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BACKGROUND: A small subset of cases of inflammatory bowel disease (IBD) occurs as a result of single gene defects, and typically occurs in young or very young pediatric patients, referred to as "monogenic very-early onset IBD (VEO-IBD)". The gene variants leading to monogenic VEO-IBD are often associated with primary immunodeficiency syndromes. CASE REPORT: A six year-old girl presented to our gastroenterology clinic with LRBA deficiency with a heterozygous mutation at c.1399 A > G, p Met467Val, histopathologic chronic active colitis without granulomas and clinical chronic colitis. Her gastrointestinal symptoms began at age 5 with bloody diarrhea, abdominal pain and weight loss. Whole exome sequencing revealed a CARD11 heterozygous de novo mutation (c.220 + 1G > A). She was in clinical remission on only abatacept. DISCUSSION: We present a case of monogenic VEO-IBD associated with two heterozygous variants in LRBA1 and CARD11, both considered as key players in the newly proposed "immune TOR-opathies".
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Colite , Doenças Inflamatórias Intestinais , Humanos , Criança , Feminino , Pré-Escolar , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Colite/diagnóstico , Colite/genética , Mutação , Heterozigoto , Idade de Início , Guanilato Ciclase/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
BACKGROUND: Pseudoprogression (psPD) represents false radiologic evidence of tumor progression and is observed in some glioblastoma (GBM) patients after postoperative chemoradiation (CRT) with temozolomide (TMZ). The ambiguity of the psPD diagnosis confounds identification of true progression and may lead to unnecessary interventions. The association between psPD and isocitrate dehydrogenase 1 (IDH1) mutational (mut) status is understudied, and its incidence may alter clinical decision making. METHODS: We retrospectively evaluated 120 patients with IDH1-mut (n = 60) and IDH1-wild-type (IDH-WT; [n = 60]) GBMs who received postoperative CRT with TMZ at 4 academic institutions. Response Assessment in Neuro-Oncology criteria were used to identify psPD rates in routine brain MRIs performed up to 90 days after CRT completion. RESULTS: Within 90 days of completing CRT, 9 GBM patients (1 [1.7%] IDH1-mut and 8 [13.3%] IDH1-WTs) demonstrated true progression, whereas 17 patients (3 [5%] IDH1-muts and 14 [23.3%] IDH1-WTs) demonstrated psPD (P = .004). IDH1-mut GBMs had a lower probability of psPD (hazard ratio: 0.173, 95% CI, 0.047-0.638, P = .008). Among the patients with radiologic signs suggestive of progression (n = 26), psPD was found to be the cause in 3 of 4 (75.0%) of the IDH1-mut GBMs and 14 of 22 (63.6%) of the IDH1-WT GBMs (P = .496). Median overall survival for IDH1-mut and IDH1-WT GBM patients was 40.3 and 23.0 months, respectively (P < .001). CONCLUSIONS: IDH1-mut GBM patients demonstrate lower absolute rates of psPD expression. Irrespective of GBM subtype, psPD expression was more likely than true progression within 90 days of completing CRT. Continuing adjuvant treatment for IDH1-mut GBMs is suggested if radiologic progression is suspected during this time interval.
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Synovial sarcoma (SS) is a soft-tissue malignancy that most often affects patients aged between 15 and 40 years, and the prognosis for patients with metastatic disease is generally poor. This study was performed to evaluate checkpoint blockade immunotherapy markers in SS, including tumor mutational burden (TMB), DNA mismatch repair (MMR) status, and PDL-1 (programmed cell death ligand 1), PD1 (programmed cell death 1), and CD8 expression by normal-tumor paired whole-exome sequencing (WES) and immunohistochemistry (IHC). Outcomes evaluated included event-free and overall survival. Twenty one (21) FISH (Fluorescence In Situ Hybridization)-confirmed SS cases (11 F, 10 M) were studied, with age ranging from 8 to 89 years at diagnosis and follow-up ranging from 1 to 16 years. TMB (n = 16) ranged from 0.83 to 212/Mb (median, 1.7). Only one case showed a high TMB of 212/Mb and missense variants of MMR genes in the primary tumor, while the other 15 cases had a low TMB of less than 5/Mb. IHC was performed on all 21 tumor samples for PD-L1, PD1, CD8, and MMR proteins. PD-L1 membranous staining was detected in 3 of 21 cases (14.3%), ranging from 1 to 5% for tumor proportion score and 1-10 for combined positive score. PD1 was detected in 15 of 21 cases (71.4%), ranging from 1 to 25/HPF (high power field) (median, 2). CD8 stain was seen in all cases, ranging from 2 to 60/HPF (median, 5). PD1 staining results correlated with CD8 staining results (P < 0.0001). No correlation of TMB or IHC markers was found with survival. No fixed pattern of TMB or IHCs between primary and metastatic tumors was observed; there was no correlation between TMB or IHCs and age, location, or diagnosis subtype. All of the cases tested showed retained expression of MMR proteins. The results show that for SS, a tumor with strong driver translocation, most cases have a low TMB, but occasionally a high TMB may be present, as observed in 1 of the 16 (6.25%) cases. The demonstration of a subgroup of SS cases with high TMB might explain the 10% response rate to checkpoint immunotherapy observed in clinical trials in patients with SS.
