RESUMEN
Vascular anomalies comprise a spectrum of disorders characterized by the abnormal development or growth of blood and lymphatic vessels. These growths have unique features and diverse behaviors, mandating a multidisciplinary approach in their evaluation, diagnosis, and management. Here we describe the case of a male toddler presenting with an abdominal mass, originally treated as a metastatic retroperitoneal tumor, but subsequently felt to represent a vascular anomaly.
Asunto(s)
Hemangioma , Neoplasias Retroperitoneales , Malformaciones Vasculares , Hemangioma/patología , Hemangioma/terapia , Humanos , Masculino , Malformaciones Vasculares/terapiaRESUMEN
Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.
Asunto(s)
Cromosomas Humanos Par 5/genética , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Síndrome de Li-Fraumeni , Trastornos Mieloproliferativos , Neoplasias Primarias Secundarias , Síndrome de Noonan , Rabdomiosarcoma , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Femenino , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/genética , Humanos , Lactante , Síndrome de Li-Fraumeni/epidemiología , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/terapia , Masculino , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/genética , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/genética , Síndrome de Noonan/epidemiología , Síndrome de Noonan/genética , Síndrome de Noonan/terapia , Rabdomiosarcoma/epidemiología , Rabdomiosarcoma/genética , Rabdomiosarcoma/terapia , Adulto JovenRESUMEN
Objectives: The gastric mucosal change accompanying gastric antral intestinal metaplasia (IM) in the pediatric population and its clinical implications remain unclear. Methods: We retrieved all patients younger than 18 years who had upper GI endoscopy with a pathology diagnosis of antral IM between 2009 and 2020. Each biopsy was evaluated for the presence of dysplasia, Helicobacter pylori, gastritis, and other pathologic changes. Results: A total of 134 patients with antral IM were identified; 72 (53.7%) with coexisting pathology including chronic gastritis (n = 22), reactive gastropathy (n = 16), focal mild chronic inflammation (n = 13), gastric eosinophilia (n = 9), chronic active gastritis associated with (n = 2) and without Helicobacter infection (n = 3), and others (n = 7). The remaining 62 (46.3%) showed isolated IM. Gastric IM increased with age, and was often accompanied by other pathologic changes, especially in female children. Twenty-seven patients had follow up biopsies; 11 of the 27 patients (40.7%) showed persistent IM in at least one repeat biopsies. None demonstrated dysplasia. Conclusions: In children, antral IM increases with age and often coexists with other pathologic changes. Gastric IM could persist for at least months to years in a significant subset of patients with chronic gastritis and gastric eosinophilia.
Asunto(s)
Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Niño , Femenino , Gastritis/complicaciones , Gastritis/diagnóstico , Gastritis Atrófica/complicaciones , Gastritis Atrófica/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/diagnóstico , Humanos , Hiperplasia , Metaplasia/complicaciones , Lesiones Precancerosas/complicaciones , Lesiones Precancerosas/epidemiología , Lesiones Precancerosas/patología , Neoplasias Gástricas/patologíaRESUMEN
Langerhans cell histiocytosis (LCH) often has a recurrent and refractory course despite multiagent treatment modalities. Common relapse treatments include intense or prolonged cytotoxic chemotherapy regimens. There are a few prior reports that the nonsteroidal anti-inflammatory drug indomethacin demonstrated activity against bone LCH. Here we report indomethacin as a successful treatment for a case of chronic skin LCH that failed multiple prior chemotherapy regimens. This experience supports the need for trials to investigate indomethacin as a treatment for LCH both in the relapsed or refractory setting as well as potential combination or maintenance therapy in newly diagnosed patients.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Indometacina/uso terapéutico , Enfermedades de la Piel/tratamiento farmacológico , Niño , Histiocitosis de Células de Langerhans/patología , Humanos , Masculino , Pronóstico , Recurrencia , Enfermedades de la Piel/patologíaRESUMEN
The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single-center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies ≤6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell-mediated rejection without clinical dysfunction) is associated with a 5-year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation.
