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BACKGROUND: Ocular medulloepithelioma (diktyoma) is a rare and potentially malignant paediatric tumour of the non-pigmented ciliary epithelium. Adjuvant chemotherapy can be given in advanced cases, but the indications and regimens remain to be defined. The aim was to identify whether adjuvant chemotherapy offers treatment benefit in advanced ocular medulloepithelioma. METHODS: This was a retrospective case series of subjects referred to a single specialist ocular oncology centre for advanced ocular medulloepithelioma subsequently treated with enucleation, including those needing adjuvant systemic vincristine, etoposide and carboplatin. A case-note review was performed for included subjects meeting referral criteria. The outcomes were histopathology characteristics, recurrence, metastases and survival. RESULTS: Between March 2010 and June 2017, four male patients (mean age 31 months) underwent enucleation for ocular medulloepithelioma. Adjuvant chemotherapy was commenced in 3 patients (75%) due to malignant histopathological features. With a mean follow-up time of 81.5 months (median 71 months, range 49-135 months) none of the patients have had recurrence, metastases or death from the tumour. CONCLUSIONS: This series is unique in reporting the management of advanced malignant ocular medulloepithelioma with adjuvant systemic vincristine, etoposide and carboplatin for advanced tumours with malignant features. This regimen appears to be safe and may be effective in preventing metastatic spread.
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Tumores Neuroectodérmicos Primitivos , Criança , Humanos , Masculino , Pré-Escolar , Estudos Retrospectivos , Carboplatina/uso terapêutico , Etoposídeo/uso terapêutico , Vincristina/uso terapêutico , Enucleação Ocular , Quimioterapia Adjuvante , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Tumores Neuroectodérmicos Primitivos/patologia , Tumores Neuroectodérmicos Primitivos/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
We observed an increased frequency of massive perivillous fibrin deposition (MPFD) during the second coronavirus disease 2019 (COVID-19) pandemic wave dominated by the Alpha variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MPFD associated with 100% reverse transcription polymerase chain reaction (RT-PCR) positivity for SARS-CoV-2 and detection by immunohistochemistry. The Alpha variant was identified in all placentas with MPFD that could be sequenced.
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COVID-19 , Complicações Infecciosas na Gravidez , Feminino , Fibrina/análise , Humanos , Placenta , Gravidez , SARS-CoV-2RESUMO
Background: Retinoblastoma (Rb) is a childhood tumor of the developing retina where predisposition is caused by RB1 pathogenic variants. MYCN amplification (MYCNA) has been implicated in around 2% of sporadic unilateral Rb tumors with no detectable RB1 variants. We audited data from tumors collected between 1993 and 2019 to determine if this is the case for patients treated at Barts Health NHS Trust, and how often it occurred alongside RB1 variants. Materials and methods: Screening for MYCNA was carried out by Multiple Ligation Probe Analysis of tumor and blood samples collected for RB1 genetic screening. The cohort consisted of 149 tumors, of which 114 had matched blood samples. Results: 10/149 (6.7%) tumors were positive for MYCNA in a population containing a disproportionate number of cases negative for RB1 pathogenic variants. Of 65 unbiased tumors collected from 2014 to 2019, 2 (3.1%) had MYCNA. All MYCNA samples were from sporadic, unilateral patients and 3/10 (30%) had RB1 pathogenic variants. MYCNA was not detected in any blood sample. No MYCNA tumor had 6p gain which is usually a common alteration in Rbs. Conclusions:MYCNA occurs in a small fraction of Rbs and can occur in the presence of pathogenic RB1 variants. However, where it occurs alongside RB1 alterations, the age of onset appears to be later. MYCNA has yet to be seen as a heritable change. In sporadic cases with early diagnosis, Rbs with no RB1 pathogenic variant identified should be tested for MYCNA. Conversely, tumors with MYCNA should still be screened for RB1 pathogenic variants.
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Amplificação de Genes/genética , Proteína Proto-Oncogênica N-Myc/genética , Neoplasias da Retina/genética , Retinoblastoma/genética , Criança , Pré-Escolar , Éxons , Feminino , Testes Genéticos , Humanos , Lactente , Masculino , Técnicas de Amplificação de Ácido Nucleico/métodos , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.
