44 results on '"Kurek KC"'
Search Results
2. Abstract 68
- Author
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Hassanein, AH, primary, Couto, RA, additional, Kurek, KC, additional, Rogers, GF, additional, Mulliken, JB, additional, and Greene, AK, additional
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- 2012
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3. Lichen sclerosus of the upper eyelid in a paediatric patient: a novel presentation.
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Kryshtalskyj MT, Agi J, Ramien ML, Kurek KC, and Kherani F
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- Humans, Child, Eyelids surgery, Lichen Sclerosus et Atrophicus diagnosis
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- 2023
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4. Transitional care and clinical management of adolescents, young adults, and suspected new adult patients with congenital central hypoventilation syndrome.
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Slattery SM, Perez IA, Ceccherini I, Chen ML, Kurek KC, Yap KL, Keens TG, Khaytin I, Ballard HA, Sokol EA, Mittal A, Rand CM, and Weese-Mayer DE
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- Child, Humans, Adolescent, Young Adult, Mutation, Transcription Factors genetics, Homeodomain Proteins genetics, Transitional Care
- Abstract
Purpose: With contemporaneous advances in congenital central hypoventilation syndrome (CCHS), recognition, confirmatory diagnostics with PHOX2B genetic testing, and conservative management to reduce the risk of early morbidity and mortality, the prevalence of identified adolescents and young adults with CCHS and later-onset (LO-) CCHS has increased. Accordingly, there is heightened awareness and need for transitional care of these patients from pediatric medicine into a multidisciplinary adult medical team. Hence, this review summarizes key clinical and management considerations for patients with CCHS and LO-CCHS and emphasizes topics of particular importance for this demographic., Methods: We performed a systematic review of literature on diagnostics, pathophysiology, and clinical management in CCHS and LO-CCHS, and supplemented the review with anecdotal but extensive experiences from large academic pediatric centers with expertise in CCHS., Results: We summarized our findings topically for an overview of the medical care in CCHS and LO-CCHS specifically applicable to adolescents and adults. Care topics include genetic and embryologic basis of the disease, clinical presentation, management, variability in autonomic nervous system dysfunction, and clarity regarding transitional care with unique considerations such as living independently, family planning, exposure to anesthesia, and alcohol and drug use., Conclusions: While a lack of experience and evidence exists in the care of adults with CCHS and LO-CCHS, a review of the relevant literature and expert consensus provides guidance for transitional care areas., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
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- 2023
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5. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding.
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Khaytin I, Victor AK, Barclay SF, Benson LA, Slattery SM, Rand CM, Kurek KC, and Weese-Mayer DE
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- Humans, Hypoventilation diagnosis, Hypoventilation etiology, Hypoventilation therapy, Obesity complications, Obesity diagnosis, Syndrome, Autonomic Nervous System Diseases diagnosis, Autonomic Nervous System Diseases etiology, Autonomic Nervous System Diseases therapy, Hypothalamic Diseases complications, Hypothalamic Diseases diagnosis, Hypothalamic Diseases genetics, Primary Dysautonomias
- Abstract
Purpose: To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents., Methods: The literature (1965-2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause., Results: ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions., Conclusion: ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
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- 2023
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6. Workload Measurement in Subspecialty Placental Pathology in Canada.
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Wright JR Jr, Chan S, Morgen EK, Maung RTA, Brundler MA, El Demellawy D, Fraser RB, Kurek KC, Magee F, Nizalik E, Oligny LL, Somers GR, Stefanovici C, and Terry J
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- Female, Pregnancy, Humans, Child, Canada, Workload, Placenta, Pathology Department, Hospital
- Abstract
Background: Workload measurement is important to help determine optimal staffing and workload distribution for pathology laboratories. The Level 4 Equivalent (L4E) System is the most widely used Anatomical Pathology (AP) workload measurement tool in Canada. However, it was initially not developed with subspecialties in mind., Methods: In 2016, a Pan-Canadian Pediatric-Perinatal Pathology Workload Committee (PCPPPWC) was organized to adapt the L4E System to assess Pediatric-Perinatal Pathology workload. Four working groups were formed. The Placental Pathology Working Group was tasked to develop a scheme for fair valuation of placental specimens signed out by subspecialists in the context of the L4E System. Previous experience, informal time and motion studies, a survey of Canadian Pediatric-Perinatal Pathologists, and interviews of Pathologists' Assistants (PA) informed the development of such scheme., Results: A workload measurement scheme with average L4E workload values for examination and reporting of singleton and multiple gestation placentas was proposed. The proposal was approved by the Canadian Association of Pathologist - Association canadienne des pathologistes Workload and Human Resources Committee for adoption into the L4E System., Conclusion: The development of a workload measurement model for placental specimens provides an average and fair valuation of these specimen types, enabling its use for resource planning and workload distribution.
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- 2022
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7. CAP-ACP Workload Model for Advanced Diagnostics in Precision Medicine.
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Park PC, Kurek KC, DeCoteau J, Howlett CJ, Hawkins C, Izevbaye I, Carter MD, Redpath M, Lo B, Alex D, Yousef G, Yip S, and Maung R
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- Canada, Humans, Medical Oncology, Workload, Neoplasms genetics, Precision Medicine methods
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Objectives: In precision medicine, where oncologic management is tailored to the individual's clinical and genetic profiles, advanced diagnostic testing provides prognostic information and guides management in a growing number of malignancies. There is a need to capture the work pathologists perform to meet this demand by providing medically relevant, timely, and accurate testing results. This work includes not only direct patient consults (interpretation of results and issuing reports) but the administrative and medical oversight as well as the research needed to provide the necessary quality assurance, quality control, direction, and framework for the laboratory., Methods: An expert panel of Canadian pathologists involved in advanced diagnostics was convened to establish and beta test a model for workload assessment in advanced diagnostics., Results: All aspects of the advanced diagnostics workload were detailed and applied to models based on members' experience, including medical oversight, administration, and the introduction of new testing and platforms. Models for biomarker testing were developed for simple and complex or multiplexed assays, and a detailed model was developed to assess the workload for next-generation sequencing-based assays., Conclusions: This paper provides the first detailed proposal for capturing an advanced diagnostic workload to enable appropriate pathologist allotment for performing all the steps required to run an advanced diagnostic service., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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8. Kaposiform Lymphangiomatosis: Pathologic Aspects in 43 Patients.
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Perez-Atayde AR, Debelenko L, Al-Ibraheemi A, Eng W, Ruiz-Gutierrez M, O'Hare M, Croteau SE, Trenor CC 3rd, Boyer D, Balkin DM, Barclay SF, Hsi Dickie B, Liang MG, Chaudry G, Alomari AI, Mulliken JB, Adams DM, Kurek KC, Fishman SJ, and Kozakewich HPW
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- Boston, Child, Humans, Endothelial Cells, Lung
- Abstract
Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Herein, we document the pathology in 43 patients evaluated by the Boston Children's Hospital Vascular Anomalies Center from 1999 to 2020. The most frequent presentations were respiratory difficulty, hemostatic abnormalities, and a soft tissue mass. Imaging commonly revealed involvement of some combination of mediastinal, pulmonary, pleural, and pericardial compartments and most often included spleen and skeleton. Histopathology was characterized by dilated, redundant, and abnormally configured lymphatic channels typically accompanied by dispersed clusters of variably canalized, and often hemosiderotic, spindled lymphatic endothelial cells that were immunopositive for D2-40, PROX1, and CD31. An activating lesional NRAS variant was documented in 9 of 10 patients. The clinical course was typically aggressive, marked by hemorrhage, thrombocytopenia, diminished fibrinogen levels, and a mortality rate of 21%., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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9. Cutaneous B-Cell Pseudolymphoma (Lymphocytoma Cutis) of the Earlobe: A Poorly Recognized Complication of Ear Piercing in Children.
- Author
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Slack JC, Kurek KC, Fraulin FOG, and Brundler MA
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- Adolescent, Adult, Child, Diagnosis, Differential, Female, Humans, Male, Skin pathology, Body Piercing adverse effects, Pseudolymphoma diagnosis, Pseudolymphoma etiology, Pseudolymphoma pathology, Skin Neoplasms complications
- Abstract
Background: Cutaneous pseudolymphoma (CPL) refers to a group of benign, reactive processes that mimic cutaneous lymphoma and are associated with a variety of triggering immune stimuli, including arthropod bites, drugs, and foreign bodies. In children, most cases of CPL are due to a variant of Borreliosis that is specific to Eurasia. Cutaneous pseudolymphoma secondary to ear piercing has only been documented in adults. Case Reports : We present the clinical and pathological findings of cutaneous Bcell psuedolymphoma in two adolescent patients (11-year-old female and 15-year-old male) secondary to ear piercing. Conclusion : Our report expands the clinico-pathological spectrum of CPL associated with ear piercing by documenting its occurrence in children.