Asunto(s)
Rechazo de Injerto/etiología , Inflamación/epidemiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias , Enfermedades Vasculares/epidemiología , Adolescente , Alabama/epidemiología , Niño , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Incidencia , Pruebas de Función Renal , Masculino , Fenotipo , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Malignant rhabdoid tumors (MRT; atypical teratoid/rhabdoid tumor [ATRT] in the central nervous system) are aggressive tumors in infants and children which can overlap with other sarcomas, such as synovial sarcoma (SS). The gold standard for SS diagnosis is characterization of the t(X;18) chromosomal translocation. However, stratification of cases for molecular analysis is not always straightforward or feasible. Recent literature suggests transducer-like enhancer of split 1 (TLE1) protein expression may distinguish SS from certain histologic mimics; however, this has not been investigated in MRT and ATRT. We stained whole-tissue sections of 18 archived cases of MRT and ATRT with TLE1. Nuclear expression was scored using a 4-tiered (0, 1+, 2+, and 3+) scale describing staining intensity, extent, or combination of both. The majority of MRT and ATRT cases showed some TLE1 immunoreactivity (n = 16; 89% for ≥1 + staining); 14 (78%) of total cases showed ≥2 + positivity using any of the 3 scoring systems. Over half (n = 10; 56%) of cases showed ≥2 + staining; 4 (22%) cases showed 3 + strong and diffuse TLE1 staining measured by all scoring systems in agreement. Although still of potential use, we urge caution in the interpretation of TLE1 when the differential diagnosis includes both SS and MRT or ATRT.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Complejas y Mixtas/diagnóstico , Proteínas Represoras/metabolismo , Tumor Rabdoide/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Teratoma/diagnóstico , Adolescente , Niño , Preescolar , Proteínas Co-Represoras , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Neoplasias Complejas y Mixtas/metabolismo , Tumor Rabdoide/metabolismo , Neoplasias de los Tejidos Blandos/metabolismo , Teratoma/metabolismoRESUMEN
MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.
Asunto(s)
Hiperoxia/metabolismo , MicroARNs/genética , Alveolos Pulmonares/metabolismo , Animales , Animales Recién Nacidos , Displasia Broncopulmonar/metabolismo , Proliferación Celular/genética , Proliferación Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Humanos , Ratones Endogámicos C57BLRESUMEN
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
Asunto(s)
Genoma Humano , Impresión Genómica , Síndrome de Circulación Fetal Persistente/patología , Alveolos Pulmonares/anomalías , Venas Pulmonares/patología , Cromosomas Humanos Par 16/genética , Hibridación Genómica Comparativa , Femenino , Factores de Transcripción Forkhead/genética , Genes Letales , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién Nacido , Masculino , Linaje , Síndrome de Circulación Fetal Persistente/genética , Alveolos Pulmonares/patología , Eliminación de SecuenciaRESUMEN
Neonates and young infants exposed to extracorporeal circulation during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass are at risk of developing a systemic inflammatory response syndrome with multi-organ dysfunction. We used a piglet model of ECMO to investigate the hypothesis that epithelial apoptosis is an early event that precedes villous damage during ECMO-related bowel injury. Healthy 3-week-old piglets were subjected to ECMO for up to 8 h. Epithelial apoptosis was measured in histopathological analysis, nuclear imaging, and terminal deoxynucleotidyl transferase dUTP nick end labeling. Plasma intestinal fatty acid-binding protein (I-FABP) levels were measured by enzyme immunoassay. Intestinal mast cells were isolated by fluorescence-assisted cell sorting. Cleaved caspase-8, caspase-9, phospho-p38 MAPK, and fas ligand expression were investigated by immunohistochemistry, western blots, and reverse transcriptase-quantitative PCR. Piglet ECMO was associated with increased gut epithelial apoptosis. Extensive apoptotic changes were noted on villus tips and in scattered crypt cells after 2 h of ECMO. After 8 h, the villi were denuded and apoptotic changes were evident in a majority of crypt cells. Increased circulating I-FABP levels, a marker of gut epithelial injury, showed that epithelial injury occurred during ECMO. We detected increased cleaved caspase-8, but not cleaved caspase-9, in epithelial cells indicating that the extrinsic apoptotic pathway was active. ECMO was associated with increased fas ligand expression in intestinal mast cells, which was induced through activation of the p38 mitogen-activated protein kinase. We conclude that epithelial apoptosis is an early event that initiates gut mucosal injury in a piglet model of ECMO.
