Lung transcriptional unresponsiveness and loss of early influenza virus control in infected neonates is prevented by intranasal Lactobacillus rhamnosus GG.

Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Using our previously established neonatal murine model of influenza infection, we demonstrate that three-day old mice are exceptionally sensitive to influenza virus infection and exhibit high mortality and viral load. Intranasal pre- and post-treatment of neonatal mice with Lactobacillus rhamnosus GG (LGG), an immune modulator in respiratory viral infection of adult mice and human preterm neonates, considerably improves neonatal mice survival after influenza virus infection. We determine that both live and heat-killed intranasal LGG are equally efficacious in protection of neonates. Early in influenza infection, neonatal transcriptional responses in the lung are delayed compared to adults. These responses increase by 24 hours post-infection, demonstrating a delay in the kinetics of the neonatal anti-viral response. LGG pretreatment improves immune gene transcriptional responses during early infection and specifically upregulates type I IFN pathways. This is critical for protection, as neonatal mice intranasally pre-treated with IFNß before influenza virus infection are also protected. Using transgenic mice, we demonstrate that the protective effect of LGG is mediated through a MyD88-dependent mechanism, specifically via TLR4. LGG can improve both early control of virus and transcriptional responsiveness and could serve as a simple and safe intervention to protect neonates.

Nonkeratinizing Nasopharyngeal Carcinoma, Undifferentiated Type With Trisomy 2: A Case Report and Short Review of Cytogenetic and Molecular Literature.

Carcinoma originating from the surface epithelium of the nasopharynx is classified by the World Health Organization (WHO) as nasopharyngeal carcinoma (NPC) and has 3 main types: keratinizing squamous cell carcinoma (WHO type 1) and nonkeratinizing carcinoma, differentiated (WHO type II), and undifferentiated (WHO type III). Nonkeratinizing NPC is strongly associated with prior Epstein-Barr virus (EBV) infection. These tumors may be divided into differentiated and undifferentiated carcinoma. Histologically, the tumor is characterized by syncytia of large malignant cells with vesicular nuclei, conspicuous nucleoli, and easily observed mitotic figures. We report a case of a 14-year-old boy diagnosed with EBV and human papillomavirus (HPV)-positive NPC (WHO type 3) with cytogenetics showing the presence of mosaic trisomy 2. This case report brings to light a rare cytogenetic aberration to our knowledge only reported once before in the literature in a xenograft model.

A Pediatric Patient With an Orbital Respiratory Epithelial Cyst.

Respiratory epithelial cysts are rare orbital cysts that can arise secondary to choristomatous rests of respiratory epithelium. Approximately 15 congenital cases have been described in the literature, making it a rare disease entity. We present a case of a 14-month-old Middle Eastern male with a right infraorbital respiratory epithelial cyst. Magnetic resonance imaging of the brain and orbits revealed a right infraorbital cyst hyperintense on T1-weighted images and followed fluid density on T2-weighted images. This cyst was noted to displace the globe superiorly and inferior rectus muscle laterally. This cyst was excised using a transconjunctival approach. Histologically, the cyst wall was lined by ciliated columnar cells with interspersed mucus-containing cells and ciliated transitional epithelium was present, establishing the diagnosis of respiratory epithelial cyst. To our knowledge, this is the youngest patient with a respiratory epithelial cyst of the orbit reported in the literature.

Malignant glioma with primitive neuroectodermal tumor-like component (MG-PNET): novel microarray findings in a pediatric patient.

