi.org/10.18632/oncotarget.7103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991393PMC
April 2016

Occurrence of nephroblastomatosis with dup(18)(q11.2-q23) implicates trisomy 18 tumor screening protocol in select patients with 18q duplication.

Am J Med Genet A 2014 Apr 4;164A(4):1079-82. Epub 2014 Mar 4.

Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.

Duplications of the long arm of chromosome 18 have been previously reported in patients with phenotypic findings similar to full trisomy 18. Trisomy 18 increases the risk for Wilms tumor and it is currently recommended that these patients undergo abdominal ultrasonography screening every 6 months. We report on nephroblastomatosis in a 27-month-old male with a 55 Mb duplication of chromosome 18q11.2-q23 (chr18:22693370-77982126, hg 19) and propose that the trisomy 18 tumor screening protocol could also benefit patients with large 18q duplications.
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http://dx.doi.org/10.1002/ajmg.a.36432DOI Listing
April 2014

Early onset, EBV(-) PTLD in pediatric liver-small bowel transplantation recipients: a spectrum of plasma cell neoplasms with favorable prognosis.

Blood 2013 Feb 18;121(8):1377-83. Epub 2012 Dec 18.

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.

EBV(-) posttransplantation lymphoproliferative disorders (PTLDs) are rare compared with EBV(+) PTLDs, occur later after transplantation, and have a poor response to treatment. Few studies have reported EBV(-) PTLD in pediatric solid-organ transplantation recipients. We describe 5 cases of EBV(-) PTLD in recipients of combined liver and small bowel allografts ranging in age from 16 months to 7 years. EBV(-) PTLD developed 9-22 months (median, 15) after transplantation. Morphologically, the lesions ranged from atypical plasma cell hyperplasia (a term not currently included in the World Health Organization classification) to plasmacytoma like. In all cases, in situ hybridization for EBV was negative, and molecular studies demonstrated clonal IgH gene rearrangements. Protein electrophoresis showed multiple clonal paraproteins in 4 of 5 cases. In 2 cases with a donor-recipient sex mismatch, FISH cytogenetics demonstrated that the plasma cells were of mixed donor/recipient origin. One patient died before therapy. Four patients were treated with high-dose dexamethasone, and 1 patient subsequently required thalidomide. All 4 remain in remission 75-128 months (median, 86) after diagnosis. In contrast to reports of EBV(-) PTLD in adults, these plasma cell lesions occurred early after transplantation and resolved completely after minimal treatment.
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http://dx.doi.org/10.1182/blood-2012-06-438549DOI Listing
February 2013