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- 2022
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10. Developmental disorders affecting the respiratory system: CCHS and ROHHAD.
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Ceccherini I, Kurek KC, and Weese-Mayer DE
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- Child, Developmental Disabilities, Humans, Hypoventilation congenital, Respiratory System, Syndrome, Transcription Factors, Autonomic Nervous System Diseases, Endocrine System Diseases, Hypothalamic Diseases, Sleep Apnea, Central
- Abstract
Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) and Congenital Central Hypoventilation Syndrome (CCHS) are ultra-rare distinct clinical disorders with overlapping symptoms including altered respiratory control and autonomic regulation. Although both disorders have been considered for decades to be on the same spectrum with necessity of artificial ventilation as life-support, recent acquisition of specific knowledge concerning the genetic basis of CCHS coupled with an elusive etiology for ROHHAD have definitely established that the two disorders are different. CCHS is an autosomal dominant neurocristopathy characterized by alveolar hypoventilation resulting in hypoxemia/hypercarbia and features of autonomic nervous system dysregulation (ANSD), with presentation typically in the newborn period. It is caused by paired-like homeobox 2B (PHOX2B) variants, with known genotype-phenotype correlation but pathogenic mechanism(s) are yet unknown. ROHHAD is characterized by rapid weight gain, followed by hypothalamic dysfunction, then hypoventilation followed by ANSD, in seemingly normal children ages 1.5-7 years. Postmortem neuroanatomical studies, thorough clinical characterization, pathophysiological assessment, and extensive genetic inquiry have failed to identify a cause attributable to a traditional genetic basis, somatic mosaicism, epigenetic mechanism, environmental trigger, or other. To find the key to the ROHHAD pathogenesis and to improve its clinical management, in the present chapter, we have carefully compared CCHS and ROHHAD., (Copyright © 2022 Elsevier B.V. All rights reserved.)
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- 2022
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11. Novel findings and expansion of phenotype in a mosaic RASopathy caused by somatic KRAS variants.
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Chang CA, Perrier R, Kurek KC, Estrada-Veras J, Lehman A, Yip S, Hendson G, Diamond C, Pinchot JW, Tran JM, Arkin LM, Drolet BA, Napier MP, O'Neill SA, Balci TB, and Keppler-Noreuil KM
- Subjects
- Abnormalities, Multiple genetics, Adolescent, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Kidney Neoplasms genetics, Male, Phenotype, Vascular Malformations genetics, Wilms Tumor genetics, Abnormalities, Multiple pathology, Kidney Neoplasms pathology, Mosaicism, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Vascular Malformations pathology, Wilms Tumor pathology
- Abstract
Mosaic KRAS variants and other RASopathy genes cause oculoectodermal, encephalo-cranio-cutaneous lipomatosis, and Schimmelpenning-Feuerstein-Mims syndromes, and a spectrum of vascular malformations, overgrowth and other associated anomalies, the latter of which are only recently being characterized. We describe eight individuals in total (six unreported cases and two previously reported cases) with somatic KRAS variants and variably associated features. Given the findings of somatic overgrowth (in seven individuals) and vascular or lymphatic malformations (in eight individuals), we suggest mosaic RASopathies (mosaic KRAS variants) be considered in the differential diagnosis for individuals presenting with asymmetric overgrowth and lymphatic or vascular anomalies. We expand the association with embryonal tumors, including the third report of embryonal rhabdomyosarcoma, as well as novel findings of Wilms tumor and nephroblastomatosis in two individuals. Rare or novel findings in our series include the presence of epilepsy, polycystic kidneys, and T-cell deficiency in one individual, and multifocal lytic bone lesions in two individuals. Finally, we describe the first use of targeted therapy with a MEK inhibitor for an individual with a mosaic KRAS variant. The purposes of this report are to expand the phenotypic spectrum of mosaic KRAS-related disorders, and to propose possible mechanisms of pathogenesis, and surveillance of its associated findings., (© 2021 Wiley Periodicals LLC.)
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- 2021
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12. Molecular Alterations in Pediatric Fibroblastic/Myofibroblastic Tumors: An Appraisal of a Next Generation Sequencing Assay in a Retrospective Single Centre Study.
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Slack JC, Bründler MA, Nohr E, McIntyre JB, and Kurek KC
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- Adolescent, Child, Child, Preschool, Female, Fibroma classification, Fibroma diagnosis, Fibroma pathology, Granuloma, Plasma Cell classification, Granuloma, Plasma Cell diagnosis, Granuloma, Plasma Cell pathology, Humans, Infant, Infant, Newborn, Male, Mutation, Myofibroma classification, Myofibroma diagnosis, Myofibroma pathology, Oncogene Proteins, Fusion genetics, Retrospective Studies, Sarcoma classification, Sarcoma diagnosis, Sarcoma pathology, Soft Tissue Neoplasms classification, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms pathology, World Health Organization, Biomarkers, Tumor genetics, Fibroma genetics, Granuloma, Plasma Cell genetics, High-Throughput Nucleotide Sequencing, Myofibroma genetics, Sarcoma genetics, Soft Tissue Neoplasms genetics
- Abstract
Background: Pediatric fibroblastic/myofibroblastic tumors (PFMTs) can be challenging to definitively classify. Large case series or diagnostic updates have not been recently published despite identification of molecular alterations that could improve diagnostic accuracy. Our review of the literature found that over two-thirds of the more than 30 types of PFMTs harbor recurrent molecular alterations. We performed an institutional review of PFMTs to highlight limitations of a predominantly morphological classification, and evaluated the utility of a next-generation sequencing assay to aid diagnosis., Methods: PFMTs identified over a period of 12 years were reviewed, categorized per the new WHO classification, and tested using the Oncomine Childhood Cancer Research Assay., Results: Eighty-seven specimens from 58 patients were reviewed; 50 were chosen for molecular analysis, 16 (32%) lacking definitive classification. We identified alterations, some novel, in 33% of assayed cases. Expected alterations were identified for most known diagnoses and mutations were identified in 6 of 16 tumors (38%) that were initially unclassified., Conclusion: We confirmed a significant subset of PFMTs remain difficult to classify using current criteria, and that a combined DNA/RNA assay can identify alterations in many of these cases, improving diagnostic certainty and suggesting a clinical utility for challenging cases.
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- 2021
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13. Unilateral congenital pulmonary lymphangiectasis presenting with pneumothorax and an NRAS variant.
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AlTeneiji M, Brundler MA, Noseworthy M, and Kurek KC
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- GTP Phosphohydrolases, Humans, Membrane Proteins, Lung Diseases diagnostic imaging, Lung Diseases genetics, Lymphangiectasis diagnostic imaging, Lymphangiectasis genetics, Pneumothorax diagnostic imaging, Pneumothorax genetics
- Published
- 2021
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14. Bilateral Nephroblastic Tumors and a Complex Renal Vascular Anomaly in a Patient With a Mosaic RASopathy: Novel Histopathologic Features and Molecular Insights.
- Author
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Slack JC, Bründler MA, Chang CA, Perrier R, Lafay-Cousin L, and Kurek KC
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- Child, Preschool, Humans, Infant, Male, Nevus genetics, Kidney abnormalities, Kidney Neoplasms genetics, Proto-Oncogene Proteins p21(ras) genetics, Vascular Malformations genetics, Wilms Tumor genetics
- Abstract
Mosaic RASopathies are an emerging group of disorders characterized by mosaic or post-zygotic activating mutations in genes of the RAS/MAPKinase signaling pathway. The phenotype is highly variable, ranging from limited or localized forms to cases with a syndromic presentation with extensive or multiorgan involvement, and also overlaps with other mosaic disorders. While there are several reports of malignancies in patients with mosaic RASopathies, specifically rhabdomyosarcoma and transitional urothelial carcinoma, the lifetime risk and molecular mechanisms that lead to the development of malignancies remain unclear. We report a 22-month-old boy with a somatic RASopathy due to an underlying KRAS p.G12D mutation who presented with a large unilateral epidermal nevus, asymmetric lower limb overgrowth with lytic and sclerotic bone lesions, capillary malformation, bilateral nephrogenic rests and Wilms tumors, and a novel complex renal vascular anomaly that resembles Fibro-Adipose Vascular Anomaly (FAVA). This report further expands the phenotypic spectrum of somatic RASopathies, and discusses the potential phenotypic and pathogenetic overlap with PIK3CA -related overgrowth disorders, specifically CLOVES. The occurrence of a secondary cancer hotspot mutation ( FBXW7 p.R479G ) in the Wilms tumor, but not the associated nephrogenic rest, moreover suggests that additional driver mutations are involved in the development of Wilms tumor in somatic overgrowth disorders.