Asunto(s)
Apoptosis/fisiología , Oxigenación por Membrana Extracorpórea/efectos adversos , Mucosa Intestinal/lesiones , Mucosa Intestinal/fisiopatología , Animales , Animales Recién Nacidos , Western Blotting , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Núcleo Celular/ultraestructura , Cartilla de ADN/genética , Ensayo de Inmunoadsorción Enzimática , Proteína Ligando Fas/metabolismo , Proteínas de Unión a Ácidos Grasos/sangre , Citometría de Flujo , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Mucosa Intestinal/citología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no Paramétricas , Porcinos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Although they have been studied for nearly 50 years, the source of the FMNH2 needed for effective biooxidation by the 2,5- and 3,6-diketocamphane monooxygenase (DKCMO) isoenzymes induced by the growth of Pseudomonas putida NCIMB 10007 (ATCC 17453) on camphor remains incompletely characterized. Prior studies have focussed exclusively on enzymes present in cells harvested during late-exponential-phase growth despite considerable circumstantial evidence that the flavin reductase (FR) component of these multicomponent monooxygenases is subject to growth-phase-dependent variation. In this study, a number of alternative FMNH2-generating activities, including both conventional FRs and enzymes also able to serve as ferric reductases, were isolated from camphor-grown cells, and the relative level, and hence potential contribution, of these various proteins shown to vary considerably depending on the point of harvest of NCIMB 10007 within exponential-phase growth. While two constitutive monomeric ferric reductases (molecular masses 27.0 and 28.5 kDa) were found to be the major relevant sources of FMNH2 during the initial stages of growth on camphor-based media, a significant subsequent contribution throughout the mid- to late-exponential phases of growth was also made by the camphor-induced homodimeric 37.0 kDa FR Fred, recently reported to serve such a role exclusively. The possible involvement of camphor-induced putidaredoxin reductase (51.0 kDa) as a contributory activity was also investigated and considered. Studies with highly purified preparations of the isofunctional DKCMOs confirmed the potential of the various reductases to function effectively as sources of the requisite FMNH2 to both monooxygenases at different times throughout growth on camphor.
Asunto(s)
Alcanfor/metabolismo , FMN Reductasa/metabolismo , Isoenzimas/metabolismo , Oxigenasas/metabolismo , Pseudomonas putida/enzimología , Secuencia de Aminoácidos , FMN Reductasa/genética , Isoenzimas/química , Isoenzimas/genética , Datos de Secuencia Molecular , Oxigenasas/química , Oxigenasas/genética , Pseudomonas putida/química , Pseudomonas putida/genética , Pseudomonas putida/crecimiento & desarrollo , Alineación de SecuenciaRESUMEN
Systemic polyarteritis nodosa (PAN) is a vasculitis that affects small to medium-size arteries. Onset in childhood is rare and can cause significant morbidity. Often, cutaneous manifestations can provide early clues toward diagnosis. This article describes a case of childhood systemic PAN that presented with fever, a necrotic skin lesion, and oral ulceration. Intestinal perforation complicated this case. Prompt recognition of childhood PAN is important to prevent serious complications.
