Browsing by Author "Ferguson, Michael J."
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Item Diagnosis and Follow-up of Incidental Liver Lesions in Children(Wolters Kluwer, 2022-03) Karmazyn, Boaz; Rao, Girish S.; Johnstone, Lindsey S.; Severance, Tyler S.; Ferguson, Michael J.; Marshalleck, Francis E.; Molleston, Jean P.; Radiology and Imaging Sciences, School of MedicineABSTRACT: Incidental liver lesions are identified in children without underlying liver disease or increased risk of hepatic malignancy in childhood. Clinical and imaging evaluation of incidental liver lesions can be complex and may require a multidisciplinary approach. This review aims to summarize the diagnostic process and follow-up of incidental liver lesions based on review of the literature, use of state-of-the-art imaging, and our institutional experience. Age at presentation, gender, alpha fetoprotein levels, tumor size, and imaging characteristics should all be taken into consideration to optimize diagnosis process. Some lesions, such as simple liver cyst, infantile hemangioma, focal nodular hyperplasia (FNH) and focal fatty lesions, have specific imaging characteristics. Recently, contrast-enhanced ultrasound (CEUS) was FDA-approved for the evaluation of pediatric liver lesions. CEUS is most specific in lesions smaller than 3 cm and is most useful in the diagnosis of infantile hemangioma, FNH, and focal fatty lesions. The use of hepatobiliary contrast in MRI increases specificity in the diagnosis of FNH. Recently, lesion characteristics in MRI were found to correlate with subtypes of hepatocellular adenomas and associated risk for hemorrhage and malignant transformation. Biopsy should be considered when there are no specific imaging characteristics of a benign lesion. Surveillance with imaging and AFP should be performed to confirm the stability of lesions when the diagnosis cannot be determined, and when biopsy is not feasible.Item Early administration of imatinib mesylate reduces plexiform neurofibroma tumor burden with durable results after drug discontinuation in a mouse model of neurofibromatosis type 1(Wiley, 2020-05-27) Armstrong, Amy E.; Rhodes, Steven D.; Smith, Abbi; Chen, Shi; Bessler, Waylan; Ferguson, Michael J.; Jiang, Li; Li, Xiaohong; Yuan, Jin; Yang, Xianlin; Yang, Feng-Chun; Robertson, Kent A.; Ingram, David A.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of MedicineBACKGROUND Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of pre-existing pNF, however imatinib’s role on preventing pNF development has yet to be explored. PROCEDURE We evaluated the effect of imatinib dosed at 10–100 mg/kg/day for 12 weeks to 1-month old Nf1flox/flox;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib to vehicle treated mice. We assessed gross and histopathological analysis of tumor burden. RESULTS Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared to age-matched littermates that received vehicle control. CONCLUSIONS Early administration of imatinib inhibits pNF genesis in vivo and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to substantial development of pNF.Item Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion(Springer Nature, 2023-06-06) Damayanti, Nur P.; Saadatzadeh, M. Reza; Dobrota, Erika; Ordaz, Josue D.; Bailey, Barbara J.; Pandya, Pankita H.; Bijangi-Vishehsaraei, Khadijeh; Shannon, Harlan E.; Alfonso, Anthony; Coy, Kathy; Trowbridge, Melissa; Sinn, Anthony L.; Zhang, Zhong-Yin; Gallagher, Rosa I.; Wulfkuhle, Julia; Petricoin, Emanuel; Richardson, Angela M.; Marshall, Mark S.; Lion, Alex; Ferguson, Michael J.; Balsara, Karl E.; Pollok, Karen E.; Neurological Surgery, School of MedicinePleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.Item Gene Co-Expression Networks Restructured Gene Fusion in Rhabdomyosarcoma Cancers(MDPI, 2019-08-30) Helm, Bryan R.; Zhan, Xiaohui; Pandya, Pankita H.; Murray, Mary E.; Pollok, Karen E.; Renbarger, Jamie L.; Ferguson, Michael J.; Han, Zhi; Ni, Dong; Zhang, Jie; Huang, Kun; Medicine, School of MedicineRhabdomyosarcoma is subclassified by the presence or absence of a recurrent chromosome translocation that fuses the FOXO1 and PAX3 or PAX7 genes. The fusion protein (FOXO1-PAX3/7) retains both binding domains and becomes a novel and potent transcriptional regulator in rhabdomyosarcoma subtypes. Many studies have characterized and integrated genomic, transcriptomic, and epigenomic differences among rhabdomyosarcoma subtypes that contain the FOXO1-PAX3/7 gene fusion and those that do not; however, few investigations have investigated how gene co-expression networks are altered by FOXO1-PAX3/7. Although transcriptional data offer insight into one level of functional regulation, gene co-expression networks have the potential to identify biological interactions and pathways that underpin oncogenesis and tumorigenicity. Thus, we examined gene co-expression networks for rhabdomyosarcoma that were FOXO1-PAX3 positive, FOXO1-PAX7 positive, or fusion negative. Gene co-expression networks were mined using local maximum Quasi-Clique Merger (lmQCM) and analyzed for co-expression differences among rhabdomyosarcoma subtypes. This analysis observed 41 co-expression modules that were shared between fusion negative and positive samples, of which 17/41 showed significant up- or down-regulation in respect to fusion status. Fusion