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- 2021
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15. Adipocyte-rich CTNNB1 -mutated Intramuscular Gardner Fibroma Progressing to Desmoid Fibromatosis.
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Bakker A, Slack JC, Caragea M, Kurek KC, and Bründler MA
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- Child, Preschool, Disease Progression, Fibroma pathology, Fibroma surgery, Fibromatosis, Aggressive pathology, Fibromatosis, Aggressive surgery, Gardner Syndrome pathology, Gardner Syndrome surgery, Genetic Predisposition to Disease, Humans, Male, Muscle Neoplasms pathology, Muscle Neoplasms surgery, Phenotype, Adipocytes pathology, Fibroma genetics, Fibromatosis, Aggressive genetics, Gardner Syndrome genetics, Muscle Neoplasms genetics, Mutation, beta Catenin genetics
- Abstract
Gardner fibroma (GF) is a benign soft-tissue tumor that is associated with Gardner syndrome and can progress to, or co-occur with, desmoid fibromatosis (DF). Herein, we report a unique case of an 11-year-old boy who presented with a rapidly growing soft-tissue mass after biopsy of a stable fat-rich lesion present in the calf muscles since infancy, with Magnetic resonance imaging findings suggesting an intramuscular adipocytic tumor. The resection showed GF and DF. DF arising from a preexisting GF (the so-called "GF-DF sequence") is a well-documented phenomenon. Although immunohistochemistry was negative for nuclear β-catenin expression, a CTTNB1 S45F mutation, which has been associated with aggressive behavior in DF, was identified in both components using a next-generation sequencing-based molecular assay. This is the first time a mutation in CTNNB1 has been identified in GF and the GF-DF sequence, thus expanding our knowledge of the molecular pathogenesis of the GF-DF sequence and highlighting the role of molecular testing in pediatric soft-tissue tumors. The histologic findings of an adipocyte-rich intramuscular GF also are unique, expanding the morphological spectrum of GF and adding GF to the differential diagnosis of intramuscular lesions with an adipocytic component.
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- 2021
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16. MiR-16-1-3p and miR-16-2-3p possess strong tumor suppressive and antimetastatic properties in osteosarcoma.
- Author
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Maximov VV, Akkawi R, Khawaled S, Salah Z, Jaber L, Barhoum A, Or O, Galasso M, Kurek KC, Yavin E, and Aqeilan RI
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- Animals, Cell Line, Tumor, Cell Movement, Cell Proliferation, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, Neoplasm Transplantation, Osteonecrosis genetics, Osteosarcoma genetics, Down-Regulation, Lung Neoplasms secondary, MicroRNAs genetics, Osteonecrosis pathology, Osteosarcoma pathology, Receptor, Fibroblast Growth Factor, Type 2 genetics
- Abstract
Osteosarcoma (OS) is an aggressive malignancy affecting mostly children and adolescents. MicroRNAs (miRNAs) play important roles in OS development and progression. Here we found that miR-16-1-3p and miR-16-2-3p "passenger" strands, as well as the "lead" miR-16-5p strand, are frequently downregulated and possess strong tumor suppressive functions in human OS. Furthermore, we report different although strongly overlapping functions for miR-16-1-3p and miR-16-2-3p in OS cells. Ectopic expression of these miRNAs affected primary tumor growth, metastasis seeding and chemoresistance and invasiveness of human OS cells. Loss-of-function experiments verified tumor suppressive functions of these miRNAs at endogenous levels of expression. Using RNA immunoprecipitation (RIP) assays, we identify direct targets of miR-16-1-3p and miR-16-2-3p in OS cells. Moreover, validation experiments identified FGFR2 as a direct target for miR-16-1-3p and miR-16-2-3p. Overall, our findings underscore the importance of passenger strand miRNAs, at least some, in osteosarcomagenesis., (© 2019 UICC.)
- Published
- 2019
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17. A somatic activating NRAS variant associated with kaposiform lymphangiomatosis.
- Author
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Barclay SF, Inman KW, Luks VL, McIntyre JB, Al-Ibraheemi A, Church AJ, Perez-Atayde AR, Mangray S, Jeng M, Kreimer SR, Walker L, Fishman SJ, Alomari AI, Chaudry G, Trenor Iii CC, Adams D, Kozakewich HPW, and Kurek KC
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Genetic Variation, Humans, Infant, Lymphatic Diseases pathology, Male, Polymerase Chain Reaction, Exome Sequencing, GTP Phosphohydrolases genetics, Lymphatic Diseases genetics, Membrane Proteins genetics
- Abstract
Purpose: Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development., Methods: We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital polymerase chain reaction (dPCR) to validate the exome findings and to screen KLA samples from six other individuals., Results: We identified a somatic activating NRAS variant (c.182 A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1% to 28%, that was absent from the tested control tissues., Conclusion: The activating NRAS p.Q61R variant is a known "hotspot" variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways. This discovery will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors.
- Published
- 2019
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18. Novel presentation of cranial fasciitis of the mandible: Case report and literature review.
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de Champlain K, Kurek KC, and Yunker WK
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- Fasciitis surgery, Humans, Infant, Male, Mandible pathology, Myofibroblasts pathology, Tomography, X-Ray Computed, Fasciitis diagnostic imaging, Fasciitis pathology, Mandible diagnostic imaging
- Abstract
Cranial fasciitis (CF) is a rare benign fibroblastic lesion of the scalp, most commonly affecting the pediatric population. The authors conducted a literature review and include a summary of reported cases of CF. CF is most commonly located in the parietal and temporal regions of the skull. The majority of cases are found in males and in children under a few years of ago. We describe the clinical, pathological and radiological findings of the first reported case of CF of the mandible. In this case, the patient was a 12 month-old male who presented with a one-month history of a rapidly enlarging mass along his left mandibular ramus. Treatment of CF involves surgical resection and has a low rate of recurrence. The patient in question was managed surgically with no complications and has not had any evidence of disease recurrence., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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19. Submucosal Colonic Lipoblastoma Presenting With Colo-colonic Intussusception in an Infant.
- Author
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Brundler MA, Kurek KC, Patel K, and Jester I
- Subjects
- Colonic Neoplasms complications, Colonic Neoplasms pathology, Humans, Infant, Intestinal Mucosa pathology, Intussusception diagnosis, Lipoblastoma complications, Lipoblastoma pathology, Male, Colonic Neoplasms diagnosis, Intussusception etiology, Lipoblastoma diagnosis
- Abstract
Lipoblastoma is a benign adipose tumor typically presenting in infancy in superficial soft tissues of extremities. Intestinal complications secondary to intraabdominal or retroperitoneal involvement are exceedingly rare. We describe a unique case of a primary intestinal lipoblastoma arising from the submucosa of the transverse colon in an otherwise healthy 18-month-old boy. He presented with a history of reducible rectal prolapse, rectal bleeding, and episodic abdominal pain and was initially treated for constipation. Imaging identified a short colo-colonic intussusception, confirmed at laparotomy, and a fatty mass thought to arise from the mesentery. Pathological examination of the resected transverse colon revealed a submucosal tumor composed of a mixture of mature adipose tissue, foci of myxoid mesenchymal tissue with desmin positive, HMGA2 negative spindle cells, and scattered lipoblasts, characteristic of lipoblastoma. Lipoblastoma should be considered as a potential albeit rare cause of intussusception in young children, where a pathologic lead point is infrequently identified.
- Published
- 2018
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20. Hamartoma-like lesions in the mouse retina: an animal model of Pten hamartoma tumour syndrome.
