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AIM: Actinomycosis is a rare subacute to chronic granulomatous infection which can mimic other infectious or malignant diseases. This study examined the epidemiology and treatment outcome of actinomycosis in children. METHODS: A retrospective study on children admitted for actinomycosis in a tertiary paediatric hospital in Singapore, from January 2004 to December 2020. Clinical profile, therapeutic interventions and outcomes were examined. RESULTS: A total of 10 patients were identified; 7 were female. The median age at first presentation was 9.8 years (range 4.7-15.7). The most common presenting symptom was fever (n = 6, 60%), followed by facial or neck swelling (n = 3, 30%) and ear pain (n = 3, 30%). Actinomycosis occurred predominantly in the orocervicofacial region (n = 6, 60%). Four patients (40%) had preceding dental infections in the form of dental caries or gingivitis. One patient had poorly controlled insulin-dependent diabetes mellitus. Actinomycosis was confirmed via culture in four patients, histopathology in four patients and both methods in two patients. All except one patient (n = 9, 90%) underwent surgical procedures. All patients received ampicillin or amoxicillin/clavulanate or other beta-lactams, for a median duration of 6.5 months (range 1.5-14). Complications included osteomyelitis (n = 4, 40%), mastoiditis (n = 2, 20%), brain abscess (n = 1, 10%) and recurrent neck abscess (n = 1, 10%). There was no mortality and all patients achieved complete resolution. CONCLUSIONS: Paediatric actinomycosis was rare in our 16-year review, but had a high complication rate. It can occur in immunocompetent patients, and dental infection was the predominant risk factor identified. Prognosis was excellent after surgical intervention and appropriate antimicrobial therapy.
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Actinomicose , Cárie Dentária , Humanos , Criança , Feminino , Pré-Escolar , Adolescente , Masculino , Estudos Retrospectivos , Antibacterianos/uso terapêutico , Actinomyces , Actinomicose/diagnóstico , Actinomicose/tratamento farmacológico , Actinomicose/epidemiologiaRESUMO
COVID-19 can be severe in pregnant women, and have adverse consequences for the subsequent infant. We profiled the post-infectious immune responses in maternal and child blood as well as breast milk in terms of antibody and cytokine expression and performed histopathological studies on placentae obtained from mothers convalescent from antenatal COVID-19. Seventeen mother-child dyads (8 cases of antenatal COVID-19 and 9 healthy unrelated controls; 34 individuals in total) were recruited to the Gestational Immunity For Transfer (GIFT) study. Maternal and infant blood, and breast milk samples were collected over the first year of life. All samples were analyzed for IgG and IgA against whole SARS-CoV-2 spike protein, the spike receptor-binding domain (RBD), and previously reported immunodominant epitopes, as well as cytokine levels. The placentae were examined microscopically. The study is registered at clinicaltrials.gov under the identifier NCT04802278. We found high levels of virus-specific IgG in convalescent mothers and similarly elevated titers in newborn children. Thus, antenatal SARS-CoV-2 infection led to high plasma titers of virus-specific antibodies in infants postnatally. However, this waned within 3-6 months of life. Virus neutralization by plasma was not uniformly achieved, and the presence of antibodies targeting known immunodominant epitopes did not assure neutralization. Virus-specific IgA levels were variable among convalescent individuals' sera and breast milk. Antibody transfer ratios and the decay of transplacentally transferred virus-specific antibodies in neonatal circulation resembled that for other pathogens. Convalescent mothers showed signs of chronic inflammation marked by persistently elevated IL17RA levels in their blood. Four placentae presented signs of acute inflammation, particularly in the subchorionic region, marked by neutrophil infiltration even though > 50 days had elapsed between virus clearance and delivery. Administration of a single dose of BNT162b2 mRNA vaccine to mothers convalescent from antenatal COVID-19 increased virus-specific IgG and IgA titers in breast milk, highlighting the importance of receiving the vaccine even after natural infection with the added benefit of enhanced passive immunity.
