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1.
J Am Acad Dermatol ; 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39181404

RESUMEN

BACKGROUND: Pediatric Mycosis Fungoides (MF) management extrapolates from adult guidelines, despite differing clinical aspects. Recommendations are essential to address unique challenges in this distinct patient group. OBJECTIVE: This project aims to derive consensus recommendations for pediatric MF management. METHODS: Experts from pediatric dermatology, general dermatology, dermato-pathology, and pediatric hematology-oncology (N=83) were invited to contribute to consensus recommendations. The process involved three eDelphi rounds, concluding with a final consensus meeting using a modified Nominal Group Technique for unresolved items. RESULTS: Consensus included more clinical severity measures than TNMB staging: pruritus, functional or esthetic impairment (e.g., palms, soles, genitalia), quality of life impact, and psychological aspects (e.g., embarrassment, anxiety, depression), plus parental anxiety. Ten recommendations were made for managing early and advanced pediatric MF. Disagreement emerged in choosing therapies beyond stage I of the disease. DISCUSSION: This multinational initiative aimed to standardize optimal pediatric MF management and successfully generated consensus recommendations. Additional work is needed for structured, prospective protocols in advanced-stage pediatric MF. LIMITATIONS: Lack of pediatric hematologists-oncologists and patients' representatives. CONCLUSION: Documentation of extended clinical severity and outcome measures is recommended. Addressing the need for structured protocols in advanced-stage pediatric MF and implementing systematic, prospective data collection is crucial..

2.
J Autoimmun ; 137: 102946, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36402602

RESUMEN

BACKGROUND: Genetic aberrations in the NFκB pathway lead to primary immunodeficiencies with various degrees of severity. We previously demonstrated that complete ablation of the RelB transcription factor, a key component of the alternative pathway, results in an early manifested combined immunodeficiency requiring stem cell transplantation. OBJECTIVE: To study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients. METHODS: Whole exome sequencing was performed to identify the genetic defect. Molecular and cellular techniques were utilized to assess the variant impact on NFκB signaling, canonical and alternative pathway crosstalk, as well as the resultant effects on immune function. RESULTS: Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life. This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+ cells. Whole exome sequencing identified a novel homozygous c. C1091T (P364L) transition in RELB. The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation. Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function. This is likely the main driver of autoimmune manifestations in these patients. CONCLUSION: Incomplete loss of RelB provided a unique opportunity to gain insights into NFκB's pathway interactions as well as the pathogenesis of autoimmunity. The P364L RelB mutation leads to gradual decline in immune function with progression of severe debilitating autoimmunity.


Asunto(s)
Enfermedades Autoinmunes , Factor de Transcripción ReIB , Humanos , Factor de Transcripción ReIB/genética , Factor de Transcripción ReIB/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Regulación de la Expresión Génica , Enfermedades Autoinmunes/genética
3.
Pediatr Blood Cancer ; 70(12): e30674, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37715724

RESUMEN

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS). PROCEDURE: Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed. RESULTS: We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS. CONCLUSION: Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.

4.
J Pediatr Hematol Oncol ; 45(4): e530-e533, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36716052

RESUMEN

Differentiating hepatoblastomas from other congenital benign hepatic tumors is key to surgical management. We, herein, present an unusual case of an antenatally diagnosed liver lesion assessed in the neonatal period. Because of its predominantly cystic ultrasound/MRI appearance and borderline alpha-fetoprotein serum levels the diagnosis of mesenchymal hamartoma was favored and protocol-based tumor resection was performed. Due to the intraoperative diagnosis of a fetal subtype of hepatoblastoma with positive resection margins the child had to undergo a second laparotomy. This report raises awareness to an unusual appearance of hepatoblastoma and discusses noninvasive imaging clues to consider atypical appearances of hepatoblastoma preoperatively as they can have profound implications in patient management.