positive and negative rhabdomyosarcoma showed differing modularity of co-expression networks with fusion negative (n = 109) having significantly more individual modules than fusion positive (n = 53). Subsequent analysis of gene co-expression networks for PAX3 and PAX7 type fusions observed 17/53 were differentially expressed between the two subtypes. Gene list enrichment analysis found that gene ontology terms were poorly matched with biological processes and molecular function for most co-expression modules identified in this study; however, co-expressed modules were frequently localized to cytobands on chromosomes 8 and 11. Overall, we observed substantial restructuring of co-expression networks relative to fusion status and fusion type in rhabdomyosarcoma and identified previously overlooked genes and pathways that may be targeted in this pernicious disease.Item Immature teratoma in an adolescent with Proteus syndrome: A novel association(Wiley, 2021-05-04) Underwood, John S.; Ours, Christopher; Burns, R. Cartland; Ferguson, Michael J.; Pediatrics, School of MedicineProteus syndrome (PS) is a complex disorder characterized by variable clinical findings of overgrowth and tumor susceptibility. This report presents the first known association between PS and an ovarian germ cell tumor in an adolescent with immature teratoma. A review of the diagnosis of PS and associated tumors is included.Item Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors(MDPI, 2022-12-30) Pandya, Pankita H.; Jannu, Asha Jacob; Bijangi-Vishehsaraei, Khadijeh; Dobrota, Erika; Bailey, Barbara J.; Barghi, Farinaz; Shannon, Harlan E.; Riyahi, Niknam; Damayanti, Nur P.; Young, Courtney; Malko, Rada; Justice, Ryli; Albright, Eric; Sandusky, George E.; Wurtz, L. Daniel; Collier, Christopher D.; Marshall, Mark S.; Gallagher, Rosa I.; Wulfkuhle, Julia D.; Petricoin, Emanuel F.; Coy, Kathy; Trowbridge, Melissa; Sinn, Anthony L.; Renbarger, Jamie L.; Ferguson, Michael J.; Huang, Kun; Zhang, Jie; Saadatzadeh, M. Reza; Pollok, Karen E.; Pediatrics, School of MedicineEstablishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug−gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy.Item Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas(MDPI, 2022-07-25) Barghi, Farinaz; Shannon, Harlan E.; Saadatzadeh, M. Reza; Bailey, Barbara J.; Riyahi, Niknam; Bijangi-Vishehsaraei, Khadijeh; Just, Marissa; Ferguson, Michael J.; Pandya, Pankita H.; Pollok, Karen E.; Medical and Molecular Genetics, School of MedicineDespite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.Item Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas(John Wiley & Sons, Inc., 2016-02) Ferguson, Michael J.; Rhodes, Steven D.; Jiang, Li; Li, Xiaohong; Yuan, Jin; Yang, Xianlin; Zhang, Shaobo; Vakili, Saeed T.; Territo, Paul; Hutchins, Gary; Yang, Feng-Chun; Ingram, David A.; Clapp, D. Wade; Chen, Shi; Department of Pediatrics, Indiana University School of MedicinePlexiform neurofibromas (pNF) are pathognomonic nerve and soft tissue tumors of neurofibromatosis type I (NF1), which are highly resistant to conventional chemotherapy and associated with significant morbidity/mortality. Disruption of aberrant SCF/c-Kit signaling emanating from the pNF microenvironment induced the first ever objective therapeutic responses in a recent phase 2 trial. Sunitinib malate is a potent, highly selective RTK inhibitor with activity against c-Kit, PDGFR, and VEGFR, which have also been implicated in the pathogenesis of these lesions. Here, we evaluate the efficacy of sunitinib malate in a preclinical Krox20;Nf1flox/− pNF murine model. Experimental Design Proliferation, β-hexosaminidase release (degranulation), and Erk1/2 phosphorylation were assessed in sunitinib treated Nf1+/− mast cells and fibroblasts, respectively. Krox20;Nf1flox/− mice with established pNF were treated sunitinib or PBS-vehicle control for a duration of 12 weeks. pNF metabolic activity was monitored by serial [18F]DG-PET/CT imaging. Results Sunitinib suppressed multiple in vitro gain-in-functions of Nf1+/− mast cells and fibroblasts and attenuated Erk1/2 phosphorylation. Sunitinib treated Krox20;Nf1flox/− mice exhibited significant reductions in pNF size, tumor number, and FDG uptake compared to control mice. Histopathology revealed reduced tumor cellularity and infiltrating mast cells, markedly diminished collagen deposition, and increased cellular apoptosis in sunitinib treated pNF. Conclusions Collectively, these results demonstrate the efficacy of sunitinib in reducing tumor burden in Krox20;Nf1flox/− mice. These preclinical findings demonstrate the utility of inhibiting multiple RTKs in pNF and provide insights into the design of future clinical trials.Item Previously Unreported Somatic Variants in Two Patients with Pleuropulmonary Blastoma with Metastatic Brain Recurrence(Wiley, 2021) Ferguson, Michael J.; Ivanovich, Jennifer; Stansell, Paige; Vik, Terry A.; Helvie, Amy E.; Schmitt, Morgan R.; Schultz, Kris Ann; Dehner, Louis P.; Renbarger, Jamie L.; Marshall, Mark A.; Pediatrics, School of MedicineItem Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant(Wolters Kluwer, 2020-04-30) Tramontana, Timothy F.; Marshall, Mark S.; Helvie, Amy E.; Schmitt, Morgan R.; Ivanovich, Jennifer; Carter, Jacquelyn L.; Renbarger, Jamie L.; Ferguson, Michael J.; Pediatrics, School of Medicine