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BACKGROUND: Deletion of 1p is associated with poor prognosis in neuroblastoma, however selected 1p-intact patients still experience poor outcomes. Since mutations of 1p genes may mimic the deleterious effects of chromosomal loss, we studied the incidence, spectrum and effects of mutational variants in 1p-intact neuroblastoma. METHODS: We characterized the 1p status of 325 neuroblastoma patients, and correlated the mutational status of 1p tumor suppressors and neuroblastoma candidate genes with survival outcomes among 100 1p-intact cases, then performed functional validation of selected novel variants of 1p36 genes identified from our patient cohort. RESULTS: Among patients with adverse disease characteristics, those who additionally had 1p deletion had significantly worse overall survival. Among 100 tumor-normal pairs sequenced, somatic mutations of 1p tumor suppressors KIF1Bß and CHD5 were most frequent (2%) after ALK and ATRX (8%), and BARD1 (3%). Mutations of neuroblastoma candidate genes were associated with other synchronous mutations and concurrent 11q deletion (P = 0.045). In total, 24 of 38 variants identified were novel and predicted to be deleterious or pathogenic. Functional validation identified novel KIF1Bß I1355M variant as a gain-of-function mutation with increased expression and tumor suppressive activity, correlating with indolent clinical behavior; another novel variant CHD5 E43Q was a loss-of-function mutation with decreased expression and increased long-term cell viability, corresponding with aggressive disease characteristics. CONCLUSIONS: Our study showed that chromosome 1 gene mutations occurred frequently in 1p-intact neuroblastoma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may augment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactivation in neuroblastoma.
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Genes Supressores de Tumor , Neuroblastoma , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Estudos de Coortes , DNA Helicases/genética , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Neuroblastoma/genética , Neuroblastoma/patologiaRESUMO
Volvariella volvacea is a fungus found in tropical regions, commonly associated with straw mushrooms. This is a 50-year-old Singaporean female post living donor renal transplant who presented with fever, cough and headache. She was diagnosed to have Volvariella volvacea brain abscess. She was treated with combination anti-fungal therapy without surgical debridement and remains stable. The pathogenicity of this rare fungus in immunocompromised hosts is demonstrated here and is of significance particularly in Asia where ingestion of straw mushrooms may be a risk factor for invasive fungal disease.
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Agaricales , Abscesso Encefálico , Volvariella , Abscesso Encefálico/tratamento farmacológico , Feminino , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-IdadeRESUMO
Importance: Three-dimensionally printed nasopharyngeal swabs (3DP swabs) have been used to mitigate swab shortages during the coronavirus disease 2019 (COVID-19) pandemic. Clinical validation for diagnostic accuracy and consistency, as well as patient acceptability, is crucial to evaluate the swab's performance. Objective: To determine the accuracy and acceptability of the 3DP swab for identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Design, Setting, and Participants: A diagnostic study was conducted from May to July 2020 at 2 tertiary care centers in Singapore with different reference swabs (FLOQSwab [COPAN Diagnostics] or Dacron swab [Deltalab]) and swab processing techniques (wet or dry) to evaluate the performance of the 3DP swab compared with traditional, standard-of-care nasopharyngeal swabs used in health care institutions. The participants were patients with COVID-19 in the first 2 weeks of illness and controls with acute respiratory illness with negative test results for SARS-CoV-2. Paired nasopharyngeal swabs were obtained from the same nostril and tested for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction. The sequence of swabs was randomized based on odd and even participant numbers. Main Outcomes and Measures: Primary outcome measures were overall agreement (OA), positive percentage agreement (PPA), and negative percentage agreement of the 3DP swab compared with reference swabs. Secondary outcome measures were the correlation of cycle threshold (Ct) values of both swabs. Results: The mean (SD) age of participants was 45.4 (13.1) years, and most participants were men (87 of 89 [97.8%]), in keeping with the epidemiology of the COVID-19 pandemic in Singapore. A total of 79 patients with COVID-19 and 10 controls were recruited. Among the patients with COVID-19, the overall agreement and PPA of the 3DP swab was 91.1% and 93.5%, respectively, compared with reference swabs. The PPA was 100% for patients with COVID-19 who were tested within the first week of illness. All controls tested negative. The reverse-transcriptase polymerase chain reaction Ct values for the ORF1ab and E-gene targets showed a strong correlation (intraclass correlations coefficient, 0.869-0.920) between the 3DP and reference swab on independent testing at each institution despite differences in sample processing. Discordant results for both gene targets were observed only at high Ct values. Conclusions and Relevance: In this diagnostic study of 79 patients with COVID-19 and 10 controls, the 3DP swab performed accurately and consistently across health care institutions and could help mitigate strained resources in the escalating COVID-19 pandemic.