Central nervous system (CNS) tumors exhibiting dual features of malignant glioma (MG) and primitive neuroectodermal tumor (PNET) are rare and diagnostically challenging. Previous studies have shown that MG-PNET carry MYCN or MYC gene amplifications within the PNET component concomitant with glioma-associated alterations, most commonly 10q loss, in both components [9]. Here we confirm and extend the profile of molecular genetic findings in a MG-PNET involving the left frontal lobe of a 12-year-old male. Histologically, the PNET-like component showed morphological features akin to anaplastic medulloblastoma highlighted by widespread immunoreactivity for ßIII-tubulin (TUBB3) and nonphosphorylated neurofilament protein, and to a lesser degree, Neu-N, synaptophysin, and CD99, whereas the gliomatous component was demarcated by glial fibrillary acidic protein (GFAP) labeling. Immunohistochemical labeling with an anti-H3K27M mutant-specific antibody was not detectable in either gliomatous and/or PNET-like areas. Interphase fluorescent in situ hybridization (FISH) study on touch preparations from frozen tumor and formaldehyde-fixed, paraffin-embedded histological sections showed amplification of MYC in both PNET-like and gliomatous areas. Single nucleotide polymorphism (SNP) microarray analysis revealed that the tumor carried gains of multiple chromosomes and chromosome arms, losses of multiple chromosomes and chromosome arms, gains of multiple chromosomal segments (not limited to amplification of chromosomal segments 4q12 including PDGFRA, and 8q24.21 including MYC), and a hitherto unreported chromothripsis-like abnormality on chromosome 8. No mutations were identified for IDH1, IDH2, or BRAF genes by sequence analysis. The molecular genetic findings support the presence of a CNS-PNET as an integral part of the tumor coupled with overlapping genetic alterations found in both adult and pediatric high-grade gliomas/glioblastoma. Collectively, microarray data point to a complex underpinning of genetic alterations associated with the MG-PNET tumor phenotype.
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Unusual genetic aberrations including a deletion of KLF6 tumor suppressor gene revealed by integrated cytogenetic approaches in a pediatric ewing sarcoma.

Ewing sarcoma is the third most common sarcoma in children and young adults. Its characteristic chromosomal rearrangement results in a chimerical EWSR1-ETS transcription factor. Secondary genetic alterations are very common. Membranous expression of CD99 is seen in almost all tumors. We report 2 unusual cytogenetic findings in a pediatric Ewing sarcoma, an insertion of the MIC2 gene encoding CD99 from Xp to 10p and a submicroscopic deletion of the well-known tumor supressor gene KLF6. The latter has not been described previously in pediatric neoplasms. Molecular pathways in tumorigenesis and genetic complexity in cancer are discussed.

Co-occurrence of non-mosaic trisomy 22 and inherited balanced t(4;6)(q33;q23.3) in a liveborn female: case report and review of the literature.

Trisomy 22 is the third most common autosomal trisomy occurring in about 0.4% of all clinically recognized pregnancies. Complete non-mosaic trisomy 22 is extremely rare in live births. Most affected children die before one year of age. To date, only 29 liveborn cases have been reported and none has carried an additional genetic lesion. In this report, we describe the clinical presentation, cytogenetic, and cytogenomic findings in a liveborn female with complete non-mosaic trisomy 22 as well as a paternally inherited, balanced reciprocal chromosomal rearrangement t(4;6)(q33;q23.3). The proband manifested features commonly seen in individuals with non-mosaic trisomy 22 such as intrauterine growth retardation (IUGR), single umbilical artery, cranial abnormalities, short neck, cleft lip and palate, dysmorphic ears, hypoplastic nipples, digital malformation, congenital heart defects, dysplastic kidneys, and genital anomalies. In addition, she had lobar holoprosencephaly, aqueductal stenosis, and limb and eye problems that have not been associated with complete trisomy 22 in previous reports. She died at 35 days of age of complex heart disease and renal failure. We are hereby expanding the cytogenetic and clinical spectrum of this rare chromosome disorder. Clinical features of liveborn children with non-mosaic trisomy 22 are reviewed and compared to those in our proband. The impact of genomic content in relation to the survival of trisomies in humans is also discussed.

Tetrasomy 13q32.2qter due to an apparent inverted duplicated neocentric marker chromosome in an infant with hemangiomas, failure to thrive, laryngomalacia, and tethered cord.

BACKGROUND: Approximately 100 small supernumerary marker chromosomes (sSMCs) with a non-α-satellite neocentromere structure have been reported in the literature. Of the few derived from chromosome 13, five have consisted of inverted duplicated segment 13q32qter. CASE REPORT: We herein describe the sixth case, characterized by genome wide SNP array, conventional cytogenetics and FISH studies. The de novo occurrence of the marker, the poor prognosis and the presence of hemangiomas are consistent with previous cases. CONCLUSION: We hereby expand the clinical spectrum of this rare cytogenetic disorder and suggest a possible mechanism for the pathogenesis of associated congenital vascular malformations.

Chemotherapy-related leiomyopathy: a suggested morphological explanation for the intestinal dysmotility affecting patients treated with anthracyclines.