- Author
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Tachibana N, Touahri Y, Dixit R, David LA, Adnani L, Cantrup R, Aavani T, Wong RO, Logan C, Kurek KC, and Schuurmans C
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- Animals, Animals, Newborn, Cell Division, Disease Models, Animal, Ependymoglial Cells metabolism, Ependymoglial Cells pathology, Hamartoma Syndrome, Multiple drug therapy, Mice, Knockout, Mosaicism, Mutation genetics, Neuroglia metabolism, Neuroglia pathology, PTEN Phosphohydrolase deficiency, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, Proto-Oncogene Proteins c-akt metabolism, Retinal Pigment Epithelium pathology, Signal Transduction drug effects, Sirolimus administration & dosage, Sirolimus pharmacology, TOR Serine-Threonine Kinases metabolism, Hamartoma Syndrome, Multiple pathology, Retina pathology
- Abstract
PTEN hamartoma tumour syndrome (PHTS) is a heterogeneous group of rare, autosomal dominant disorders associated with PTEN germline mutations. PHTS patients routinely develop hamartomas, which are benign tissue overgrowths comprised of disorganized 'normal' cells. Efforts to generate PHTS animal models have been largely unsuccessful due to the early lethality of homozygous germline mutations in Pten , together with the lack of hamartoma formation in most conditional mutants generated to date. We report herein a novel PHTS mouse model that reproducibly forms hamartoma-like lesions in the central retina by postnatal day 21. Specifically, we generated a Pten conditional knockout (cKO) using a retinal-specific Pax6 :: Cre driver that leads to a nearly complete deletion of Pten in the peripheral retina but produces a mosaic of 'wild-type' and Pten cKO cells centrally. Structural defects were only observed in the mosaic central retina, including in Müller glia and in the outer and inner limiting membranes, suggesting that defective mechanical integrity partly underlies the hamartoma-like pathology. Finally, we used this newly developed model to test whether rapamycin, an mTOR inhibitor that is currently the only PHTS therapy, can block hamartoma growth. When administered in the early postnatal period, prior to hamartoma formation, rapamycin reduces hamartoma size, but also induces new morphological abnormalities in the Pten cKO retinal periphery. In contrast, administration of rapamycin after hamartoma initiation fails to reduce lesion size. We have thus generated and used an animal model of retinal PHTS to show that, although current therapies can reduce hamartoma formation, they might also induce new retinal dysmorphologies.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)
- Published
- 2018
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21. Unusual case of coronal complete bladder duplication associated with rectoprostatic fistula to duplicated prostatic urethra.
- Author
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Lam JY, Lopushinsky SR, Kurek KC, and Beaudry P
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- Humans, Infant, Male, Urethra diagnostic imaging, Urinary Bladder diagnostic imaging, Fistula diagnostic imaging, Prostatic Diseases diagnostic imaging, Rectal Fistula diagnostic imaging, Urethra abnormalities, Urinary Bladder abnormalities
- Abstract
Anorectal malformations are a common congenital anomaly, while bladder duplication is rare. Bladder duplications are classified as complete or incomplete and sagittal or coronal. We present a rare case of coronal complete bladder duplication with rectoprostatic fistula to the blind ending prostatic urethra of the duplicated bladder.
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- 2018
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22. Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.
- Author
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Powers JT, Tsanov KM, Pearson DS, Roels F, Spina CS, Ebright R, Seligson M, de Soysa Y, Cahan P, Theißen J, Tu HC, Han A, Kurek KC, LaPier GS, Osborne JK, Ross SJ, Cesana M, Collins JJ, Berthold F, and Daley GQ
- Subjects
- 3' Untranslated Regions genetics, Animals, Chromosome Deletion, Female, Gene Deletion, Genes, Neoplasm genetics, Humans, Mice, MicroRNAs metabolism, Models, Genetic, N-Myc Proto-Oncogene Protein, Neuroblastoma pathology, Xenograft Model Antitumor Assays, Gene Amplification genetics, MicroRNAs genetics, Neuroblastoma genetics, Nuclear Proteins genetics, Oncogene Proteins genetics, RNA-Binding Proteins genetics
- Abstract
Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis., Competing Interests: GQD holds options and intellectual property relating to 28/7 Therapeutics, a company seeking to develop inhibitors of the LIN28/let-7 pathway.
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- 2016
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23. An Experimental Study of Particulate Bone Graft for Secondary Inlay Cranioplasty Over Scarred Dura.
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Maclellan RA, Hassanein AH, Kurek KC, Mulliken JB, Rogers GF, and Greene AK
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- Animals, Craniotomy, Frontal Bone surgery, Osteogenesis, Parietal Bone pathology, Rabbits, Reoperation, Bone Transplantation methods, Cicatrix, Dura Mater pathology, Parietal Bone surgery, Plastic Surgery Procedures methods
- Abstract
Background: Inlay cranioplasty in children is challenging because autologous bone is limited. Cranial particulate bone graft effectively closes defects when placed over normal dura. The purpose of this study was to determine if particulate bone graft will ossify when used for secondary cranioplasty over scarred dura., Methods: A 17 × 17-mm critical-sized defect was made in the parietal bone of 16 rabbits. Four animals had no implant (group 1). Twelve animals had the defect remade 16 weeks postoperatively, which was managed in 2 ways: group 2 (no implant; n = 6) and group 4 (particulate bone graft; n = 6). Particulate graft was obtained using a brace and bit from the frontal bone. Computed tomography was used to determine the area of ossification and thickness of the healed graft. Eight animals previously managed with particulate bone graft over normal dura were used as an additional control (group 3)., Results: Critical-sized defects filled with particulate bone graft over scarred dura (group 4) exhibited superior healing of the area (83.8%; range, 73.0%-90.6%) compared to control defects over normal dura (group 1: 62.9%; range, 56.5%-73.4%) or scarred dura (group 2: 56.9%; range, 40.0%-68.3%) (P = 0.0004). Particulate bone on scarred dura exhibited less ossified area (P = 0.002), and thinner bone (0.95 mm, range, 0.71-1.32 mm) compared to defects in which graft was placed over normal dura (group 3: area, 99.2%; range, 96.8%-100%; thickness, 1.9 mm, range; 1.1-3.1 mm) (P = 0.04)., Conclusions: Particulate bone graft ossifies inlay cranial defects over scarred dura although inferior to placement over normal dura. Clinically, particulate bone graft may be used for secondary inlay cranioplasty.
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- 2016
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24. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA.
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Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovée JV, Rialon KL, Guevara CJ, Alomari AI, Greene AK, Fishman SJ, Kozakewich HP, Maclellan RA, Mulliken JB, Rahbar R, Spencer SA, Trenor CC 3rd, Upton J, Zurakowski D, Perkins JA, Kirsh A, Bennett JT, Dobyns WB, Kurek KC, Warman ML, McCarroll SA, and Murillo R
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- Child, Child, Preschool, Class I Phosphatidylinositol 3-Kinases, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Klippel-Trenaunay-Weber Syndrome diagnosis, Klippel-Trenaunay-Weber Syndrome metabolism, Lymphatic Abnormalities diagnosis, Lymphatic Abnormalities metabolism, Male, Phosphatidylinositol 3-Kinases metabolism, Polymerase Chain Reaction, Vascular Malformations diagnosis, Vascular Malformations metabolism, Abnormalities, Multiple, DNA genetics, Klippel-Trenaunay-Weber Syndrome genetics, Lymphatic Abnormalities genetics, Mutation, Phosphatidylinositol 3-Kinases genetics, Vascular Malformations genetics
- Abstract
Objectives: To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS)., Study Design: We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital., Results: Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼ 80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells., Conclusions: Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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25. Anti-lubricin monoclonal antibodies created using lubricin-knockout mice immunodetect lubricin in several species and in patients with healthy and diseased joints.
