RESUMO
PURPOSE: Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). PATIENTS AND METHODS: This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. RESULTS: Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p = .14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). DISCUSSION: Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.
Assuntos
Neoplasias Ósseas , Neoplasias Pulmonares , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patologia , Feminino , Masculino , Criança , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/secundário , Estudos Retrospectivos , Adolescente , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/terapia , Neoplasias Ósseas/secundário , Neoplasias Ósseas/patologia , Pré-Escolar , Taxa de Sobrevida , Prognóstico , Seguimentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto Jovem , Indução de Remissão , Lactente , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Quimioterapia de InduçãoRESUMO
OBJECTIVE: The American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) is a widely used method for the management of adult thyroid nodules. However, its use in paediatric patients is controversial because adult fine needle aspiration biopsy (FNAB) recommendations may lead to delayed diagnoses of cancer in children. The objectives of this study were to evaluate the performance of TI-RADS in paediatric thyroid nodules and to tailor FNAB recommendations for children. METHODS: Consecutive surgically resected paediatric thyroid nodules from two tertiary care centres between 2003 and 2021 were reviewed. Ultrasounds were blindly scored by radiologists according to TI-RADS. Management recommendations based on TI-RADS were evaluated. Various modelling methodologies were used to determine the optimal cutoff for FNAB in children. RESULTS: Of the 96 patients, 79 (82%) were female and the median age at surgery was 16.1 years. Fifty (52%) nodules were malignant on surgical pathology. The area under the receiver operating characteristic curve of TI-RADS for predicting malignancy was 0.78. Adult TI-RADS recommendations would have resulted in 4% of cancerous nodules being lost to follow-up. Modifications to TI-RADS (FNAB of all TR3 nodules ≥1.5 cm, FNAB of TR4 and TR5 nodules ≥0.5 cm, surveillance of nodules ≥1 cm, consider surgery for nodules >4 cm) reduced this missed malignancy rate to 0%. CONCLUSIONS: TI-RADS can risk-stratify paediatric thyroid nodules. However, the system requires modifications to reduce the missed malignancy rate in paediatric thyroid nodules. Our data suggest that lower size thresholds for FNAB are warranted in children.
RESUMO
INTRODUCTION: Large-volume fat grafting is emerging as a promising technique in plastic and reconstructive surgery. However, the unpredictable graft volume retention rate remains a critical challenge. To address this issue, we need a profound understanding of the survival mechanisms following large-volume fat transplantation. This review summarizes known survival mechanisms and strategies to enhance graft retention. METHODS: This review comprehensively examines the current literature on the survival mechanisms and retention strategies in large-volume fat grafting. A thorough literature search was conducted using PubMed, Medline and Google Scholar databases, focusing on studies published from 2009 to 2023. CONCLUSION: In the current research on fat survival mechanisms, few have focused on large-volume fat grafting. This review provides an overview of the survival mechanisms specific to large-volume fat grafting and identifies a survival pattern distinct from that of small-volume fat grafting. Additionally, we have summarized existing strategies to improve graft retention across five stages (harvesting, processing, enrichment, grafting and post-graft care), analyzed their advantages and disadvantages and identified some of the most promising strategies. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
RESUMO
BACKGROUND: Bile staining in the hepatobiliary tree is a well-known phenomenon, but bilirubin can also be deposited in and stain the umbilical cord, amniotic fluid, placental disk and placental membranes. CASE REPORT: We present a placenta with grossly greenish discoloration of the placental disk and microscopic villous bilirubin deposition due to maternal hyperbilirubinemia. Conclusion: Maternal hyperbilirubinemia causes massive bilirubin deposition in villous synctiotrophoblasts and Hofbauer cells leading to grossly green discoloration of the placental disk.
Assuntos
Placenta , Complicações na Gravidez , Humanos , Gravidez , Feminino , Bilirrubina , Hiperbilirrubinemia/complicações , CórionRESUMO
Background: DICER1 tumor predisposition syndrome is characterized by an increased risk for development of pleuropulmonary blastoma, pituitary blastoma, multinodular thyroid goiter, thyroid carcinoma, sex cord stromal tumor, cystic nephroma, embryonal rhabdomyosarcoma, and tumors of the CNS, amongst others. Of this list, only pituitary blastoma is recognized as pathognomonic for the syndrome. Case report: We describe a 15-year-old female with bilateral, asynchronous Sertoli-Leydig cell tumors (SLCT). Both tumors harbored an identical germline frameshift mutation as well as unique somatic DICER1 hot-spot point mutations. Discussion: A review of bilateral SLCTs demonstrates that all patients with available DICER1 mutation status carried a germline DICER1 mutation (100%, 9 of 9). In cases with known somatic DICER1 status on bilateral tumors, all harbored distinct somatic mutations (100%, 5 of 5). Our findings support the notion that bilateral ovarian SLCTs are indeed separate events and do not represent recurrent or metastatic disease.