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Antígeno B7-H1/análise , Biomarcadores Tumorais , Antígenos CD8/análise , Mutação , Receptor de Morte Celular Programada 1/análise , Sarcoma Sinovial/genética , Sarcoma Sinovial/imunologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Criança , Reparo de Erro de Pareamento de DNA , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Intervalo Livre de Progressão , Estudos Retrospectivos , Sarcoma Sinovial/secundário , Sarcoma Sinovial/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
This report describes a case of an ependymoma found in the setting of tethered cord syndrome. We present a 3-month-old girl with prenatal diagnosis of lumbar meningocele who later underwent tethered cord release. After birth, she was neurologically intact and only found to have a skin-covered meningocele. An MRI was obtained and significant for low-lying conus terminating at L5, a focal syrinx, and Chiari II malformation. She underwent an elective meningocele repair and resection of thickened filum for tethered cord release at 3 months of age. Unexpectedly, microscopic evaluation of the filum was consistent with a small focus of ependymoma in addition to the filum tissue. Previous case reports have suggested a link between thickened filum in the setting of spinal dysraphism and myxopapillary ependymoma, but to our knowledge, this is the first report of ependymoma in the setting of tethered cord syndrome.
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Cauda Equina/patologia , Ependimoma/diagnóstico , Meningocele/cirurgia , Neoplasias do Sistema Nervoso Periférico/diagnóstico , Feminino , Humanos , Lactente , Laminectomia , Imageamento por Ressonância Magnética , Defeitos do Tubo Neural/cirurgia , Disrafismo Espinal/complicaçõesRESUMO
NUT midline carcinoma (NMC) is a rare, aggressive poorly differentiated carcinoma genetically defined by NUTM1 gene rearrangement. The purpose of this study was to determine the tumor mutational burden (TMB) and the expression of immunohistochemical (IHC) markers in NMCs that are generally used to identify patients that might benefit from checkpoint immunotherapy. Three cases in a 39-year-old male (case 1) and two 13-year-old females (cases 2, 3) were identified from departmental files, with confirmation by NUT IHC and 15q14 rearrangement by fluorescent in situ hybridization. Normal-tumor paired whole exome sequencing (WES) was applied to determine TMB. IHC for DNA mismatch repair proteins, Programmed cell death ligand 1, programmed cell death 1 (PD1), and CD8 was also performed. WES yielded a TMB of 7.61 and 1.52 per Mbp in the primary and pulmonary metastasis in case 1, respectively, and a TMB of 1.04 per Mbp in the primary tumor of case 2. Programmed cell death ligand 1 tumor proportion score was 20%, 1%, and 0% and combined positive score was 25, 5, and 0 in cases 1, 2, and 3, respectively; PD1 stain counts were 25, 52, and 35 per high-power field and the PD1/CD8 ratio was 95%, 95%, and 99% in cases 1, 2, and 3, respectively. The CD8 count per high-power field was 15, 33, and 30 per high-power field in cases 1, 2, and 3, respectively. Mismatch repair IHCs showed retained staining. Although the number of cases is limited, this study is the first to investigate checkpoint immunotherapy markers in NMCs and the results demonstrate no clear biomarker association. However, the results suggest that, if checkpoint therapy is under consideration, a comprehensive workup utilizing WES and IHC is warranted.
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Carcinoma/genética , Inibidores de Checkpoint Imunológico/metabolismo , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Antígenos CD8/genética , Antígenos CD8/metabolismo , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma/secundário , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Sequenciamento do ExomaRESUMO
Williams syndrome is a rare genetic disease that affects elastin production, leading to medium and large vessel stenoses and other abnormalities. Cardiac manifestations of Williams syndrome are the most life-threatening, occurring in 80% of children. Children with Williams syndrome are known to be at risk for sudden cardiac death. These tragic events are often precipitated by diagnostic or therapeutic procedures requiring anaesthesia or sedation, such as cardiac catheterisation. We present the case of a 3-month-old infant with Williams syndrome who suffered sudden cardiac arrest during cardiac catheterisation and subsequent arrest approximately 48 hours after the procedure. We also review the current literature focused on children with Williams syndrome who have suffered sudden cardiac arrest during or after cardiac catheterisation procedures.
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Ewing sarcoma (ES) is an aggressive, primary bone malignancy with occasional soft tissue extension. Purely extra-osseous ES is rare. A primary intraspinal, intradural ES without bone involvement is exceedingly rare. ES may be differentiated from other primitive neuroectodermal tumors by molecular analysis. The authors report the case of a 14-year-old female who suffered an acute neurologic decline from a hemorrhagic, intraspinal, intradural ES. The patient has been tumor free for 2 years after the initial emergency surgery. Our management of the patient and a review of the literature are provided. Considering only those cases with molecular or genetic confirmation of ES, our patient is the fifth pediatric case reported in the English literature.