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BACKGROUND: RB1 gene screening aids clinical management and genetic counselling in retinoblastoma families. Here we present epigenetic changes identified during routine molecular RB1 screening of tumor and blood samples. Complications in interpreting RB1 methylation are discussed. MATERIALS AND METHODS: Screening for RB1 promoter hypermethylation was carried out by Methylation Specific PCR (MS-PCR) after bisulphite modification of DNA. The cohort consisted of 315 tumors, and 204 blood samples, from 497 retinoblastoma patients (22 patients had both blood and tumor screened). RESULTS: 11.4% of retinoblastoma tumors had promoter hypermethylation. It was not routinely detected in blood samples, or in tumors with two other oncogenic RB1 changes. One blood sample had promoter hypermethylation due to an X;13 translocation. One tumor had low level methylation as well as two other oncogenic changes. Histopathological analysis of a small subset of age-matched tumors was similar regardless of promoter hypermethylation status. CONCLUSIONS: Promoter hypermethylation was detected in 11.4% of the retinoblastoma tumors and should be tested for in routine RB1 screening programmes. Constitutional samples are not expected to display RB1 hypermethylation. In a small proportion of cases it may not be possible to use this somatic change in patient management.
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Metilação de DNA , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/genética , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/diagnóstico , Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Criança , Pré-Escolar , Primers do DNA/química , Eletroforese em Gel de Ágar , Epigênese Genética , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase , Regiões Promotoras GenéticasRESUMO
Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood, but an uncommon paediatric cancer, with a constant incidence worldwide of 1:15,000-1:20,000 live births. Despite its rarity, Rb has served as a cornerstone in the field of oncology in many of the aspects that comprise cancer management, including classification schemes, treatment modalities, genetic testing and screening. Until just over half a century ago, the major treatment for Rb was eye removal, and prognosis was poor with outcome fatal for most children. The dramatic evolution, in a short period of time across all fields of Rb management, as well as the development of specialized centres, better infrastructure and introduction of awareness campaigns, has resulted in nearly 100% survival in developed countries and allowed eye salvage in many of the cases. External beam radiotherapy was used as the main treatment choice for four decades, but replaced by chemotherapy at the turn of the century. Initially, and still in many centres, chemotherapy is administered intravenously, but recently is targeted directly into the eye by means of intra-ophthalmic artery and intravitreal chemotherapy. To date, a range of treatments is available to the Rb expert, including enucleation, but there is lack of consensus in a number of scenarios as to what to use and when. In such a rare cancer, treatment outcomes are reported usually via retrospective analyses, with few prospective randomized controlled trials. Classification schemes have also evolved following the introduction of new treatment modalities, but discrepancies exist among centres with respect to the preferred schema and its interpretation. Retinoblastoma management is a remarkable success story, but the future will require a collaborative effort in the form of multicentre randomized controlled trials in order to further improve the quality of care for this subset of young children with ocular cancer.
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Neoplasias da Retina/terapia , Retinoblastoma/terapia , Criança , Enucleação Ocular/métodos , Humanos , Incidência , Tratamentos com Preservação do Órgão/métodos , Prognóstico , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/genética , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiologia , Retinoblastoma/genética , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment. DESIGN: Retrospective analysis. PARTICIPANTS: A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments. METHODS: Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion. MAIN OUTCOME MEASURES: High-risk histopathologic features, metastasis, and death. RESULTS: Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P = 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7-153.0). CONCLUSIONS: The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.
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Enucleação Ocular , Neoplasias da Retina/classificação , Neoplasias da Retina/patologia , Retinoblastoma/classificação , Retinoblastoma/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Classificação Internacional de Doenças , Masculino , Neoplasias da Retina/cirurgia , Retinoblastoma/cirurgia , Estudos Retrospectivos , Fatores de RiscoRESUMO
The organ weights in cases of sudden infant death syndrome (SIDS) and undetermined deaths in previously healthy infants do not correspond to "the normal range" of organ weights in international standard charts for infants currently in use in some institutions. The aim of our study was to ascertain the organ weights of infants dying suddenly and unexpectedly in England and for whom a cause of death was not found, therefore falling under the category of SIDS or undetermined. We collated the organs weights from 2 institutions covering between them the South East and North of England including London, Yorkshire, and Derbyshire. The cases from The Royal London Hospital were autopsied between 1997 and 2013, and the cases from Sheffield Children's Hospital were autopsied between 2006 and 2013. There were 188 babies who had been born at term (62 female and 126 male) and 26 ex-premature babies (15 female and 11 male). Organs of male babies were slightly heavier than those of female babies but as there was no significant differences male and female babies were considered together. Comparison with standard charts (from 1932 and 1962) and with more recent charts confirmed the discrepancy between the older charts commonly in use with more recent measurements, including ours. The main reason for these differences is that babies in the recent charts were previously healthy babies with no long term disease and improved in the health of the population.