Asunto(s)
Inmunosupresores/uso terapéutico , Poliarteritis Nudosa/diagnóstico , Poliarteritis Nudosa/tratamiento farmacológico , Preescolar , Colon/patología , Diagnóstico Precoz , Humanos , Masculino , Morbilidad , Poliarteritis Nudosa/patología , Piel/patologíaRESUMEN
Acute severe hepatitis associated with active human herpesvirus 6 (HHV-6) infection is a rare life-threatening condition with unclear clinical course and histopathology. In this study, we retrospectively analyzed 5 patients with indeterminate acute severe hepatitis found to have active hepatic HHV-6 infection during care. All patients were previously healthy children presenting with a nonspecific prodrome. Four developed acute liver failure (ALF) and 3 received liver transplantation. The explanted livers and biopsies demonstrated a centrilobular pattern of necroinflammation characterized by moderate to marked central perivenulitis and confluent centrilobular to panlobular necrosis in 4 cases, accompanied by marked hepatocellular swelling and milder portal inflammation in 3. Central perivenulitis was more prominent in comparison to a control of group of ALF without HHV-6 ( P =0.01). When compared with the children with acute severe hepatitis associated with adenovirus encountered in the recent outbreak, both central perivenulitis and centrilobular necrosis were significant predictors for association with HHV-6 ( P <0.01). Liver immunohistochemistry detected HHV-6 structural protein in biliary epithelium in all cases and a predominance of CD8 + T cells in the perivenular inflammatory infiltrate. Among the 4 patients with ALF, one received early anti-HHV-6 therapy and had transplant-free survival, while the other 3 received either general prophylactic antiviral treatment only (n=2) or late anti-HHV-6 therapy (n=1) and needed liver transplantation. Our findings were similar to those in previously reported cases. In summary, acute severe hepatitis associated with HHV-6 tends to affect children, progress to ALF, and exhibit characteristic centrilobular necroinflammation which likely represents an immune-mediated process.
Asunto(s)
Herpesvirus Humano 6 , Trasplante de Hígado , Infecciones por Roseolovirus , Humanos , Herpesvirus Humano 6/aislamiento & purificación , Masculino , Estudios Retrospectivos , Infecciones por Roseolovirus/patología , Infecciones por Roseolovirus/virología , Infecciones por Roseolovirus/complicaciones , Femenino , Preescolar , Niño , Lactante , Enfermedad Aguda , Hepatitis Viral Humana/patología , Hepatitis Viral Humana/virología , Fallo Hepático Agudo/virología , Fallo Hepático Agudo/patología , Índice de Severidad de la Enfermedad , Hígado/patología , Hígado/virología , Inmunohistoquímica , Biopsia , AdolescenteRESUMEN
BACKGROUND: Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare tumor with a peak incidence in young adulthood that historically has carried a poor prognosis. OBSERVATIONS: We present 2 advanced stage cases of SCCOHT in preadolescents successfully treated with a combination of cisplatin-based chemotherapy and surgical resection. The more recent patient also underwent consolidative high-dose chemotherapy with stem cell rescue and external beam radiotherapy. Her therapy was concluded with a maintenance course of bevacizumab. The patients are now disease-free 7 years and 30 months, respectively, after diagnosis. CONCLUSIONS: With aggressive multimodal therapy SCCOHT is curable in children.
Asunto(s)
Carcinoma de Células Pequeñas/complicaciones , Carcinoma de Células Pequeñas/terapia , Hipercalcemia/etiología , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/terapia , Carcinoma de Células Pequeñas/diagnóstico , Niño , Terapia Combinada , Femenino , Humanos , Imagen por Resonancia Magnética , Estadificación de Neoplasias , Neoplasias Ováricas/diagnóstico , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Proliferative (cellular) nodules (PN) which mimic malignant melanoma clinically and histologically are described in congenital melanocytic nevi (CMN) and may pose significant diagnostic challenges. We report the case of a 10-day-old male with a giant congenital nevus involving the neck, upper chest, back, and left shoulder containing several nodular lesions, some crusted. Biopsy of a nodule revealed densely packed nevus cells with hyperchromatic round to oval and occasionally irregularly shaped nuclei. There was no necrosis or pushing border, and the nodule blended with the adjacent nevus; however, the lesion demonstrated a significant number of mitoses (27 per mm2) and a 60% labeling index with Ki-67. Further analysis by fluorescence in situ hybridization (FISH) with a 4-color probe set targeting 6p25, 6q23, 11q13, and centromere 6 revealed increased chromosomal copy numbers of all 4 probes, which was interpreted as evidence of polyploidy. In addition, analysis of DNA copy number changes using a single nucleotide polymorphism microarray (Affymetrix, Santa Clara, CA) showed no chromosomal aberrations. The diagnosis of PN in a giant congenital nevus was eventually rendered. At 13-month follow-up, the nodules showed no evidence of growth. Our case illustrates that PNs in the neonatal period might demonstrate extreme mitotic activity. This feature is worrisome when encountered in melanocytic lesions; however, it should not trigger by itself a diagnosis of melanoma in the absence of other histologic criteria of malignancy. In addition, we document polyploidy by FISH in PN, which can potentially be misinterpreted as a FISH-positive result.