Asunto(s)
Hamartoma , Hepatoblastoma , Neoplasias Hepáticas , Recién Nacido , Niño , Humanos , Hepatoblastoma/diagnóstico , Hepatoblastoma/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Imagen por Resonancia Magnética , Hamartoma/diagnóstico por imagen , Hamartoma/cirugía
5.
Am J Respir Crit Care Med ; 205(7): 761-768, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35023825

RESUMEN

Rationale: Mucin homeostasis is fundamental to airway health. Upregulation of airway mucus glycoprotein MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear. Objectives: The goal of this study was to identify and characterize a family with congenital absence of MUC5B protein. Methods: We performed whole-genome sequencing in an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. Deep phenotyping over a 12-year period included assessments of pulmonary radioaerosol mucociliary clearance. Genotyping with reverse phenotyping was organized for eight family members. Extensive experiments, including immunofluorescence staining and mass spectrometry for mucins, were performed across accessible sample types. Measurements and Main Results: The proband, and her symptomatic sibling who also had extensive sinus disease with nasal polyps, were homozygous for a novel splicing variant in the MUC5B gene (NM_002458.2: c.1938 + 1G>A). MUC5B was absent from saliva, sputum, and nasal samples. Mucociliary clearance was impaired in the proband, and large numbers of apoptotic macrophages were present in sputum. Three siblings heterozygous for the familial MUC5B variant were asymptomatic but had a shared pattern of mild lung function impairments. Conclusions: Congenital absence of MUC5B defines a new category of genetic respiratory disease. The human phenotype is highly concordant with that of the Muc5b-/- murine model. Further study of individuals with decreased MUC5B production could provide unique mechanistic insights into airway mucus biology.


Asunto(s)
Enfermedades Pulmonares , Mucinas , Adulto , Animales , Femenino , Humanos , Pulmón/metabolismo , Enfermedades Pulmonares/metabolismo , Ratones , Mucina 5AC/genética , Mucina 5B/genética , Mucinas/metabolismo , Depuración Mucociliar/genética , Moco/metabolismo
6.
Pediatr Dev Pathol ; 25(3): 330-333, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34996321

RESUMEN

Congenital pseudodiverticula of the esophagus are very rare. This case report describes the presentation, management and histopathology of a peudodiverticulum of the cervical esophagus in a neonate. The infant presented with respiratory distress and a right neck mass that required surgical excision. Pathology revealed a pseudodiverticulum that contained ectopic thymic, thyroid, and parathyroid tissue within the wall of the lesion. The presence of ectopic tissues of branchial origin and an aberrant right subclavian artery suggest an error in branchial development and neural crest cell migration.


Asunto(s)
Coristoma , Cuello , Coristoma/diagnóstico , Coristoma/cirugía , Esófago , Humanos , Lactante , Recién Nacido , Arteria Subclavia
7.
J Allergy Clin Immunol ; 147(2): 727-733.e2, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32980423

RESUMEN

BACKGROUND: Genetic faults in several components of the nuclear factor-κB pathway cause immunodeficiency. Most defects lead to combined immunodeficiency with a range of severity. Heterozygous mutations in NFKB1 were associated with common variable immunodeficiency, however, homozygous mutations have not been described. OBJECTIVE: We studied the molecular basis of combined immunodeficiency in a patient who presented with failure to thrive, persistent EBV viremia and hepatitis, pneumocystis jirovecii pneumonitis, and generalized lymphadenopathy. METHODS: Whole genome and exome sequencing followed by Sanger confirmation were performed to identify the genetic defect. Molecular and cellular techniques were used to assess the variant impact on the nuclear factor-κB pathway and lymphocyte function. RESULTS: Genetic analysis revealed a novel homozygous mutation in NFKB1, c.2878G>A, p.Gly960Arg (G960R). This affected p105 phosphorylation and p50 formation on antigen and cytokine stimulation, as well as attenuating nuclear signal transmission. As a result, both T- and B-cell maturation and function were perturbed. The number of memory CD4+ T cells were reduced, while CD8+ T cells consisted predominately of expanded differentiated populations. The function of T cells were diminished as shown by reduced responses to mitogens as well as diminished cytokine secretion. B-cell maturation was also affected, with decreased IgD+CD27+ memory B cells while transitional B cells were increased, likely contributing to the reduced ability to produce specific antibodies. CONCLUSION: Homozygous G960R mutation in NFKB1 leads to a severe clinical presentation of combined immunodeficiency. This was associated with blockade of nuclear factor-κB pathway signaling, resulting in aberrations in T- and B-cell maturation and function.