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Mortalidade Infantil , Tamanho do Órgão , Morte Súbita do Lactente/patologia , Autopsia , Causas de Morte , Inglaterra/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Morte Súbita do Lactente/epidemiologiaRESUMO
Most of the individuals infected with H. pylori acquire the infection early in life. However, there is limited data regarding endoscopic and histopathologic findings of H. pylori infection when it is acquired during infancy. The aim of this study was to investigate the H. pylori-related endoscopic and histopathological findings in children younger than 2 years of age. One hundred and fifty-two infants who underwent upper gastrointestinal endoscopy were included in the study. The diagnosis of H. pylori infection was based on histopathology and a positive rapid urease test. Forty of 152 (26.3%) infants were infected with H. pylori, and 65% of the infected infants had histopathologic gastritis. There were no clinical or endoscopic findings suggestive of H. pylori infection. No correlation could be found between the density of H. pylori and the severity of gastritis. H. pylori infection is associated with various degrees of gastritis in more than half of the infected infants. Since the likelihood of normal histopathology is rare in H. pylori-infected infants, its long-term complications should be cautiously followed up in endemic areas.
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Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Estômago/microbiologia , Estômago/patologia , Biópsia , Duodeno/microbiologia , Duodeno/patologia , Endoscopia Gastrointestinal , Esôfago/microbiologia , Esôfago/patologia , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Clinical trials for chronic hepatitis B (HBV) infection in children have shown usefulness of interferon alpha 2b (IFN-alpha) in eliminating HBV replication and in improving liver histology. Although it is not the ultimate goal of the interferon treatment for chronic HBV infection, it has been suggested in adults that HBsAg clearance decreases the likelihood of development of hepatocellular carcinoma, and prolongs the survival. HBV DNA clearance has been shown to be higher with higher doses of interferon in children, but it was rarely associated with HbsAg clearance. Ten MU/m2 was tried in 46 children who had biopsy-proven chronic HBV infection. They received IFN-alpha subcutaneously three times/week for six months. The treatment regimen was completed in 41 children and the second liver hiopsy was carried out one year after the end of the treatment in 30 of 41 patients. With this schedule, 15 (36.6%) children showed persistent loss of HBV DNA 12 months after the cessation of the treatment, 20 (48.7%) lost HBeAg, and eight (19.5%) developed anti-HBs antibody with loss of HBsAg. A significant improvement in liver histology was obtained in children with HBV DNA clearance. Serum ALT levels normalized in all HBeAg seroconverters. These findings suggested that the 10 MU/m2 IFN-alpha treatment was well tolerated and resulted in a high rate of HbsAg clearance in addition to HBV DNA clearance in a group of chidren with chronic HBV infection.
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Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/imunologia , Humanos , Interferon-alfa/efeitos adversos , Masculino , Resultado do TratamentoRESUMO
Solitary rectal ulcer syndrome (SRUS) is an unusual disorder of childhood, which usually presents with rectal bleeding, mucous discharge, prolonged straining, tenesmus, and localized pain in the perineal area. After the first description by Cruveilhier, Madigan and Morson further detailed the clinical and pathologic features of SRUS in 1969. The pathogenesis of the syndrome is not well-understood. The postulated mechanism responsible for rectal prolapse in most cases seems to be excessive straining efforts during which high intra-abdominal pressure forces the anterior rectal mucosa firmly into the contracting puborectalis muscle. The anterior rectal mucosa is frequently forced into the anal canal and as a consequence becomes strangulated, causing congestion, edema, and ulceration. Histologically, the presence of fibromuscular obliteration of the lamina propria with disorientation of muscle fibers is characteristic, which could be secondary to chronic mechanical and ischemic trauma and inflammation by hard stools, and intussusception of the rectal mucosa. Although the syndrome is well-recognized in adults, the pediatric experience with this condition is limited and often remains unrecognized or misdiagnosed. A misdiagnosis has been reported in one fourth of adult cases, and the correct diagnosis usually delayed approximately 5 to 7 years. There are few pediatric case reports in English literature. Here, we describe 2 children with SRUS, aged 11 and 14 years, whose SRUS was diagnosed 2 and 6 years, respectively, after the onset of the first signs and symptoms.