Asunto(s)
Proliferación Celular , Melanoma/patología , Mitosis , Nevo Pigmentado/patología , Neoplasias Cutáneas/patología , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Recién Nacido , Antígeno Ki-67/análisis , Masculino , Nevo Pigmentado/química , Nevo Pigmentado/congénito , Nevo Pigmentado/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Poliploidía , Valor Predictivo de las Pruebas , Neoplasias Cutáneas/química , Neoplasias Cutáneas/congénito , Neoplasias Cutáneas/genéticaRESUMEN
A recent increase in reports of severe acute hepatitis of unknown etiology in children is under investigation. Although adenovirus has been frequently detected, its role remains unclear, and systematic histopathologic analysis is lacking. We conducted a retrospective study of 11 children hospitalized between October 2021 and May 2022 with unexplained acute hepatitis and concurrent adenovirus infection. Liver biopsies collected shortly after admission demonstrated moderately to severely active hepatitis in 8/11 (73%) cases, characterized by marked portal mixed inflammation, moderate-to-severe interface activity, and milder lobular inflammation. Clusters of plasma cells were present in 6/11 (55%) cases, mimicking autoimmune hepatitis. Semiquantitative scoring of 17 discrete histologic features found that greater degrees of portal inflammation, interface activity, bile duct injury, bile ductular reaction, lobular inflammation, Kupffer cell activation, and hepatocyte focal necrosis were significantly more common in these cases in comparison to the control group of unexplained acute severe hepatitis without adenovirus infection. Liver biopsy immunohistochemistry was negative for adenovirus in all cases. Polymerase chain reaction testing of liver tissue was positive for the enteric adenovirus serotypes 41 (species F) in 10/11 (91%) cases. An immunoprofile study of hepatic infiltrating lymphocytes in 1 patient revealed the presence of large numbers of CD3 + and CD4 + lymphocytes. Nine patients received supportive treatment without steroids and recovered without the need for liver transplantation. In summary, liver injury in children with severe acute hepatitis and adenovirus infection is characterized by a hepatitic pattern that resembles severe autoimmune hepatitis and may represent an immune-mediated process associated with viral infection.
Asunto(s)
Infecciones por Adenoviridae , Hepatitis Autoinmune , Humanos , Niño , Hepatitis Autoinmune/patología , Estudios Retrospectivos , Hígado/patología , Inflamación/patología , Infecciones por Adenoviridae/complicaciones , Infecciones por Adenoviridae/patología , Linfocitos T CD4-PositivosRESUMEN
BACKGROUND & AIMS: Premature neonates are predisposed to necrotizing enterocolitis (NEC), an idiopathic, inflammatory bowel necrosis. We investigated whether NEC occurs in the preterm intestine due to incomplete noninflammatory differentiation of intestinal macrophages, which increases the risk of a severe mucosal inflammatory response to bacterial products. METHODS: We compared inflammatory properties of human/murine fetal, neonatal, and adult intestinal macrophages. To investigate gut-specific macrophage differentiation, we next treated monocyte-derived macrophages with conditioned media from explanted human fetal and adult intestinal tissues. Transforming growth factor-ß (TGF-ß) expression and bioactivity were measured in fetal/adult intestine and in NEC. Finally, we used wild-type and transgenic mice to investigate the effects of deficient TGF-ß signaling on NEC-like inflammatory mucosal injury. RESULTS: Intestinal macrophages in the human preterm intestine (fetus/premature neonate), but not in full-term neonates and adults, expressed inflammatory cytokines. Macrophage cytokine production was suppressed in the developing intestine by TGF-ß, particularly the TGF-ß(2) isoform. NEC was associated with decreased tissue expression of TGF-ß(2) and decreased TGF-ß bioactivity. In mice, disruption of TGF-ß signaling worsened NEC-like inflammatory mucosal injury, whereas enteral supplementation with recombinant TGF-ß(2) was protective. CONCLUSIONS: Intestinal macrophages progressively acquire a noninflammatory profile during gestational development. TGF-ß, particularly the TGF-ß(2) isoform, suppresses macrophage inflammatory responses in the developing intestine and protects against inflammatory mucosal injury. Enterally administered TGF-ß(2) protected mice from experimental NEC-like injury.