Assuntos
Neoplasias Ovarianas , Blastoma Pulmonar , Tumor de Células de Sertoli-Leydig , Masculino , Feminino , Humanos , Adolescente , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Mutação , Blastoma Pulmonar/patologia , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
Histologic features of idiopathic noncirrhotic portal hypertension (INCPH), loosely termed as obliterative portal venopathy (OPV), are heterogenous, often subtle, and overlap with other entities. To this date, no consensus histopathologic diagnostic criteria have been established for INCPH. For these reasons, rendering a reproducible consensus histologic diagnosis of OPV on a liver biopsy may often be challenging even for experienced hepatopathologists. We report herein a two-phase interobserver agreement study on the diagnosis of OPV and assessed the relative value of histologic features in 104 liver biopsies in distinguishing between INCPH and non-INCPH with the goal to obtain a consensus on specific practical diagnostic criteria. Six hepatopathologists blinded to clinical information and original pathologic diagnosis reviewed internet-based case study sets with high-resolution whole-slide images. The initial interobserver agreement on OPV was expectedly low, but significantly improved (moderate agreement in most categories) upon adopting a consensus view recognizing portal vein sclerosis as the only strong independent histologic predictor for INCPH, and that contrary to the conventional view, aberrant portal/periportal vessels does not significantly contribute to the positive assignment of OPV status. We propose a three-tiered classification with diagnostic criteria to facilitate the histologic assignment of OPV status for the evaluation of INCPH. Furthermore, we have validated the performance of the proposed criteria either based on histology alone or coupled with clinicopathologic correlation. This classification may aid in practical histologic assessment of liver biopsies with or without portal hypertension and help to improve diagnostic consistency and accuracy.
Assuntos
Hipertensão Portal/patologia , Fígado/patologia , Veia Porta/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Criança , Bases de Dados Factuais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Extra-axial chordomas in the pediatric population are extremely rare and diagnostically challenging; only four cases have been previously reported with ages ranging from 13 to 20 years. We report a primary extra-axial chordoma involving the soft tissue directly dorsal and ulnar to proximal phalanx in the right thumb of a 12-year-old girl who presented with worsening right thumb pain for 1.5 years. The diagnosis was confirmed by excisional biopsy demonstrating proliferation of large, polygonal epithelioid cells with diffuse expression of pan-cytokeratin and brachyury. The patient required repeat excision for local recurrence seven months later. Since then, she has remained disease free through 15 months surveillance. Extra-axial chordomas share the same histopathological and immunohistochemical characteristics with their axial counterparts and should be considered in the differential diagnosis for any extra-axial bone or soft tissue mass with epithelioid morphology.
Assuntos
Cordoma , Adolescente , Adulto , Biópsia , Criança , Cordoma/diagnóstico , Cordoma/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Adulto JovemRESUMO
BACKGROUND: Papillary thyroid carcinoma (PTC) in children has a distinctive set of clinicopathologic features and molecular signature compared to their adult counterparts. The recent recommendation to reclassify encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) without invasion as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is based on evidence derived almost exclusively from studies in adults. Clinicopathologic studies restricted to pediatric NIFTP are limited. METHODS: We retrospectively analyzed all pediatric PTC and NIFTP diagnosed and treated in our institution from 1999 to 2016 (n = 31). RESULTS: Using recently published consensus diagnostic criteria, we identified 3 NIFTP and 2 infiltrative follicular variants of papillary thyroid carcinoma (FVPTC) among 31 cases. Two of the NIFTP cases were initially diagnosed as EFVPTC. All 3 patients with NIFTP had unifocal tumors of lower American Joint Committee on Cancer (AJCC) classification (T2 or lower) and were free of lymph node or distant metastasis. Total (n = 1) or completion (n = 2) thyroidectomy was performed in all cases, and only 1 NIFTP patient received subsequent radioablative therapy. No residual or recurrent disease has been observed during follow-up (15-138 months) in patients with NIFTP. CONCLUSIONS: Our experience with NIFTP in children is similar to outcomes reported in adult studies, suggesting that pediatric NIFTP behave indolently as evidenced by the absence of local recurrence in our cohort.