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Teste de Ácido Nucleico para COVID-19/instrumentação , COVID-19/diagnóstico , Nasofaringe/virologia , Impressão Tridimensional , Adulto , Desenho de Equipamento , Humanos , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2RESUMO
Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.
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Neoplasias Abdominais/genética , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Fusão Gênica , Rearranjo Gênico , Mesotelioma/genética , Neoplasias Testiculares/genética , Neoplasias Abdominais/enzimologia , Neoplasias Abdominais/patologia , Adolescente , Biomarcadores Tumorais/análise , Criança , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma/enzimologia , Mesotelioma/patologia , Técnicas de Diagnóstico Molecular , Neoplasias Testiculares/enzimologia , Neoplasias Testiculares/patologiaRESUMO
Although IKK-ß has previously been shown as a negative regulator of IL-1ß secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1ß expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1ß secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1ß correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1ß release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1ß secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.
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Genes Dominantes , Transplante de Células-Tronco Hematopoéticas , Interleucina-1beta , Hepatopatias , Mutação , Inibidor de NF-kappaB alfa , Imunodeficiência Combinada Severa , Aloenxertos , Animais , Feminino , Células HEK293 , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Hepatopatias/genética , Hepatopatias/imunologia , Hepatopatias/terapia , Masculino , Camundongos , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/imunologia , Neutropenia/genética , Neutropenia/imunologia , Neutropenia/terapia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
Ex vivo evaluation of personalized models can facilitate individualized treatment selection for patients, and advance the discovery of novel therapeutic options. However, for embryonal malignancies, representative primary cultures have been difficult to establish. We developed patient-derived cell cultures (PDCs) from chemo-naïve and post-treatment neuroblastoma tumors in a consistent and efficient manner, and characterized their in vitro growth dynamics, histomorphology, gene expression, and functional chemo-response. From 34 neuroblastoma tumors, 22 engrafted in vitro to generate 31 individual PDC lines, with higher engraftment seen with metastatic tumors. PDCs displayed characteristic immunohistochemical staining patterns of PHOX2B, TH, and GD2 synthase. Concordance of MYCN amplification, 1p and 11q deletion between PDCs and patient tumors was 83.3%, 72.7%, and 80.0% respectively. PDCs displayed a predominantly mesenchymal-type gene expression signature and showed upregulation of pro-angiogenic factors that were similarly enriched in culture medium and paired patient serum samples. When tested with standard-of-care cytotoxics at human Cmax -equivalent concentrations, MYCN-amplified and non-MYCN-amplified PDCs showed a differential response to cyclophosphamide and topotecan, which mirrored the corresponding patients' responses, and correlated with gene signatures of chemosensitivity. In this translational proof-of-concept study, early-phase neuroblastoma PDCs enriched for the mesenchymal cell subpopulation recapitulated the individual molecular and phenotypic profile of patient tumors, and highlighted their potential as a platform for individualized ex vivo drug-response testing.