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Ai M, Cui Y, Sy MS, Lee DM, Zhang LX, Larson KM, Kurek KC, Jay GD, and Warman ML
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- Adult, Aged, Amino Acid Sequence, Animals, Antibody Specificity, Case-Control Studies, Epitopes chemistry, Epitopes immunology, Female, Glycoproteins blood, Glycoproteins genetics, Humans, Male, Mice, Mice, Knockout, Middle Aged, Oligopeptides chemistry, Oligosaccharides chemistry, Synovial Fluid metabolism, Antibodies, Monoclonal immunology, Arthropathy, Neurogenic blood, Coxa Vara blood, Enzyme-Linked Immunosorbent Assay, Glycoproteins deficiency, Glycoproteins immunology, Hand Deformities, Congenital blood, Joints metabolism, Synovitis blood
- Abstract
Lubricin, encoded by the gene PRG4, is the principal lubricant in articulating joints. We immunized mice genetically deficient for lubricin (Prg4-/-) with purified human lubricin, and generated several mAbs. We determined each mAb's binding epitope, sensitivity, and specificity using biologic samples and recombinant lubricin sub-domains, and we also developed a competition ELISA assay to measure lubricin in synovial fluid and blood. We found the mAbs all recognized epitopes containing O-linked oligosaccharides conjugated to the peptide motif KEPAPTTT. By western blot, the mAbs detected lubricin in 1 μl of synovial fluid from several animal species, including human. The mAbs were specific for lubricin since they did not cross-react with other synovial fluid constituents from patients with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), who genetically lack this protein. The competition ELISA detected lubricin in blood samples from healthy individuals but not from patients with CACP, indicating blood can be used in a diagnostic test for patients suspected of having CACP. Lubricin epitopes in blood do not represent degradation fragments from synovial fluid. Therefore, although blood lubricin levels did not differentiate patients with inflammatory joint disease from healthy controls, epitope-specific anti-lubricin mAbs could be useful for monitoring disease activity in synovial fluid.
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- 2015
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26. Villin immunohistochemistry is a reliable method for diagnosing microvillus inclusion disease.
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Shillingford NM, Calicchio ML, Teot LA, Boyd T, Kurek KC, Goldsmith JD, Bousvaros A, Perez-Atayde AR, and Kozakewich HP
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- Biomarkers analysis, Child, Child, Preschool, Female, Humans, Infant, Male, Microfilament Proteins analysis, Retrospective Studies, Immunohistochemistry methods, Malabsorption Syndromes diagnosis, Microfilament Proteins biosynthesis, Microvilli pathology, Mucolipidoses diagnosis
- Abstract
Microvillus inclusion disease (MVID) is a rare congenital disorder that manifests early in infancy as intractable watery diarrhea. The entity is characterized morphologically by a deficient brush border and apical cytoplasmic inclusions within absorptive cells (enterocytes) due to misplaced assembly of brush border proteins. The diagnosis is based upon histopathology, special stains, immunohistochemistry (IHC), and ultimately upon electron microscopy. Currently, the periodic acid-Schiff stain (PAS) and CD10 IHC are commonly used as adjuncts, but in addition to brush border structures, they stain a variety of apical cytoplasmic inclusions and organelles, thereby interfering with recognition of microvillus inclusions. Villin is a protein that specifically binds to the actin core bundle of microvilli. We utilized villin IHC in formalin-fixed paraffin-embedded gastrointestinal biopsies from 6 patients with MVID, 5 with celiac disease, and 17 children with normal intestinal biopsies and compared the results with those obtained with CD10 IHC and PAS staining. All MVID cases had confirmatory electron microscopy at the time of diagnosis. Villin immunoreactivity was restricted to the brush border in the control groups. In MVID, villin IHC showed attenuation or loss of the surface brush border and also highlighted the cytoplasmic microvillus inclusions with clarity. In MVID, CD10 IHC and the PAS stain also showed attenuation or loss of the surface brush border, but staining of a variety of cytoplasmic structures largely obscured the microvillus inclusions. In sum, villin IHC is a reliable and superior adjunct in the diagnosis of MVID. Study of additional cases will determine whether villin IHC would obviate the need for electron microscopic confirmation.
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- 2015
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27. The genomic landscape of pediatric Ewing sarcoma.
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Crompton BD, Stewart C, Taylor-Weiner A, Alexe G, Kurek KC, Calicchio ML, Kiezun A, Carter SL, Shukla SA, Mehta SS, Thorner AR, de Torres C, Lavarino C, Suñol M, McKenna A, Sivachenko A, Cibulskis K, Lawrence MS, Stojanov P, Rosenberg M, Ambrogio L, Auclair D, Seepo S, Blumenstiel B, DeFelice M, Imaz-Rosshandler I, Schwarz-Cruz Y Celis A, Rivera MN, Rodriguez-Galindo C, Fleming MD, Golub TR, Getz G, Mora J, and Stegmaier K
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- Antigens, Nuclear metabolism, Bone Neoplasms metabolism, Cell Cycle Proteins, Cell Line, Tumor, Child, DNA, Neoplasm genetics, Female, Gene Rearrangement, Genomics, Humans, Male, Mutation, Sarcoma, Ewing metabolism, Sequence Analysis, DNA, Antigens, Nuclear genetics, Bone Neoplasms genetics, Sarcoma, Ewing genetics
- Abstract
Unlabelled: Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS-ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease., Significance: We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS-ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma., (©2014 American Association for Cancer Research.)
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- 2014
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28. SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates.
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Bowen ME, Ayturk UM, Kurek KC, Yang W, and Warman ML
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- Animals, Bone Neoplasms genetics, Bone Neoplasms pathology, Cartilage pathology, Chondrocytes metabolism, Chondrocytes pathology, Chondrogenesis genetics, Chondroma genetics, Chondroma pathology, Chondromatosis genetics, Chondromatosis pathology, Exostoses genetics, Exostoses pathology, Exostoses, Multiple Hereditary genetics, Exostoses, Multiple Hereditary pathology, Growth Plate, Humans, MAP Kinase Signaling System genetics, Mice, Osteogenesis genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Cartilage metabolism, Cell Differentiation genetics, Paracrine Communication genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
- Abstract
Loss of PTPN11/SHP2 in mice or in human metachondromatosis (MC) patients causes benign cartilage tumors on the bone surface (exostoses) and within bones (enchondromas). To elucidate the mechanisms underlying cartilage tumor formation, we investigated the role of SHP2 in the specification, maturation and organization of chondrocytes. Firstly, we studied chondrocyte maturation by performing RNA-seq on primary chondrocyte pellet cultures. We found that SHP2 depletion, or inhibition of the ERK1/2 pathway, delays the terminal differentiation of chondrocytes from the early-hypertrophic to the late-hypertrophic stage. Secondly, we studied chondrocyte maturation and organization in mice with a mosaic postnatal inactivation of Ptpn11 in chondrocytes. We found that the vertebral growth plates of these mice have expanded domains of early-hypertrophic chondrocytes that have not yet terminally differentiated, and their enchondroma-like lesions arise from chondrocytes displaced from the growth plate due to a disruption in the organization of maturation and ossification zones. Furthermore, we observed that lesions from human MC patients also display disorganized chondrocyte maturation zones. Next, we found that inactivation of Ptpn11 in Fsp1-Cre-expressing fibroblasts induces exostosis-like outgrowths, suggesting that loss of SHP2 in cells on the bone surface and at bone-ligament attachment sites induces ectopic chondrogenesis. Finally, we performed lineage tracing to show that exostoses and enchondromas in mice likely contain mixtures of wild-type and SHP2-deficient chondrocytes. Together, these data indicate that in patients with MC, who are heterozygous for inherited PTPN11 loss-of-function mutations, second-hit mutations in PTPN11 can induce enchondromas by disrupting the organization and delaying the terminal differentiation of growth plate chondrocytes, and can induce exostoses by causing ectopic chondrogenesis of cells on the bone surface. Furthermore, the data are consistent with paracrine signaling from SHP2-deficient cells causing SHP2-sufficient cells to be incorporated into the lesions.
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- 2014
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29. PIK3CA activating mutations in facial infiltrating lipomatosis.