Assuntos
Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Adolescente , Criança , Estudos de Coortes , Feminino , Humanos , Linfonodos/patologia , Masculino , Pediatria , Estudos Retrospectivos , Câncer Papilífero da Tireoide/classificação , Neoplasias da Glândula Tireoide/classificação , Adulto JovemRESUMO
When an unusual intraplacental lesion is identified during pathologic examination, it becomes of substantial import to determine whether it represents a normal structure, metastasis from the mother, or a primary benign tumor, including those secondary to abnormal embryologic development versus a primary malignant placental tumor. In this case report, we identified an incidental nest of intraplacental cells with nondiagnostic morphology and negative initial Glypican-3 stain in a healthy 35-wk gestation. This negative result prompted a broadening of the differential before ultimately determining this lesion was indeed ectopic liver with positive Arginase-1 and HepPar-1 staining. This may represent the mature hepatocyte phenotype within the lesional cells of this near-term birth, a dichotomy not previously discussed in the literature, which focuses on the fetal hepatocyte phenotype, also rarely seen. In this report, we summarize the previous literature regarding intraplacental ectopic liver, and we propose a sensitive approach to suspected ectopic liver of the placenta that may be sufficient to capture both the fetal and mature hepatocyte immunophenotypes. This approach may extend to other related pathologies including assessment of suspected intraumbilical hepatocytes.
Assuntos
Coristoma/patologia , Feto , Fígado , Doenças Placentárias/patologia , Adulto , Antígenos de Neoplasias/análise , Arginase/análise , Feminino , Glipicanas/análise , Humanos , GravidezRESUMO
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that regulates gene expression through poly(ADP)-ribosylation, resulting in the loosening of chromatin structure. PARP-1 enzymatic activity has been shown to be necessary for the expression of several genes required for memory formation and consolidation. Previously, we showed that nucleolar PARP-1 is significantly decreased in hippocampal pyramidal cells in Alzheimer's disease (AD). We proposed that the displacement of PARP-1 from the nucleolus results in downregulation of new rRNA expression and ribosome biogenesis, leading to cognitive impairment. To further investigate the relationship between nucleolar PARP-1 and memory impairment, we examined PARP-1 expression in the hippocampi of individuals with mild cognitive impairment (MCI) compared to control and AD cases. We used immunohistochemical techniques to examine the nucleolar distribution of PARP-1 in the Cornu Ammonis (CA region) of the hippocampus. PARP-1 positive cells were then scored for the presence or absence of PARP-1 in the nucleolus. We found a significant decrease of PARP-1 staining in the nucleolar compartment of hippocampal pyramidal cells in MCI compared with Control and AD. When the four CA (CA1-4) regions were considered separately, only the CA1 region showed significant differences in nucleolar PARP-1 with Control > AD > MCI cases. Categorization of nucleolar PARP-1 into "distinct" and "diffuse" groups suggest that most of the changes occur within the distinct group. In addition, measurements of the nucleolar diameter of nucleolar PARP-1 positive cells in CA2 and CA4 showed Control > MCI. Thus, MCI cases had a lower percentage of PARP-1 nucleolar positive cells in CA1 and smaller nucleolar diameters in CA2 and CA4, compared to Control. Our data suggest that disruption of nucleolar form and function is an early and important step in the progression of cognitive impairment.
Assuntos
Disfunção Cognitiva/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo , Cognição/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismoRESUMO
The regulatory network of factors that center on master transcription factors such as Oct4, Nanog, and Sox2 help maintain embryonic stem (ES) cells and ensure their pluripotency. The target genes of these master transcription factors define the ES cell transcriptional landscape. In this study, we report our findings that Dido1, a target of canonical transcription factors such as Oct4, Sox2, and Nanog, plays an important role in regulating ES cell maintenance. We found that depletion of Dido1 in mouse ES cells led to differentiation, and ectopic expression of Dido1 inhibited differentiation induced by leukemia inhibitory factor withdrawal. We further demonstrated that whereas Nanog and Oct4 could occupy the Dido1 locus and promote its transcription, Dido1 could also target to the loci of pluripotency factors such as Nanog and Oct4 and positively regulate their expression. Through this feedback and feedforward loop, Dido1 is able to regulate self-renewal of mouse ES cells.