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Proteínas de Homeodomínio/genética , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/tratamento farmacológico , Fatores de Transcrição/genética , Tirosina 3-Mono-Oxigenase/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , N-Acetilgalactosaminiltransferases/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Medicina de Precisão , Topotecan/farmacologia , Transcriptoma/genéticaRESUMO
BACKGROUND: Spinal manipulative therapy (SMT) is frequently used to manage cervicogenic headache (CGHA). No meta-analysis has investigated the effectiveness of SMT exclusively for CGHA. OBJECTIVE: To evaluate the effectiveness of SMT for CGHA. DATABASES AND DATA TREATMENT: Five databases identified randomized controlled trials comparing SMT with other manual therapies. The PEDro scale assessed the risk-of-bias. Pain and disability data were extracted and converted to a common scale. A random effects model was used for several follow-up periods. GRADE described the quality of evidence. RESULTS: Seven trials were eligible. At short-term follow-up, there was a significant, small effect favouring SMT for pain intensity (mean difference [MD] -10.88 [95% CI, -17.94, -3.82]) and small effects for pain frequency (standardized mean difference [SMD] -0.35 [95% CI, -0.66, -0.04]). There was no effect for pain duration (SMD - 0.08 [95% CI, -0.47, 0.32]). There was a significant, small effect favouring SMT for disability (MD - 13.31 [95% CI, -18.07, -8.56]). At intermediate follow-up, there was no significant effects for pain intensity (MD - 9.77 [-24.21 to 4.68]) and a significant, small effect favouring SMT for pain frequency (SMD - 0.32 [-0.63 to - 0.00]). At long-term follow-up, there was no significant effects for pain intensity (MD - 0.76 [-5.89 to 4.37]) and for pain frequency (SMD - 0.37 [-0.84 to 0.10]). CONCLUSION: For CGHA, SMT provides small, superior short-term benefits for pain intensity, frequency and disability, but not pain duration, however, high-quality evidence in this field is lacking. The long-term impact is not significant. SIGNIFICANCE: CGHA are a common headache disorder. SMT can be considered an effective treatment modality, with this review suggesting it providing superior, small, short-term effects for pain intensity, frequency and disability when compared with other manual therapies. These findings may help clinicians in practice better understand the treatment effects of SMT alone for CGHA.
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Manipulação da Coluna , Cefaleia Pós-Traumática , Humanos , Cefaleia Pós-Traumática/terapia , Resultado do TratamentoAssuntos
Fusão Gênica , Proteínas/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias de Tecidos Moles/genética , Coxa da Perna/patologia , Antígenos CD34/genética , Antígenos CD34/metabolismo , Pré-Escolar , Humanos , Masculino , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologiaRESUMO
Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16-gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non-Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild-type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Análise Mutacional de DNA , Fibroadenoma/genética , Perfilação da Expressão Gênica , Mutação , Tumor Filoide/genética , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Diagnóstico Diferencial , Feminino , Fibroadenoma/etnologia , Fibroadenoma/patologia , Predisposição Genética para Doença , Humanos , Taxa de Mutação , Gradação de Tumores , Fenótipo , Tumor Filoide/etnologia , Tumor Filoide/patologia , Valor Preditivo dos Testes , Estudos Retrospectivos , TranscriptomaRESUMO
We describe the clinical, pathological, and molecular features of a primary adrenal angiomatoid fibrous histiocytoma (AFH) in an 11-year-old girl presenting with pyrexia of unknown origin. We performed next-generation sequencing-based anchored multiplex polymerase chain reaction (Archer® FusionPlex® sarcoma assay), which revealed an EWSR1-ATF1 gene fusion with novel breakpoints in exon 11 of EWSR1 and exon 3 of ATF1. The pyrexia resolved fully after surgical resection, and the patient was disease-free on follow-up at 1 year and 6 months. This case exemplifies the value of molecular testing of pediatric neoplasms presenting at unusual sites for diagnosis and identification of novel gene fusion breakpoints.