Asunto(s)
Subunidad p50 de NF-kappa B/genética , Inmunodeficiencia Combinada Grave/genética , Homocigoto , Humanos , Lactante , Masculino , Mutación , Linaje
8.
Pediatr Dev Pathol ; 24(4): 366-370, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33729851

RESUMEN

Post-hematopoietic stem cell transplant secondary solid neoplasms are uncommon and usually host-derived. We describe a 6-year-old female who developed a mixed donor-recipient origin mesenchymal stromal tumor-like lesion in the liver following an unrelated hematopoietic stem cell transplant complicated by severe graft-versus-host disease. This lesion arose early post-transplant in association with hepatic graft-versus-host disease. At 12 years post-transplant, the neoplasm has progressively shrunken in size and the patient remains well with no neoplasm-associated sequelae. This report characterizes a novel lesion of mixed origin post-transplant and offers unique insights into the contribution of bone marrow-derived cells to extra-medullary tissues.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neoplasias Hepáticas/etiología , Hígado/patología , Células Madre Mesenquimatosas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Proliferación Celular , Niño , Femenino , Enfermedad Injerto contra Huésped/complicaciones , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Trasplante Homólogo
9.
Pediatr Radiol ; 51(2): 273-281, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33030586

RESUMEN

BACKGROUND: No study has evaluated the diagnostic accuracy of sonography for the depiction of metastatic cervical adenopathy in children with differentiated thyroid carcinoma at presentation or determined which sonographic features are most useful. OBJECTIVE: To evaluate the diagnostic accuracy of sonography for identifying metastatic cervical adenopathy in children with differentiated thyroid carcinoma at presentation and to determine the most useful sonographic features. MATERIALS AND METHODS: We evaluated cervical lymph node sonography and histology in children with proven thyroid carcinoma in a 10-year period. We excluded children in whom a preoperative sonogram was not available and those who did not have surgical resection of lymph nodes. We used histology as the gold standard. On sonography, we analyzed the size, shape, echotexture and vascularity of the lymph nodes and correlated these findings with the histology. RESULTS: We reviewed sonograms and histology of resected lymph nodes in 52 children and adolescents with proven differentiated thyroid carcinoma (33 females; ages 5-18 years, mean 13.2 years). Metastatic cervical lymph node disease was proved on histology in 33/52 (64%) of our patients at presentation. Sonographic findings correctly predicted whether the nodes were histologically involved with metastatic disease in 42/52 (81%). Sensitivity of sonography was 79%, specificity 84%, positive predictive value (PPV) 90%, negative predictive value (NPV) 70% and accuracy 81%. A significant association was seen between round shape (P=0.0002), abnormal echotexture (P≤0.0001) and vascularity (P≤0.0001), and abnormal lymph node histology. Importantly, in 11/26 (47%) patients with sonographic and histologically proven abnormal nodes, the nodes were normal in size and shape and the presence of metastatic involvement was recognized sonographically only on the basis of abnormal echogenicity and vascularity. CONCLUSION: Sonography has a high accuracy, specificity and PPV for identifying metastatic cervical lymph node involvement in children with differentiated thyroid carcinoma at presentation. Most of the abnormal lymph nodes were round in shape and had abnormal echogenicity and vascularity. Importantly, this paper emphasizes that in children, nodes with histologically proven metastases from differentiated thyroid carcinoma can be normal in size and shape. In these patients the presence of metastatic involvement might be recognized sonographically only on the basis of abnormal echogenicity and vascularity.


Asunto(s)
Carcinoma Papilar , Linfadenopatía , Neoplasias de la Tiroides , Adolescente , Niño , Preescolar , Femenino , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática/diagnóstico por imagen , Cuello/diagnóstico por imagen , Sensibilidad y Especificidad , Neoplasias de la Tiroides/diagnóstico por imagen , Ultrasonografía
10.
Am J Transplant ; 19(10): 2764-2774, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30884098

RESUMEN

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital-based registry, we identified biopsy-proven cases of PTLD among children during a 15-year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow-up after the diagnosis of PTLD. We studied 82 patients with first-episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2-12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan-Meier survival curves showed that T/A PTLD was associated with decreased all-cause mortality compared with PTLD at other sites (log-rank 0.004), even after adjustment for histological subtype (P = .047). PTLD-related mortality was also decreased among T/A PTLD (log-rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence.