Assuntos
Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Fatores de Transcrição/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/efeitos dos fármacos , Retroalimentação Fisiológica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Humanos , Fator Inibidor de Leucemia/farmacologia , Camundongos , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismoRESUMO
Embryonic stem (ES) cells exhibit general characteristics of open chromatin, a state that may be necessary for ES cells to efficiently self-renew while remaining poised for differentiation. Histone H3K4 and H3K9 trimethylation associate as a general rule, with open and silenced chromatin, respectively, for ES cell pluripotency maintenance. However, how histone modifications are regulated to maintain open chromatin in ES cells remains largely unknown. Here, we demonstrate that trithorax protein Ash2l, homologue of the Drosophila Ash2 (absent, small, homeotic-2) protein, is a key regulator of open chromatin in ES cells. Consistent with Ash2l being a core subunit of mixed lineage leukemia methyltransferase complex, RNAi knockdown of Ash2l was sufficient to reduce H3K4 methylation levels and drive ES cells to a silenced chromatin state with high H3K9 trimethylation. Genome-wide ChIP-seq analysis indicated that Ash2l is recruited to target loci through two distinct modes and enriched at a family of genes implicated in open chromatin regulation, including chromatin remodeler Cdh7, transcription factor c-Myc, and H3K9 demethylase Kdm4c. Our results underscore the importance of Ash2l in open chromatin regulation and provide insight into how the open chromatin landscape is maintained in ES cells.
Assuntos
Cromatina/química , Proteínas de Ligação a DNA/fisiologia , Células-Tronco Embrionárias/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Animais , Diferenciação Celular , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/metabolismo , Genoma , Histonas/metabolismo , Metilação , Camundongos , Microscopia de Fluorescência/métodos , Modelos Biológicos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Nucleares/metabolismo , Células-Tronco Pluripotentes/citologia , Interferência de RNA , Fatores de Transcrição/metabolismoRESUMO
Ectopic pituitary adenomas are uncommon entities that may pose substantial diagnostic challenges. In the majority of these cases, patients present with endocrine and/or nasal obstruction symptoms. We report the case of an ectopic pituitary adenoma in a 76-year-old man with an empty sella who initially presented with right-sided hearing loss progressing to bilateral hearing loss over the next 4 years. Neuroimaging studies revealed a large, expansile central skull base mass replacing the clivus and sphenoid sinus, and invading the internal auditory canals and inner ear bilaterally. The tumor also involved the floor of the middle cranial fossae and bilateral medial temporal and occipital bones. Histopathologic examination, including immunohistochemical studies, revealed a sparsely granulated lactotroph adenoma. Hearing loss in a patient with ectopic pituitary adenoma constitutes an extremely unusual presentation. This case was further complicated by the presence of an empty sella and the absence of symptoms related to hyperprolactinemia.
Assuntos
Adenoma/complicações , Coristoma/complicações , Síndrome da Sela Vazia/etiologia , Perda Auditiva Unilateral/etiologia , Neoplasias Hipofisárias/complicações , Adenoma/patologia , Idoso , Coristoma/patologia , Síndrome da Sela Vazia/patologia , Perda Auditiva Unilateral/patologia , Humanos , Masculino , Neoplasias Hipofisárias/patologiaRESUMO
Central nervous system (CNS) metastases represent a small portion of pediatric CNS neoplasms and data surrounding this condition with high morbidity is scarce. Single institutional archival institutional pathology records between 1999 and 2022 were searched for patients over 21 years old and younger with CNS, dura, cranial nerve, CSF, or leptomeningeal metastases; 41 cases were identified. We documented primary tumor types and locations, metastasis locations, types of invasion (direct extension vs distant metastasis), times from imaging or pathologic diagnosis to CNS involvement, and outcomes. Distant metastasis was the most common mechanism of metastasis (n = 32, 78%). Interval times to CNS metastasis varied by both tumor type and primary tumor location. In this cohort, osteosarcoma portended the shortest survival following CNS metastasis. This study highlights the diverse mechanisms and locations of CNS involvement in pediatric CNS metastases and illuminates a need for varied monitoring strategies when considering primary tumor type and anatomic location.
Assuntos
Neoplasias do Sistema Nervoso Central , Segunda Neoplasia Primária , Adulto , Criança , Humanos , Adulto Jovem , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/patologia , Estudos RetrospectivosRESUMO
In this paper, a digital microfluidic thermal control system was introduced for the stable polymerase chain reaction (PCR). The system consists of a thermoelectric cooler unit, a thermal control board, and graphical-user-interface software capable of simultaneously achieving temperature control and on-chip droplet observation. A fuzzy proportional-integral-derivative (PID) method was developed for this system. The simulation analysis was performed to evaluate the temperature of different reagents within the chip. Based on the results, applying fuzzy PID control for PCR will enhance the thermal stability by 67.8% and save the time by 1195 s, demonstrating excellent dynamic response capability and thermal robustness. The experimental results are consistent with the simulation results on the planar temperature distribution, with a data consistency rate of over 99%. The PCR validation was carried out on this system, successfully amplifying the rat GAPDH gene at a concentration of 193 copies/µL. This work has the potential to be useful in numerous existing lab-on-a-chip applications.