Asunto(s)
Citocinas/metabolismo , Enterocolitis Necrotizante/inmunología , Intestinos/crecimiento & desarrollo , Macrófagos/metabolismo , Factor de Crecimiento Transformador beta2/metabolismo , Adulto , Animales , Células Cultivadas , Quimiotaxis de Leucocito , Humanos , Recién Nacido , Intestinos/inmunología , Lipopolisacáridos/metabolismo , Activación de Macrófagos , Ratones , Ratones Transgénicos , FN-kappa B/metabolismo , Neutrófilos/metabolismo , Factor de Crecimiento Transformador beta2/farmacologíaRESUMEN
To evaluate the consequences of expression of the protein encoded by PAX3-FOXO1 (P3F) in the pediatric malignancy alveolar rhabdomyosarcoma (A-RMS), we developed and evaluated a genetically defined in vitro model of A-RMS tumorigenesis. The expression of P3F in cooperation with simian virus 40 (SV40) Large-T (LT) antigen in murine C3H10T1/2 fibroblasts led to robust malignant transformation. Using 2-dimensional-difference gel electrophoresis (2D-DIGE), we compared proteomes from lysates from cells that express P3F + LT versus from cells that express LT alone. Analysis of 2D gel spot patterns by DeCyder image analysis software indicated 93 spots that were different in abundance. Peptide mass fingerprint analysis of the 93 spots by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis identified 37 nonredundant proteins. 2D-DIGE analysis of cell culture media conditioned by cells transduced by P3F + LT versus by LT alone found 29 spots in the P3F + LT cells leading to the identification of 11 nonredundant proteins. A substantial number of proteins with potential roles in tumorigenesis and myogenesis were detected, most of which have not been identified in previous wide-scale expression studies of RMS experimental models or tumors. We validated the 2D gel image analysis findings by Western blot analysis and immunohistochemistry (IHC). Thus, the 2D-DIGE proteomics methodology described here provided an important discovery approach to the study of RMS biology and complements the findings of previous mRNA expression studies.
Asunto(s)
Electroforesis en Gel Bidimensional , Proteínas de Neoplasias/metabolismo , Proteoma/análisis , Proteómica , Rabdomiosarcoma Alveolar/metabolismo , Animales , Antígenos Transformadores de Poliomavirus , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Western Blotting , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Medios de Cultivo Condicionados , Fibroblastos , Humanos , Inmunohistoquímica , Ratones , Modelos Biológicos , Desarrollo de Músculos , Mapeo Peptídico , Proteoma/metabolismo , Reproducibilidad de los Resultados , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
The fetal lung vasculature forms in tandem with developing airways. Whereas saccular airway morphogenesis is arrested in bronchopulmonary dysplasia (BPD), the potential vascular phenotype in BPD at this stage of development is less well-understood. As inflammation increases the risk of BPD and induces arrest of saccular airway morphogenesis, we tested the effects of Escherichia coli LPS on fetal mouse lung vascular development. Injecting LPS into the amniotic fluid of Tie2-lacZ endothelial reporter mice at embryonic day 15 stimulated angiogenesis in the saccular stage fetal lung mesenchyme. LPS also increased the number of endothelial cells in saccular stage fetal mouse lung explants. Inflammation appeared to directly promote vascular development, as LPS stimulated pulmonary microvascular endothelial cell angiogenesis, cell migration, and proliferation in vitro. Whereas LPS did not increase expression of VEGF, angiopoietin-1 (Ang-1), Tie2, fetal liver kinase-1 (Flk-1), fms-like tyrosine kinase-1 (Flt-1), PDGFA, PDGFB, heparin-binding EGF-like growth factor (HB-EGF), or connective tissue growth factor (CTGF), LPS did stimulate the production of the angiogenic CC chemokines macrophage inflammatory protein-1α (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1). Both MIP-1α and MCP-1 increased angiogenesis in fetal mouse lung explants. In addition, inhibitory antibodies against MIP-1α and MCP-1 blocked the effects of LPS on fetal lung vascular development, suggesting these chemokines are downstream mediators of LPS-induced angiogenesis. We speculate that an inflammation-mediated surge in angiogenesis could lead to formation of aberrant alveolar capillaries in the lungs of patients developing BPD.