Asunto(s)
Trastornos Linfoproliferativos/mortalidad , Trasplante de Órganos/mortalidad , Complicaciones Posoperatorias/mortalidad , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/patología , Masculino , Trasplante de Órganos/efectos adversos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/patología , Pronóstico , Sistema de Registros/estadística & datos numéricos , Factores de Riesgo , Tasa de Supervivencia
11.
Pediatr Blood Cancer ; 66(9): e27822, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31136091

RESUMEN

BACKGROUND: Lymphoid malignancies other than acute lymphoblastic leukemia (ALL) are rare in children with Down syndrome (DS). Information about the toxicity of chemotherapy and prognosis is largely derived from the experience of children with DS and ALL or children without DS. PROCEDURE: We describe the treatment and outcome of two unusual lymphoid malignancies in children with DS. One patient was diagnosed with Burkitt lymphoma (BL) and the second, after treatment for B precursor ALL, with T-cell EBV-positive proliferative disorder (LPD). RESULTS: BL was treated with standard doses of LMB group B therapy subsequently intensified to group C therapy, including high-dose methotrexate (HD-MTX, 3-8 g/m2 ). The patient did not experience excessive toxicity and remains in complete remission 13 months later. Despite presentation with disseminated disease the patient with T-cell EBV-positive LPD after treatment for B precursor ALL responded to dexamethasone and rituximab and remains in complete remission two years later. CONCLUSIONS: Upfront reduction of the high treatment intensity, which is associated with excellent survival outcomes in BL, may not be warranted in all children with DS. Response to therapy and prognosis of T-cell EBV-positive LPD in a patient with DS was not predicted by reported experience in the absence of DS.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Burkitt , Síndrome de Down , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/virología , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Herpesvirus Humano 4 , Humanos , Masculino , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/virología , Linfocitos T/virología
12.
Pediatr Dev Pathol ; 22(4): 365-369, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30497332

RESUMEN

Hepatic mesenchymal hamartoma is a rare benign neoplasm principally encountered in young children. Its origin is unknown. We report an unusual hepatic mesenchymal hamartoma in a 7-month-old girl, including histopathologic findings, immunophenotype, and karyotype. Chromosomal microarray analysis of tumoral tissue and circulating lymphocytes found 4 copies of a segment at 1q44 and fluorescence in situ hybridization indicated tandem triplication, ascribed to expansion of a paternal tandem duplication. This genetic abnormality may have played a role in pathogenesis.


Asunto(s)
Hamartoma/genética , Neoplasias Hepáticas/genética , Cariotipo Anormal , Femenino , Hamartoma/diagnóstico por imagen , Hamartoma/patología , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Lactante , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Mesodermo/diagnóstico por imagen , Mesodermo/patología
13.
Pediatr Dermatol ; 36(6): 902-905, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31359449

RESUMEN

Dieulafoy's lesion (DL) is a small gastrointestinal (GI) mucosal erosion due to an abnormally large caliber and persistent submucosal arteriole. Typically occurring in adults, they are an extremely rare cause of GI bleeding in pediatrics. We report a case of multiple jejunal DLs in a 9-year-old girl with posterior fossa brain malformations, hemangiomas, arterial lesions, cardiac abnormalities, eye abnormalities (PHACE) syndrome, and the first described use of rapamycin in the treatment of pediatric DLs.


Asunto(s)
Coartación Aórtica/complicaciones , Malformaciones Arteriovenosas/etiología , Anomalías del Ojo/complicaciones , Hemorragia Gastrointestinal/etiología , Enfermedades del Yeyuno/etiología , Yeyuno/irrigación sanguínea , Síndromes Neurocutáneos/complicaciones , Malformaciones Arteriovenosas/cirugía , Niño , Endoscopía Gastrointestinal , Femenino , Hemorragia Gastrointestinal/cirugía , Humanos , Enfermedades del Yeyuno/cirugía
14.
J Clin Ultrasound ; 47(2): 100-103, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30393869

RESUMEN

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, benign neoplasm of neural crest origin more commonly seen in the craniofacial region. We report a case of MNTI of the epididymis in a 6-month-old male child with emphasis on the sonographic appearance which has not been previously described. In this case, the mass was inseparable from the testicle and therefore the differential diagnosis considered both extratesticular and intratesticular masses. MNTI should be added to the differential diagnosis of scrotal masses, particularly if they present in a child younger than 12 months of age.