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Maclellan RA, Luks VL, Vivero MP, Mulliken JB, Zurakowski D, Padwa BL, Warman ML, Greene AK, and Kurek KC
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- Child, Preschool, Class I Phosphatidylinositol 3-Kinases, Face pathology, Facies, Gene Library, Genetic Heterogeneity, Humans, Lipomatosis metabolism, Magnetic Resonance Imaging, Male, Mosaicism, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction genetics, Subcutaneous Tissue pathology, Lipomatosis genetics, Lipomatosis pathology, Mutation, Missense, Phosphatidylinositol 3-Kinases genetics
- Abstract
Background: Facial infiltrating lipomatosis is a nonheritable disorder characterized by hemifacial soft-tissue and skeletal overgrowth, precocious dental development, macrodontia, hemimacroglossia, and mucosal neuromas. The authors tested the hypothesis that this condition is caused by a somatic mutation in the phosphatidylinositide-3 kinase (PI3K) signaling pathway, which has been indicted in other anomalies with overgrowth., Methods: The authors extracted DNA from abnormal tissue in six individuals, generated sequencing libraries, enriched the libraries for 26 genes involved in the PI3K pathway, and designed and applied a sequential filtering strategy to analyze the sequence data for mosaic mutations., Results: Unfiltered sequence data contained variant reads affecting ~12 percent of basepairs in the targeted genes. Filtering reduced the fraction of targeted basepairs containing variant reads to ~0.008 percent, allowing the authors to identify causal missense mutations in PIK3CA (p.E453K, p.E542K, p.H1047R, or p.H1047L) in each affected tissue sample., Conclusions: Affected tissue from individuals with facial infiltrating lipomatosis contains PIK3CA mutations that have previously been reported in cancers and in affected tissue from other nonheritable, overgrowth disorders, including congenital lipomatous overgrowth, vascular, epidermal, and skeletal anomalies syndrome, Klippel-Trenaunay syndrome, hemimegalencephaly, fibroadipose overgrowth, and macrodactyly. Because PIK3CA encodes a catalytic subunit of PI3K, and in vitro studies have shown that the overgrowth-associated mutations increase this enzyme's activity, PI3K inhibitors currently in clinical trials for patients with cancer may have a therapeutic role in patients with facial infiltrating lipomatosis. The strategy used to identify somatic mutations in patients with facial infiltrating lipomatosis is applicable to other somatic mosaic disorders that have allelic heterogeneity.
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- 2014
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30. Experimental Comparison of Cranial Particulate Bone Graft, rhBMP-2, and Split Cranial Bone Graft for Inlay Cranioplasty.
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Hassanein AH, Couto RA, Kurek KC, Rogers GF, Mulliken JB, and Greene AK
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- Animals, Bone Regeneration, Bone Transplantation, Humans, Parietal Bone, Skull, Inlays, X-Ray Microtomography
- Abstract
Background : Particulate bone graft and recombinant human bone morphogenetic protein-2 (rhBMP-2) are options for inlay cranioplasty in children who have not developed a diploic space. The purpose of this study was to determine whether particulate bone graft or rhBMP-2 has superior efficacy for inlay cranioplasty and to compare these substances to split cranial bone. Methods : A 17 mm × 17 mm critical-sized defect was made in the parietal bones of 22 rabbits and managed in four ways: Group I (no implant; n=5), Group II (particulate bone graft; n=5), Group III (rhBMP-2; n=7), and Group IV (split cranial bone graft; n=5). Animals underwent microcomputed tomography and histologic analysis 16 weeks after cranioplasty. Results : Defects without an implant (Group I) demonstrated inferior ossification (41.4%; interquartile range [IQR], 28.9% to 42.5%) compared to those treated with particulate bone graft (Group II: 99.5%; IQR, 97.8% to 100%), rhBMP-2 (Group III: 99.6%; IQR, 99.5% to 100%), or split cranial bone (Group IV: 100%) (P < .0001). There was no difference between Groups II, III, and IV (P = .1). Defects treated with rhBMP-2 exhibited thinner bone (0.90 mm; IQR, 0.64 to 0.98) than particulate bone graft (1.95 mm; IQR, 1.09 to 2.83) or split cranial bone (1.72 mm; IQR, 1.54 to 1.88) (P = .006); particulate and split cranial bone grafted defects had a similar thicknesses (P = .6). Conclusions : Particulate bone graft, rhBMP-2, and split cranial bone close inlay calvarial defect areas equally, although the thickness of bone healed with rhBMP-2 is inferior. Clinically, particulate bone graft or split cranial bone graft may be superior to rhBMP-2 for inlay cranioplasty.
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- 2013
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31. R132C IDH1 mutations are found in spindle cell hemangiomas and not in other vascular tumors or malformations.
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Kurek KC, Pansuriya TC, van Ruler MA, van den Akker B, Luks VL, Verbeke SL, Kozakewich HP, Sciot R, Lev D, Lazar AJ, Fletcher CD, and Bovée JV
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- Adolescent, Carcinoma enzymology, Carcinoma pathology, Child, Demography, Female, Hemangioma enzymology, Hemangioma pathology, Humans, Immunohistochemistry, Male, Middle Aged, Vascular Malformations enzymology, Vascular Malformations pathology, Young Adult, Amino Acid Substitution genetics, Carcinoma genetics, Hemangioma genetics, Isocitrate Dehydrogenase genetics, Mutation genetics, Vascular Malformations genetics
- Abstract
Spindle cell hemangioma (SCH) is a rare, benign vascular tumor of the dermis and subcutis. The lesions can be multifocal and are overrepresented in Maffucci syndrome, in which patients also have multiple enchondromas. Somatic mosaic R132C IDH1 hotspot mutations were recently identified in Maffucci syndrome. We evaluated the presence of mutations in solitary and multiple SCHs in patients without multiple enchondromas and tested a range of other vascular lesions that enter into the differential diagnosis. The R132C IDH1 mutation was identified by hydrolysis probes assay and confirmed by Sanger sequencing in 18 of 28 (64%) SCHs; of the 10 negative cases, 2 harbored a mutation in IDH2 (R172T and R172M) by Sanger sequencing. None of 154 other vascular malformations and tumors harbored an IDH1 R132C mutation, and R132H IDH1 mutations were absent in all 182 cases. All 16 SCHs examined by immunohistochemistry were negative for expression of HIF-1α. In conclusion, 20 of 28 (71%) SCHs harbored mutations in exon 4 of IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, the mutation seems to be highly specific for SCH. The mutation does not induce expression of HIF-1α in SCH, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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32. B7-h1 as a biomarker for therapy failure in patients with favorable histology Wilms tumor.
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Routh JC, Grundy PE, Anderson JR, Retik AB, and Kurek KC
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- Adolescent, B7-H1 Antigen biosynthesis, Biomarkers analysis, Case-Control Studies, Child, Child, Preschool, Female, Humans, Infant, Kidney Neoplasms epidemiology, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Kidney Neoplasms therapy, Male, Neoplasm Recurrence, Local epidemiology, Prognosis, Risk, Treatment Failure, Wilms Tumor epidemiology, Wilms Tumor metabolism, Wilms Tumor pathology, Wilms Tumor therapy, B7-H1 Antigen analysis, Kidney Neoplasms chemistry, Wilms Tumor chemistry
- Abstract
Purpose: A minority of children with Wilms tumor will experience tumor recurrence. In a previous pilot study we found an association between expression of an immune costimulatory molecule, B7-H1, and tumor recurrence in favorable histology Wilms tumor. We sought to verify the prognostic value of B7-H1 as a biomarker in favorable histology Wilms tumor., Materials and Methods: We performed a nested case-control study of tumors from the Fifth National Wilms Tumor Study. We randomly selected 44 children unsuccessfully treated (cases) and 49 who were successfully treated for favorable histology Wilms tumor (controls). Cases and controls were matched based on tumor stage, and the analysis was restricted to children who underwent initial resection. We excluded patients with stage IV or V disease and those treated with chemotherapy or radiation. Tumor specimens were stained for B7-H1 expression., Results: Of the 93 total samples analyzed 60 (65%) demonstrated B7-H1 staining, with staining diffusely present in 13 (22%) and blastema predominant in 34 (57%). B7-H1 expression was associated with failure of initial therapy (p = 0.006). Patients with tumors showing less than 20% B7-H1 positive cells were at lower risk for treatment failure, while those with tumors exhibiting greater than 60% B7-H1 positive cells were at greater risk for treatment failure. This association appeared to be independent of tumor stage., Conclusions: B7-H1 expression by favorable histology Wilms tumor is associated with an increased risk of failure of initial therapy., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2013
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33. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.
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Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, Mulliken JB, Bowen ME, Yamamoto GL, Kozakewich HP, and Warman ML
- Subjects
- Adolescent, Catalysis, Child, Preschool, Class I Phosphatidylinositol 3-Kinases, DNA Mutational Analysis, Female, Humans, Hypertrophy, Infant, Lipoma metabolism, Magnetic Resonance Imaging methods, Male, Models, Genetic, Mosaicism, Abnormalities, Multiple genetics, Lipoma genetics, Mutation, Phosphatidylinositol 3-Kinases genetics
- Abstract
Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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34. PTEN hamartoma of soft tissue: a distinctive lesion in PTEN syndromes.