Anthracycline, used in oncological chemotherapy, has one well-known side effect: cardiotoxicity. Another is abnormal intestinal motility such as constipation and ileus, the pathogenesis of which, to our knowledge, has not been morphologically investigated. We conducted a study in search of morphological evidence that might shed some light on the pathogenesis of the motility dysfunction. Autopsies performed between 2002 and 2007 were reviewed to select cases of children who had received anthracycline therapy for various neoplasms. The seven patients found had leukemias, lymphomas, or renal solid tumors. They all suffered from constipation or intestinal dysmotility, and no case of anthracyclin-treated neoplasia without the side effect was found in the files. Tissue samples from the heart, gastrointestinal tract, uterus, urinary bladder, and skeletal muscles were examined by light and electron microscopy. As described by others, the myocardium of all anthracycline-treated patients showed loss of myofilaments, fibrosis, mitochondrial proliferation, and pools of accumulated Z-band material. In the gastrointestinal tract and other smooth muscle-endowed organs such as muscular blood vessels, bladder and uterus, the muscularis displayed hyalinization and disorganization, including loss of myofilaments and moderate-severe fibrosis. This study illustrates changes in the smooth muscle, and that of the gastrointestinal tracts and their vessels in particular, in patients treated with anthracycline, who had experienced motility dysfunction associated with their chemotherapy, suggesting that, in addition to the heart, anthracycline may also damage smooth muscle fibers and thus be instrumental in the pathogenesis of the side effects.

Severity of neonatal influenza infection is driven by type I interferon and oxidative stress.

Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNß 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNß induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.

FOXO1-FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma.

Rhabdomyosarcoma is the most common pediatric soft tissue malignancy. Two major subtypes, alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma, constitute 20 and 60% of all cases, respectively. Approximately 80% of alveolar rhabdomyosarcoma carry two signature chromosomal translocations, t(2;13)(q35;q14) resulting in PAX3-FOXO1 fusion, and t(1;13)(p36;q14) resulting in PAX7-FOXO1 fusion. Whether the remaining cases are truly negative for gene fusion has been questioned. We are reporting the case of a 9-month-old girl with a metastatic neck mass diagnosed histologically as solid variant alveolar rhabdomyosarcoma. Chromosome analysis showed a t(8;13;9)(p11.2;q14;9q32) three-way translocation as the sole clonal aberration. Fluorescent in situ hybridization (FISH) demonstrated a rearrangement at the FOXO1 locus and an amplification of its centromeric region. Single-nucleotide polymorphism-based microarray analysis illustrated a co-amplification of the FOXO1 gene at 13q14 and the FGFR1 gene at 8p12p11.2, suggesting formation and amplification of a chimerical FOXO1-FGFR1 gene. This is the first report to identify a novel fusion partner FGFR1 for the known anchor gene FOXO1 in alveolar rhabdomyosarcoma.

Pediatric Bronchogenic Cysts: A Case Series of Six Patients Highlighting Diagnosis and Management.

Purpose: To present six cases of bronchogenic cysts while highlighting the diagnosis and management of this anomaly. Materials and Methods: A retrospective chart review was conducted using our institution's Pathology database. The database was queried for "bronchogenic cyst." From 2006 through 2017, six unusual cases were identified. Results: The six cases of bronchogenic cysts were located in the neck (two cases), chest wall, mediastinum (two cases), and thyroid. All six of our patients underwent complete excision and did not experience recurrence or other complications. Conclusion: Although rare, bronchogenic cysts should be considered in the differential diagnosis of peculiar cystic masses in the pediatric population. Considering the crucial regional anatomy that may be associated with bronchogenic cysts, intimate knowledge of surgical anatomy using preoperative imaging is critical in most cases for their safe and effective excision.

Treatment of an obstructive, recurrent, syncytial myoepithelioma of the trachea with tracheal resection and reconstruction.

Myoepithelioma is a rare occurrence in the trachea and respiratory tract with only 11 cases reported in the literature. We present a case report of a 10-year-old female who was found to have an anterior tracheal mass causing near total obstruction of the airway on bronchoscopy. Characteristics of the mass were consistent with syncytial myoepithelioma. The patient experienced multiple recurrences requiring tracheal resection with end-to-end reanastomosis. To date there have not been any reported cases of myoepithelioma of the trachea in a child and no reports of syncytial myoepithelioma in the trachea or respiratory tract.

Pulmonary capillaritis with hemorrhage due to propylthiouracil therapy in a child.