Asunto(s)
Quimiocinas CC/metabolismo , Corioamnionitis/inmunología , Pulmón/irrigación sanguínea , Pulmón/embriología , Neovascularización Fisiológica , Animales , Displasia Broncopulmonar/embriología , Displasia Broncopulmonar/etiología , Displasia Broncopulmonar/inmunología , Estudios de Casos y Controles , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/farmacología , Quimiocina CCL3/antagonistas & inhibidores , Quimiocina CCL3/farmacología , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Femenino , Humanos , Inmunidad Innata , Lactante , Recién Nacido , Lipopolisacáridos/farmacología , Pulmón/anomalías , Pulmón/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/inmunología , EmbarazoRESUMEN
Extracorporeal membrane oxygenation (ECMO) is a life-saving support system used in neonates and young children with severe cardiorespiratory failure. Although ECMO has reduced mortality in these critically ill patients, almost all patients treated with ECMO develop a systemic inflammatory response syndrome (SIRS) characterized by a 'cytokine storm', leukocyte activation, and multisystem organ dysfunction. We used a neonatal porcine model of ECMO to investigate whether rising plasma concentrations of inflammatory cytokines during ECMO reflect de novo synthesis of these mediators in inflamed tissues, and therefore, can be used to assess the severity of ECMO-related SIRS. Previously healthy piglets (3-week-old) were subjected to venoarterial ECMO for up to 8 h. SIRS was assessed by histopathological analysis, measurement of neutrophil activation (flow cytometry), plasma cytokine concentrations (enzyme immunoassays), and tissue expression of inflammatory genes (PCR/western blots). Mast cell degranulation was investigated by measurement of plasma tryptase activity. Porcine neonatal ECMO was associated with systemic inflammatory changes similar to those seen in human neonates. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) concentrations rose rapidly during the first 2 h of ECMO, faster than the tissue expression of these cytokines. ECMO was associated with increased plasma mast cell tryptase activity, indicating that increased plasma concentrations of inflammatory cytokines during ECMO may result from mast cell degranulation and associated release of preformed cytokines stored in mast cells. TNF-alpha and IL-8 concentrations rose faster in plasma than in the peripheral tissues during ECMO, indicating that rising plasma levels of these cytokines immediately after the initiation of ECMO may not reflect increasing tissue synthesis of these cytokines. Mobilization of preformed cellular stores of inflammatory cytokines such as in mucosal mast cells may have an important pathophysiological role in ECMO-related SIRS.
Asunto(s)
Citocinas/metabolismo , Oxigenación por Membrana Extracorpórea/efectos adversos , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Animales , Animales Recién Nacidos , Proteína C-Reactiva/metabolismo , Degranulación de la Célula , Citocinas/sangre , Citocinas/genética , Femenino , Hemodinámica , Mediadores de Inflamación/sangre , Interleucina-8/sangre , Recuento de Leucocitos , Masculino , Mastocitos/metabolismo , Activación Neutrófila , Concentración Osmolar , Porcinos , Síndrome de Respuesta Inflamatoria Sistémica/patología , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Factores de Tiempo , Activación Transcripcional , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Renal medullary carcinoma (RMC) is a rare and aggressive malignancy seen primarily in patients with sickle-cell trait. We report a complete response to carboplatin, paclitaxel, and gemcitabine in a patient with advanced metastatic RMC.