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Kurek KC, Howard E, Tennant LB, Upton J, Alomari AI, Burrows PE, Chalache K, Harris DJ, Trenor CC 3rd, Eng C, Fishman SJ, Mulliken JB, Perez-Atayde AR, and Kozakewich HP
- Subjects
- Adolescent, Adult, Arteriovenous Malformations pathology, Child, Child, Preschool, Female, Genetic Markers, Hamartoma Syndrome, Multiple diagnosis, Hamartoma Syndrome, Multiple genetics, Hamartoma Syndrome, Multiple surgery, Humans, Male, Muscle, Skeletal pathology, PTEN Phosphohydrolase genetics, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms surgery, Young Adult, Hamartoma Syndrome, Multiple pathology, Soft Tissue Neoplasms pathology
- Abstract
PTEN hamartoma tumor syndrome (PHTS) presents in a spectrum that encompasses the eponymous disorders Cowden and Bannayan-Riley-Ruvalcaba. Herein, we delineate the distinctive histopathology of a predominantly intramuscular lesion in PHTS, often called "arteriovenous malformation," because of certain imaging and histopathologic features. Cases were identified by review of lesions resected from patients with PHTS registered at our Vascular Anomalies Center and of unusual intramuscular vascular anomalies in our pathology database from 1985 to 2008. Thirty-four patients with this lesion were identified: 20 had a clinical diagnosis of, or were suspected to have, PHTS (genetically confirmed in 16). In 4 patients without clinical manifestations of PHTS, 2 had PTEN mutations, 1 did not, and in 1 the mutation was intronic. In the remaining 10, there was insufficient clinical information to fully assess whether they had manifestations of PHTS. Lesions manifested by 15 years of age, normally with pain and swelling, and were most often located in the lower extremity. The major mass was usually intramuscular, but often there were fascial and subcutaneous components and not infrequently a cutaneous vascular stain. Magnetic resonance imaging generally showed an infiltrative soft tissue lesion involving the muscle, fascia, and subcutis with frequently enlarged, serpiginous vessels, small arteriovenous fistulae with disproportionately dilated draining veins, and a prominent adipocytic component. Some lesions involved contiguous muscles, and 20% were multifocal. Resected specimens ranged in size from 1.2 to 25 cm; in 1 patient, amputation was necessary. Histopathologically, these unencapsulated masses, often with a nodular appearance at scanning magnification, consisted of: (1) a variable admixture of mature adipocytic and dense and/or myxoid fibrous tissues (50% to 90% of surface area); (2) a vascular component (10% to 50% of surface area) with: (a) clusters of venous channels, some with excessively and irregularly muscularized complex walls and lumens, and others with thin walls resembling pulmonary alveoli, (b) tortuous, thick-walled arteries with concentric muscular hyperplasia and relatively small lumens, (c) numerous small vessels (arteries, veins, and indeterminate channels), and (d) occasional arteriovenous communications; (3) lymphoid follicles (50%); (4) foci of bone (20%); and (5) hypertrophic nerves with "onion bulb" proliferation of periaxonal spindled cells (9%). We designate this disorganized overgrowth of essentially mesenchymal elements as PTEN hamartoma of soft tissue. It differs from other vascular and connective tissue lesions that occur in patients with PHTS. PTEN hamartoma of soft tissue is histopathologically distinctive, and its identification should prompt a thorough investigation for PHTS.
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- 2012
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35. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome.
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Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, and Bovée JV
- Subjects
- Adult, Case-Control Studies, Cell Line, Tumor, DNA Methylation, Female, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Humans, Male, Middle Aged, Mosaicism, Sequence Analysis, DNA, Transcription, Genetic, Young Adult, Enchondromatosis genetics, Isocitrate Dehydrogenase genetics, Mutation, Missense
- Abstract
Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.
- Published
- 2011
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36. Expansion thoracoplasty affects lung growth and morphology in a rabbit model: a pilot study.
- Author
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Olson JC, Kurek KC, Mehta HP, Warman ML, and Snyder BD
- Subjects
- Animals, Cell Proliferation, Disease Models, Animal, Immunohistochemistry, Ki-67 Antigen, Lung blood supply, Lung growth & development, Lung pathology, Macrophages pathology, Neovascularization, Physiologic, Nuclear Proteins metabolism, Pilot Projects, Rabbits, Respiratory Insufficiency diagnostic imaging, Respiratory Insufficiency physiopathology, Ribs diagnostic imaging, Ribs growth & development, Ribs surgery, Thyroid Nuclear Factor 1, Time Factors, Tomography, X-Ray Computed, Transcription Factors metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Lung surgery, Respiratory Insufficiency surgery, Thoracoplasty
- Abstract
Background: Thoracic insufficiency syndrome represents a novel form of postnatal restrictive respiratory disease occurring in children with early-onset scoliosis and chest wall anomalies. Expansion thoracoplasty improves lung volumes in children with thoracic insufficiency syndrome; however, how it affects lung development is unknown., Questions/purposes: Using a rabbit model of thoracic insufficiency syndrome, we evaluated the effect of expansion thoracoplasty on the response of biologic mechanisms in the alveolar microstructure., Methods: Using archived material from a previous experiment, 10 4-week-old New Zealand rabbits were divided into three groups: normal (n = 3), disease (n = 3), and treated (n = 4). Left ribs four to eight were tethered in seven rabbits at age 5 weeks to induce hypoplasia of the left hemithorax (disease). At age 10 weeks, four of these rabbits were treated by expansion thoracoplasty (treated). At age 24 weeks, lungs were excised and processed. Alveolar density and parenchymal airspace were measured on histologic sections. Immunohistochemistry was performed for vascular endothelial growth factor receptor 2 (angiogenesis), KI-67 (cell proliferation), and RAM-11 (macrophages)., Results: Alveolar walls were poorly perfused and airspace fraction was larger (emphysematous) in disease rabbits than normal or treated rabbits. Immunohistochemistry provided inconclusive evidence to support the concept that pulmonary hypoplasia is induced by thoracic insufficiency syndrome and controlled by expansion thoracoplasty., Conclusions: Treatment of thoracic insufficiency syndrome by expansion thoracoplasty may prevent emphysematous changes in the alveolar microstructure, thereby enhancing gas exchange.
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- 2011
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37. Ovarian dermoid cyst super-infected with methicillin-sensitive Staphylococcus aureus leading to the misdiagnosis of appendicitis in an adolescent.
- Author
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Spencer RJ, Kurek KC, and Laufer MR
- Subjects
- Adolescent, Anti-Bacterial Agents therapeutic use, Dermoid Cyst microbiology, Dermoid Cyst pathology, Dermoid Cyst surgery, Female, Humans, Ovarian Neoplasms microbiology, Ovarian Neoplasms pathology, Ovarian Neoplasms surgery, Staphylococcal Infections drug therapy, Staphylococcus aureus, Superinfection drug therapy, Appendicitis diagnosis, Dermoid Cyst complications, Diagnostic Errors, Ovarian Neoplasms complications, Staphylococcal Infections complications, Superinfection complications
- Abstract
Background: Mature cystic teratomas (dermoid cysts) are the most common ovarian tumor in adolescents. Super-infection of a dermoid cyst is a rare event usually associated with a concomitant infection., Case: A 14-year-old female was transferred to our institution with five days of fevers and abdominal pain. CT of the abdomen/pelvis was read as acute appendicitis with a 7.6 cm right adnexal dermoid cyst. The patient was treated for appendicitis but later found to have an infected dermoid cyst primarily infected with methicillin-sensitive staphylococcus aureus, which led the misdiagnosis of appendicitis., Summary and Conclusion: Super-infection of an ovarian dermoid cyst is an extremely rare event. We recommend that previously described evaluation, surgical management, and ovarian conservation be employed in all cases of ovarian dermoid cysts., (Copyright © 2011 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
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38. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.