We report on a case of pulmonary capillaritis with diffuse alveolar hemorrhage in a child due to propylthiouracil (PTU). PTU treatment is a rare cause of pulmonary capillaritis in adults; we report on the first case in a pediatric patient. The treatment of pulmonary capillaritis often requires corticosteroid therapy, other immunosuppressive medications, or withdrawal of the causative agent. Our patient recovered completely after treatment with a limited course of corticosteroids and removal of PTU.

Brainstem tegmental necrosis and olivary hypoplasia: raising awareness of a rare neuropathologic correlate of congenital apnea.

This case study describes an instance of death in an early term female newborn with congenital apnea in the clinical setting of multiple congenital anomalies (retrognathia, posteriorly rotated ears, camptodactyly, and arthrogryposis) and prenatal history of polyhydramnios. Postmortem neuropathologic findings were significant for tegmental necrosis in the caudal pons and medulla characterized by a coalescence of microcalcifications accompanied by neuronal loss, axonal spheroids, gliosis, and a concomitant hypoplasia of the inferior olives. This report raises awareness of the rare lethal entity of brainstem tegmental necrosis and olivary hypoplasia and its nosological relationship to the Möbius syndrome in the context of differential diagnosis of congenital apnea owing to central respiratory dysfunction.

Childhood primary angiitis of the central nervous system with metachronous hemorrhagic infarcts: a postmortem study with clinicopathologic correlation.

This neuropathologic case study illustrates the discovery of metachronous hemorrhagic infarcts insinuating round mass-like lesions by magnetic resonance imaging in the setting of childhood primary angiitis of the central nervous system (cPACNS) raising diagnostic awareness of this unusual presentation in a clinical and neuroimaging context. The report underscores the importance of recurrent vasculitis-induced ischemic brain damage as a pathologic correlate of relapsing cPACNS and offers a critical reappraisal of common imitators as well as a clinicopathologic approach to differential diagnosis. Attention is drawn to the caveat that although magnetic resonance imaging findings at initial presentation may not be typical for stroke, they later exhibit attributes of cerebral infarction at both the subacute and chronic stages. A pattern of cPACNS characterized predominantly by multiple petechial-like cortical hemorrhages with pathologic features of hemorrhagic infarcts is recognized. The present study lends credence to the practice of a rigorous autopsy-based approach aimed at a better understanding of the anatomic pathology and biology of cPACNS and at facilitating prospective neuroimaging and biopsy-based surgical pathology correlations, ultimately enhancing diagnostic accuracy in clinical settings. Although PACNS is, by definition, a diagnosis of exclusion, it should be considered from the outset in the differential diagnosis of ischemic stroke or hemorrhagic stroke or of unusual and relapsing intra-axial mass-like CNS lesions in children, necessitating appropriate pathologic evaluation of brain biopsy specimens.

Appendiceal goblet cell metaplasia and benign obstructive mucus retention in children: report of eight cases and review of the literature.

We report the clinical-pathologic study of 8 cases of pediatric benign, postobstructive, appendiceal mucus retention in patients 3-15 years of age. The appendices showed very limited acute inflammation. Their most significant change consisted of minimal to mild dilatation of the distal lumen, which was filled with mucus and lined by an epithelium showing often dramatic increase in mucus cells devoid of atypia and without any of the villous proliferation reported in instances of "mucosal hyperplasia" observed in adult patients. In all 8 cases, there was seepage of mucus through the appendiceal wall into the surrounding tissue, eliciting a macrophagic reaction. Proximal to the zones of mucus retention, the lumen of 2 of the appendices was obstructed by a fecalith, and 2 exhibited fibrous obliteration of the lumen at that site. We believe the condition results from obstruction and focal inflammation, which isolate the distal portion of the appendix and elicit goblet cell metaplasia, the secretion of which is followed by luminal distention, eventual rupture, and seepage of mucus within the wall and the mesoappendix. The clinical and radiologic picture of this condition may be mistaken for that of an acute appendicitis complicated by rupture and abscess formation. The report provides an opportunity to describe and characterize "appendiceal mucosal goblet cell metaplasia," a seldom mentioned entity associated with benign appendiceal obstructive mucus retention in children.

Ruptured abdominal aortic aneurysm in an 11-year-old boy.

We present a case of a ruptured aortic aneurysm in an 11-year-old boy presenting with loss of consciousness. The presentation, management, pathology, and gravity of this condition are discussed.