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Neoplasias das Glândulas Suprarrenais/genética , Histiocitoma Fibroso Maligno/genética , Proteínas de Fusão Oncogênica/genética , Criança , Éxons/genética , Feminino , HumanosRESUMO
BACKGROUND: Primary paediatric epidural sarcomas are extremely rare. Overall, there remains a paucity of knowledge in paediatric epidural sarcomas owing to the infrequent number of cases. The Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) is a next-generation sequencing assay that has been reported to be a useful technique to detect recurrent fusion in sarcomas. We report the molecular exploration of 3 primary paediatric epidural sarcomas-one in the cranium (mesenchymal chondrosarcoma) and 2 in the spine (mesenchymal chondrosarcoma and Ewing sarcoma respectively). CASE PRESENTATION: This is a study approved by the hospital ethics board. Clinico-pathological information from 3 consenting patients with primary epidural sarcomas was collected. These selected tumours are interrogated via Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) for genomic aberrations. Results were validated with RT-PCR and Sanger sequencing. All findings are corroborated and discussed in concordance with current literature. Our findings show 2 variants of the HEY1-NCOA2 gene fusion: HEY1 (exon 4)-NCOA2 (exon 13) and HEY1 (exon 4)-NCOA2 (exon 14), in both mesenchymal chondrosarcoma patients. Next, the Ewing sarcoma tumour is found to have EWSR1 (exon 10)-FLI1 (exon 8) translocation based on NGS. This result is not detected via conventional fluorescence in situ testing. CONCLUSIONS: This is a molecularly-centered study based on 3 unique primary paediatric epidural sarcomas. Our findings to add to the growing body of literature for these exceptionally rare and malignant neoplasms. The authors advocate global collaborative efforts and in-depth studies for targeted therapy to benefit affected children.
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Neoplasias Epidurais/diagnóstico , Sarcoma/diagnóstico , Fatores Etários , Biomarcadores Tumorais , Biópsia , Criança , Condrossarcoma Mesenquimal/diagnóstico , Condrossarcoma Mesenquimal/genética , Análise Mutacional de DNA , Neoplasias Epidurais/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Sarcoma/genética , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Avaliação de SintomasRESUMO
Wilms tumor demonstrates significant interethnic epidemiological, histological and outcome differences, and is rare and poorly studied among Asians. We compared the clinicopathological, and loss of heterozygosity (LOH) profile and survival outcomes of Asian and non-Asian patients with Wilms tumor. Clinical charts and histological slides from patients with malignant renal tumors over a period of 20 years were retrospectively reviewed. We adapted a genotyping assay to determine 1p36 and 16q21-22 LOH in formalin-fixed paraffin-embedded (FFPE) specimens, and compared these characteristics between Asian and non-Asian patients. Fifty-three (79.1%) Asian and 14 (20.9%) non-Asian patients had Wilms tumors. Compared to non-Asians, Asians were younger (mean 4.6 and 4.0 years, respectively), had more equal gender distribution (female: male = 1.8 and 1.0, respectively), fewer tumors with unfavorable histology (25.0% and 4.1%, respectively, p = 0.05), and less advanced disease at presentation, yet similar nodal metastases rates (16.7% and 18.4%, respectively). No Asian patients had bilateral tumors. Our adapted genotyping assay accurately determined LOH in FFPE specimens <10 years post-fixation. Among 30 Asian patients, 1p and 16q LOH were each detected in 5 (16.7%) patients, respectively-similar to rates reported in other ethnicities. Yet after similar treatment with National Wilms Tumor Study regimens, 15-year event-free and overall survival for Asian patients was 95.7% and 96.3% respectively. In summary, despite similar nodal metastasis and LOH rates, Asian patients had fewer unfavorable histology tumors, lower-stage disease, and better survival outcomes. The bases for these differences and implications on treatment strategy for these patients warrant further study.