Asunto(s)
Epidídimo/diagnóstico por imagen , Epidídimo/patología , Neoplasias de los Genitales Masculinos/diagnóstico por imagen , Tumor Neuroectodérmico Melanótico/diagnóstico por imagen , Escroto/patología , Diagnóstico Diferencial , Neoplasias de los Genitales Masculinos/patología , Humanos , Lactante , Masculino , Tumor Neuroectodérmico Melanótico/patología , Escroto/diagnóstico por imagen , Ultrasonografía
15.
Histopathology ; 70(6): 861-868, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27926786

RESUMEN

AIMS: NUT midline carcinoma (NMC) is a rare undifferentiated and aggressive carcinoma that locates characteristically to the midline of the head and neck, and mediastinum. NMC is characterized by chromosomal rearrangements of the gene NUT, at 15q14. The BRD4 gene on 19q13 is the most common translocation partner forming a fusion oncogene, BRD4-NUT. By the end of 2014, the International NUT Midline Carcinoma Registry had 48 patients treated for NMC. Laryngeal NMC are exceedingly rare, and we report a case series of seven cases. METHODS AND RESULTS: We searched for cases in files of different hospitals as well as a thorough search of the English language literature. The diagnosis of NMC is made by demonstration of NUT rearrangement either by immunohistochemistry, fluorescence in-situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR). We found three previously published cases, and in this series add four cases of our own. CONCLUSIONS: NMC consists of monomorphic, often discohesive, cells with an epithelioid appearance and distinct nucleoli. The tumours typically show abrupt squamous differentiation. The mean age of the patients was 34 years, hence significantly lower than that for conventional laryngeal carcinoma. All tumours were located in the supraglottis and five patients died of the disease after 3, 7, 8, 9 and 11 months. Laryngeal NMC may be underdiagnosed, and an increased awareness among pathologists is warranted. NMC has characteristic morphological features, and positive immunostaining with the NUT antibody is diagnostic. Its aggressive behaviour demands a very intense treatment strategy and the need for its recognition is emphasized further by new promising treatment strategies.


Asunto(s)
Carcinoma/patología , Neoplasias Laríngeas/patología , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Adolescente , Adulto , Anciano , Carcinoma/diagnóstico , Carcinoma/genética , Niño , Preescolar , Femenino , Humanos , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias
16.
Pediatr Blood Cancer ; 63(11): 1886-94, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27229270

RESUMEN

Primary cutaneous lymphomas are rare in children and mostly represented by mycosis fungoides and CD30(+) lymphoproliferative disorders. Most pediatric cutaneous lymphomas have similar clinical/pathological features as their adult counterparts, particularly the T-cell subtypes. With regard to outcome, adult cutaneous mature T-cell lymphomas have a tendency to progression, while this appears to be relatively infrequent in children. The outcome of cutaneous B-cell lymphomas depends on subtype, with the B-lymphoblastic entity being associated with similar outcomes to precursor B acute lymphoblastic leukemia, while there are insufficient data on other entities. The diagnosis and treatment of these patients require a close collaboration between experienced pediatric pathologists, dermatologists, and oncologists. Prospective collection of longitudinal clinical and biological data from children with these rare lymphomas is needed to better understand their biological and clinical behavior and to ultimately discover the best therapeutic strategies.