- Author
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Bowen ME, Boyden ED, Holm IA, Campos-Xavier B, Bonafé L, Superti-Furga A, Ikegawa S, Cormier-Daire V, Bovée JV, Pansuriya TC, de Sousa SB, Savarirayan R, Andreucci E, Vikkula M, Garavelli L, Pottinger C, Ogino T, Sakai A, Regazzoni BM, Wuyts W, Sangiorgi L, Pedrini E, Zhu M, Kozakewich HP, Kasser JR, Seidman JG, Kurek KC, and Warman ML
- Subjects
- Chromosomes, Human genetics, DNA Copy Number Variations, Enchondromatosis pathology, Exons, Gene Deletion, Genetic Linkage, High-Throughput Nucleotide Sequencing, Humans, Loss of Heterozygosity, Mutation, Pedigree, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Sequence Analysis, DNA, Enchondromatosis genetics, Exostoses, Multiple Hereditary genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
- Abstract
Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2011
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39. A rare case of psammomatoid ossifying fibroma in the sphenoid bone reconstructed using autologous particulate exchange cranioplasty.
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Kasliwal MK, Rogers GF, Ramkissoon S, Moses-Gardner A, Kurek KC, and Smith ER
- Subjects
- Biopsy, Bone Cysts, Aneurysmal diagnostic imaging, Bone Transplantation methods, Child, Diagnosis, Differential, Female, Fibroma, Ossifying diagnostic imaging, Fibroma, Ossifying pathology, Humans, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Skull surgery, Skull Neoplasms diagnostic imaging, Skull Neoplasms pathology, Tomography, X-Ray Computed, Transplantation, Autologous, Treatment Outcome, Fibroma, Ossifying surgery, Plastic Surgery Procedures methods, Skull Neoplasms surgery, Sphenoid Bone
- Abstract
Psammomatoid ossifying fibroma (POF), a variant of ossifying fibroma, is a benign fibroosseous lesion typically arising within the nasal cavity, paranasal sinuses, and orbit. Cranial vault involvement is exceedingly rare, with very few cases reported in the literature. The authors report a case of POF in the neurocranium of an 11-year-old child, 4 years after chemotherapy and radiation therapy for acute lymphoblastic leukemia. This case is reported in view of its rarity, novelty of presentation, and the difficulty in diagnosis due to its radiological resemblance to aneurysmal bone cyst or monostotic cystic fibrous dysplasia, further aggravated by the clinical scenario. A novel technique of cranial reconstruction called autologous particulate exchange cranioplasty was used following tumor excision.
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- 2011
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40. Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma.
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Del Mare S, Kurek KC, Stein GS, Lian JB, and Aqeilan RI
- Abstract
Osteosarcoma is the most common primary bone malignancy in children with unknown etiology and often with poor clinical outcome. In recent years, a critical role has emerged for the WW domain-containing oxidoreductase (WWOX) in osteosarcoma and bone biology. WWOX is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma and a bone metabolic disease characterized by hypocalcemia and osteopenia. Studies of human osteosarcomas have revealed that the WWOX gene is deleted in 30% of cases and WWOX protein is absent or reduced in ∼60% of tumors. Further, WWOX levels are attenuated in the majority of osteosarcoma cells, in which ectopic expression is associated with reduced proliferation, migration, invasion and tumorigenicity. At the molecular level, WWOX associates with RUNX2 and suppresses its transcriptional activity in osteoblasts and in cancer cells. This review provides new insights on the current knowledge of the spectrum of WWOX activities and future directions for the role of WWOX in bone biology and osteosarcoma.
- Published
- 2011
41. Metastatic neuroblastoma mimicking infantile hemangioma.
- Author
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Hassanein AH, Fishman SJ, Mulliken JB, Alomari AI, Kurek KC, Padua HM, and Greene AK
- Subjects
- Diagnosis, Differential, Female, Hemangioma pathology, Hemangioma ultrastructure, Humans, Infant, Neuroblastoma diagnostic imaging, Neuroblastoma pathology, Physical Examination, Skin Neoplasms diagnostic imaging, Skin Neoplasms pathology, Skin Neoplasms secondary, Subcutaneous Tissue diagnostic imaging, Subcutaneous Tissue pathology, Ultrasonography, Hemangioma diagnosis, Neuroblastoma diagnosis, Neuroblastoma secondary, Skin Neoplasms diagnosis
- Abstract
Many lesions can masquerade as deep infantile hemangioma, the most common tumor of infancy. We describe an infant with infantile hemangioma and concomitant metastatic subcutaneous neuroblastoma mimicking deep hemangioma. The patient presented at 8 months of age with 3 superficial infantile hemangiomas as well as 3 subcutaneous masses. History, physical examination, and ultrasonography of the deep lesions were consistent with subcutaneous hemangioma. New masses appeared at 10 months of age that prompted biopsy; histopathology demonstrated metastatic neuroblastoma. Deviation from the predictable clinical features of a deep infantile hemangioma should prompt consideration for other causes of a subcutaneous mass in infancy, including metastatic neuroblastoma., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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42. Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.
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Kurek KC, Del Mare S, Salah Z, Abdeen S, Sadiq H, Lee SH, Gaudio E, Zanesi N, Jones KB, DeYoung B, Amir G, Gebhardt M, Warman M, Stein GS, Stein JL, Lian JB, and Aqeilan RI
- Subjects
- Animals, Apoptosis physiology, Bone Neoplasms drug therapy, Bone Neoplasms genetics, Bone Neoplasms pathology, Cell Growth Processes physiology, Cell Line, Tumor, Cell Movement physiology, Core Binding Factor Alpha 1 Subunit genetics, Disease Progression, Female, Humans, Immunohistochemistry, Mice, Mice, Nude, Osteosarcoma drug therapy, Osteosarcoma genetics, Osteosarcoma pathology, Oxidoreductases deficiency, Oxidoreductases genetics, Transcriptional Activation, Tumor Suppressor Proteins deficiency, Tumor Suppressor Proteins genetics, WW Domain-Containing Oxidoreductase, Bone Neoplasms metabolism, Core Binding Factor Alpha 1 Subunit biosynthesis, Osteosarcoma metabolism, Oxidoreductases biosynthesis, Tumor Suppressor Proteins biosynthesis
- Abstract
The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease., (Copyright 2010 AACR.)
- Published
- 2010
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43. Recurrent bilateral serous cystadenomas in a premenarchal girl: a case report and literature review.
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Barton SE, Kurek KC, and Laufer MR
- Subjects
- Child, Cystadenoma, Serous surgery, Female, Humans, Neoplasm Recurrence, Local surgery, Ovarian Neoplasms surgery, Cystadenoma, Serous pathology, Neoplasm Recurrence, Local pathology, Ovarian Neoplasms pathology
- Abstract
Background: Ovarian serous cystadenomas are rare in children. No case of recurrence after surgical resection in a premenarchal girl has been published., Case: An 8-year-old presented with abdominal pain and ultrasound showed bilateral ovarian cystic masses with normal clinical and laboratory exam. Cystectomies were performed revealing serous cystadenomas. Ten months later, her pain returned and ultrasound showed new cysts. Persistence of cysts and symptoms required repeat surgery with the same pathology., Summary and Conclusion: Premenarchal girls with ovarian cystic masses require surgical intervention in cases of persistent symptoms, uncertain diagnosis, or concern for ovarian torsion. With reassuring imaging and tumor markers, conservation of the ovary can be achieved with cystectomy alone. Ultrasound follow-up is recommended after surgical resection until bimanual exam can be performed., (Copyright 2010 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
44. Nonrandom arrangement of bovine satellite I DNA within the interphase nucleus of Madin-Darby bovine kidney cells.
- Author
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Kurek KC and Matsumoto L
- Subjects
- Animals, Cattle, Cell Line, Centromere, In Situ Hybridization, Kidney, Poisson Distribution, Cell Nucleus chemistry, DNA, Satellite analysis, Interphase
- Abstract
The distribution of bovine satellite DNA was examined in Madin-Darby bovine kidney cells for each hour of interphase. Cells were grown on coverslips and probed using biotinylated cloned fragments of bovine satellite I DNA. Hybridization was detected using a streptavidin-alkaline phosphatase conjugate. Cells were projected onto a grid of fixed dimensions and the distribution of hybridization signal was recorded. A chi 2 analysis of fit compared this distribution of signals to a random distribution generated from the poisson distribution. Nuclear localization of bovine satellite I DNA was found to be nonrandom throughout interphase except at the G1/S border and S = 6 h. Moreover, distinct patterns of hybridization were also observed at specific times during interphase.
- Published
- 1995
- Full Text
- View/download PDF
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