RESUMO
Intracranial mesenchymal tumor (IMT), FET::CREB fusion-positive is a provisional tumor type in the 2021 WHO classification of central nervous system tumors with limited information available. Herein, we describe five new IMT cases from four females and one male with three harboring an EWSR1::CREM fusion and two featuring an EWSR1::ATF1 fusion. Uniform manifold approximation and projection of DNA methylation array data placed two cases to the methylation class "IMT, subclass B", one to "meningioma-benign" and one to "meningioma-intermediate". A literature review identified 74 cases of IMTs (current five cases included) with a median age of 23 years (range 4-79 years) and a slight female predominance (female/male ratio = 1.55). Among the confirmed fusions, 25 (33.8%) featured an EWSR1::ATF1 fusion, 24 (32.4%) EWSR1::CREB1, 23 (31.1%) EWSR1::CREM, one (1.4%) FUS::CREM, and one (1.4%) EWSR1::CREB3L3. Among 66 patients with follow-up information available (median: 17 months; range: 1-158 months), 26 (39.4%) experienced progression/recurrences (median 10.5 months; range 0-120 months). Ultimately, three patients died of disease, all of whom underwent a subtotal resection for an EWSR1::ATF1 fusion-positive tumor. Outcome analysis revealed subtotal resection as an independent factor associated with a significantly shorter progression free survival (PFS; median: 12 months) compared with gross total resection (median: 60 months; p < 0.001). A younger age (< 14 years) was associated with a shorter PFS (median: 9 months) compared with an older age (median: 49 months; p < 0.05). Infratentorial location was associated with a shorter overall survival compared with supratentorial (p < 0.05). In addition, the EWSR1::ATF1 fusion appeared to be associated with a shorter overall survival compared with the other fusions (p < 0.05). In conclusion, IMT is a locally aggressive tumor with a high recurrence rate. Potential risk factors include subtotal resection, younger age, infratentorial location, and possibly EWSR1::ATF1 fusion. Larger case series are needed to better define prognostic determinants in these tumors.
Assuntos
Neoplasias Encefálicas , Histiocitoma Fibroso Maligno , Neoplasias Meníngeas , Meningioma , Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Prognóstico , Hibridização in Situ Fluorescente , Histiocitoma Fibroso Maligno/genética , Histiocitoma Fibroso Maligno/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Proteínas de Fusão Oncogênica/genética , Biomarcadores Tumorais/genéticaRESUMO
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.
Assuntos
Herpesvirus Humano 6 , Transplante de Fígado , Infecções por Roseolovirus , Humanos , Herpesvirus Humano 6/isolamento & purificação , Masculino , Estudos Retrospectivos , Infecções por Roseolovirus/patologia , Infecções por Roseolovirus/virologia , Infecções por Roseolovirus/complicações , Feminino , Pré-Escolar , Criança , Lactente , Doença Aguda , Hepatite Viral Humana/patologia , Hepatite Viral Humana/virologia , Falência Hepática Aguda/virologia , Falência Hepática Aguda/patologia , Índice de Gravidade de Doença , Fígado/patologia , Fígado/virologia , Imuno-Histoquímica , Biópsia , AdolescenteRESUMO
Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the world's population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.
RESUMO
Detection of low-affinity or transient interactions can be a bottleneck in our understanding of signaling networks. To address this problem, we developed an arrayed screening strategy based on protein complementation to systematically investigate protein-protein interactions in live human cells, and performed a large-scale screen for regulators of telomeres. Maintenance of vertebrate telomeres requires the concerted action of members of the Telomere Interactome, built upon the six core telomeric proteins TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. Of the â¼12,000 human proteins examined, we identified over 300 proteins that associated with the six core telomeric proteins. The majority of the identified proteins have not been previously linked to telomere biology, including regulators of post-translational modifications such as protein kinases and ubiquitin E3 ligases. Results from this study shed light on the molecular niche that is fundamental to telomere regulation in humans, and provide a valuable tool to investigate signaling pathways in mammalian cells.