Asunto(s)
Linfoma Cutáneo de Células T/terapia , Micosis Fungoide/terapia , Neoplasias Cutáneas/terapia , Adolescente , Niño , Humanos , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/mortalidad , Papulosis Linfomatoide/terapia , Estudios Prospectivos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/mortalidad
17.
J Autoimmun ; 65: 90-100, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26385063

RESUMEN

Multiple receptors that control cell growth and inflammation activate the NFκB pathway that comprises of two pathways. Dysfunction of the classical pathway leads to impaired adaptive and innate immunity in humans. In contrast the exact role of the alternative NFκB pathway mediated by RelB in humans remains largely elusive. We have recently identified deleterious mutations in RelB in patients with combined immunodeficiency and autoimmunity. We studied here the biological effects of RelB deficiency on the immune system. We show that the thymus in this patient is dysplastic and consequently new thymus emigrants are rare and there is an accumulation of CD45 RO(+) T cells with an increase in CD62L(+) central memory cells. The TCR repertoire of these cells appears skewed with selective clonal expansion. In vitro responses to T cell mitogens were markedly depressed and so were PHA induced IL2 and IFNγ production. In addition, the TH1 promoting T bet and STAT1 were reduced. In contrast, hyper-activation was seen in response to anti-CD3 and CD28. T cell dependent antibody responses were low to absent in all patients. We found that BAFF-R was reduced and CD40 signaling aberrant. Critically, CD27(+) memory cells were absent. We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies. T cell maturation in the thymus appears altered with reduced output and production of a skewed T cell repertoire with expansion of clones which are likely the cause of the autoimmune features observed in these patients.


Asunto(s)
Linfocitos B/fisiología , Subgrupos de Linfocitos T/fisiología , Timo/anomalías , Factor de Transcripción ReIB/inmunología , Autoinmunidad , Diferenciación Celular/genética , Proliferación Celular , Preescolar , Humanos , Lactante , Recién Nacido , Interleucina-2/inmunología , Masculino , Subunidad p50 de NF-kappa B/inmunología , Transducción de Señal/inmunología , Timo/inmunología , Timo/patología , Factor de Transcripción ReIB/genética
18.
Pediatr Radiol ; 45(12): 1796-802, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26162466

RESUMEN

BACKGROUND: Angiomatoid fibrous histiocytoma is a rare soft-tissue tumor that more often affects children and young adults. There is little information available regarding the imaging appearance of angiomatoid fibrous histiocytoma in children. OBJECTIVE: To describe the ultrasonographic (US) and magnetic resonance (MR) imaging findings of angiomatoid fibrous histiocytoma in children. MATERIALS AND METHODS: A retrospective analysis was done of US and MR imaging findings in children with angiomatoid fibrous histiocytoma. Clinical findings and histopathology with molecular analysis results were also collected. RESULTS: There were 7 children with angiomatoid fibrous histiocytoma with a median age of 6 years (age range: 16 months-14 years). Patients presented clinically with a soft-tissue mass in the extremities or in the trunk. Four children had anemia, and three of them had additional systemic symptoms. Two patients had US and three had MR imaging while the remaining two had both. Lesion size ranged from 1.3 cm to 7.2 cm. In four patients, angiomatoid fibrous histiocytoma presented as a nonspecific predominantly solid mass. The other three patients had a combination of the following imaging findings: intralesional blood-filled cystic spaces with fluid-fluid levels, enhancing fibrous pseudocapsule and hemosiderin deposition. These findings correlated well with histopathology. CONCLUSION: The imaging detection of intralesional blood-filled cystic spaces with fluid-fluid levels, enhancing fibrous pseudocapsule and hemosiderin deposition in a soft-tissue tumor in a child may suggest the diagnosis of angiomatoid fibrous histiocytoma. A history of systemic symptoms and anemia in the presence of a soft-tissue mass may also be a clue for the diagnosis of angiomatoid fibrous histiocytoma.


Asunto(s)
Histiocitoma Fibroso Maligno/diagnóstico por imagen , Histiocitoma Fibroso Maligno/patología , Imagen por Resonancia Magnética , Adolescente , Niño , Preescolar , Extremidades/diagnóstico por imagen , Extremidades/patología , Femenino , Humanos , Lactante , Masculino , Reproducibilidad de los Resultados , Estudios Retrospectivos , Tórax/diagnóstico por imagen , Tórax/patología , Ultrasonografía
19.
J Allergy Clin Immunol ; 133(3): 807-17, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24239102