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Povo Asiático/genética , Neoplasias Renais/genética , Perda de Heterozigosidade , Tumor de Wilms/genética , Fatores Etários , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Feminino , Humanos , Lactente , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Singapura/epidemiologia , Análise de Sobrevida , Tumor de Wilms/mortalidade , Tumor de Wilms/patologiaRESUMO
We report the first case of an ovarian pericytoma with t(7;12). An 11-year-old child presented with abdominal pain and distension. A suprapubic mass was detected on examination and radiological investigations revealed a 16.5 cm solid-cystic ovarian mass. Histologically, the tumor was composed of spindle cells with S100-protein, Bcl-2, and CD10 reactivity on immunohistochemistry. Alpha fetoprotein, calretinin, alpha-inhibin, WT1, smooth muscle actin, caldesmon, desmin, cytokeratins, chromogranin, synaptophysin, EMA, Sox10, CD117, CD31, CD34, and CD68 were all negative. Molecular tests showed t(7;12)(p22;q13), resulting in the fusion of the ACTB with GLI1 genes and a diagnosis of pericytoma with t(7;12) of the ovary was made. We discuss the difficulties in diagnosing this lesion in the ovary and highlight the importance on molecular tests in characterizing challenging cases, especially primary ovarian spindle cell mesenchymal tumors.
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Cromossomos Humanos Par 12 , Cromossomos Humanos Par 7 , Neoplasias Ovarianas/genética , Translocação Genética , Criança , Feminino , Humanos , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologiaRESUMO
AIMS: This study aims to examine the molecular genetics of paediatric breast fibroepithelial tumours through the targeted sequencing of 50 genes. METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissues of fibroepithelial tumours diagnosed in a cohort of patients aged 18 years and below were subjected to next generation sequencing using the Haloplex Target Enrichment System. Twenty-five conventional and 17 juvenile fibroadenomas were studied, with MED12 mutations found in 53.8 and 35% of the tumours, respectively. There was also one benign fibroepithelial neoplasm with hybrid features of juvenile papillomatosis and infarcted benign phyllodes tumour-like areas. Most tumours did not have mutations in well-known cancer driver genes, none harboured TERT promoter mutations, while 25.6% (11 of 43) showed no mutations. Metachronous and synchronous tumours were found to have mutational heterogeneity with some containing mutations in MED12; other genes or no mutations were detected at all. Four of eight giant fibroadenomas (size 5 cm or larger) had no mutations detected, suggesting that there are other molecular mechanisms driving their growth. Tumours with MED12 mutations incidentally had a significantly higher stromal mitotic count compared with those without. CONCLUSION: While paediatric fibroepithelial lesions can have cellular stroma potentially raising concern for phyllodes tumour, their lack of TERT promoter and cancer driver mutations is reassuring. The absence of mutations in a significant proportion of tumours, especially the giant fibroadenomas, warrants investigation of pathogenetic mechanisms beyond those involving the 50 genes.
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Neoplasias da Mama/genética , Neoplasias Fibroepiteliais/genética , Adolescente , Neoplasias da Mama/patologia , Criança , Análise Mutacional de DNA , Feminino , Humanos , Mutação , Neoplasias Fibroepiteliais/patologiaRESUMO
A 3-year-old boy presented with pathologic fracture of the left proximal femur. Magnetic resonance imaging revealed an aggressive expansile bony mass associated with cortical destruction and surrounding myositis. Computed tomography-guided biopsy revealed a monomorphic small round blue cell tumor by histology. CD99 immunoreactivity and low-level EWSR1 gene translocation by break-apart fluorescent in situ hybridization initially favored a diagnosis of Ewing sarcoma and chemotherapy commenced. Subsequent molecular evaluation by an anchored multiplex polymerase chain reaction-based assay (Archer FusionPlex Sarcoma Panel) revealed a nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) gene fusion. The diagnosis was then amended to primary bone ALK-positive anaplastic large cell lymphoma and the chemotherapy regimen was modified accordingly. This report illustrates the value of this molecular assay in establishing the correct diagnosis of a very rare malignancy masquerading as another tumor type.