RESUMEN

BACKGROUND: Mutations in the gene for the signal transducer and activator of transcription 1, STAT1, have been shown to be associated with death at an early age due to overwhelming viral infection (complete STAT1 deficiency) or, more commonly, selective deficiencies to mycobacterial or fungal infection (typically heterozygous STAT1 mutations). OBJECTIVES: To define the molecular basis of progressive combined immunodeficiency in a group of patients with fatal infections. METHODS: We studied a group of unrelated patients who displayed an unusual progressive form of combined immunodeficiency. Whole exome sequencing assisted in confirming a common genetic defect in this group, which consisted of a heterozygous mutation of the STAT1 gene. STAT1 protein level as well as function was assessed, and a detailed evaluation of the immune system, including analysis of thymus tissue, was performed. RESULTS: Patients were found to carry de novo heterozygous mutations in STAT1 encoding T385A, I294T, or C284R amino acid substitutions. STAT1 expression appeared significantly decreased as a result of these changes but not completely absent, with diminished signaling responses. This group display progressive loss in lymphocyte number and function accompanied by increasing autoimmune features as well as severe, fatal infections. CONCLUSIONS: These findings show that some heterozygous aberrations of STAT1 can be associated with progressive combined immunodeficiency, quite distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. These mutations were not inherited, rather, arose de novo in each case. Accompanied by significant patient mortality, this finding suggests that this class of STAT1 mutation is ultimately fatal due to overwhelming infection.


Asunto(s)
Síndromes de Inmunodeficiencia/genética , Mutación , Factor de Transcripción STAT1/genética , Adolescente , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Síndromes de Inmunodeficiencia/mortalidad , Masculino , Factor de Transcripción STAT1/análisis , Factor de Transcripción STAT1/fisiología , Receptor fas/análisis
20.
Angiogenesis ; 17(3): 641-59, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24510304

RESUMEN

Chronic intestinal inflammation is associated with pathological angiogenesis that further amplifies the inflammatory response. Vascular endothelial growth factor (VEGF), is a major angiogenic cytokine that has been implicated in chronic colitis and inflammatory bowel diseases. Endoglin (CD105), a transforming growth factor-ß superfamily co-receptor expressed on endothelial and some myeloid cells, is a modulator of angiogenesis involved in wound healing and potentially in resolution of inflammation. We showed previously that Endoglin heterozygous (Eng (+/-)) mice subjected to dextran sodium sulfate developed severe colitis, abnormal colonic vessels and high tissue VEGF. We therefore tested in the current study if treatment with a monoclonal antibody to VEGF could ameliorate chronic colitis in Eng (+/-) mice. Tissue inflammation and microvessel density (MVD) were quantified on histological slides. Colonic wall thickness, microvascular hemodynamics and targeted MAdCAM-1(+) inflamed vessels were assessed in vivo by ultrasound. Mediators of angiogenesis and inflammation were measured by Milliplex and ELISA assays. Colitic Eng (+/-) mice showed an increase in intestinal inflammation, MVD, colonic wall thickness, microvascular hemodynamics and the number of MAdCAM-1(+) microvessels relative to colitic Eng (+/+) mice; these parameters were all attenuated by anti-VEGF treatment. Of all factors up-regulated in the inflamed gut, granulocyte colony-stimulating factor (G-CSF) and amphiregulin were further increased in colitic Eng (+/-) versus Eng (+/+) mice. Anti-VEGF therapy decreased tissue VEGF and inflammation-induced endoglin, IL-1ß and G-CSF in colitic Eng (+/-) mice. Our results suggest that endoglin modulates intestinal angiogenic and inflammatory responses in colitis. Furthermore, contrast-enhanced ultrasound provides an excellent non-invasive imaging modality to monitor gut angiogenesis, inflammation and responses to anti-angiogenic treatment.


Asunto(s)
Colitis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Intestinos/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Colitis/patología , Colon/efectos de los fármacos , Colon/patología , Endoglina , Femenino , Factor Estimulante de Colonias de Granulocitos/metabolismo , Hemodinámica/efectos de los fármacos , Heterocigoto , Inflamación/fisiopatología , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Intestinos/efectos de los fármacos , Intestinos/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Masculino , Ratones Endogámicos C57BL , Microvasos/efectos de los fármacos , Microvasos/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
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