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1.
Mod Pathol ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296931

RESUMO

We report two malignant sacrococcygeal tumors in infants that were associated with pathogenic DICER1 variation. These tumors were composed of primitive neuroepithelium, embryonal rhabdomyosarcoma, and cartilage and initially diagnosed as immature teratomas. One child developed intracranial metastasis and died. The second child underwent surgery and chemotherapy and achieved complete remission. This child subsequently developed five additional DICER1-associated neoplasms by age nine. Genetic analysis revealed that both tumors harbored biallelic pathogenic DICER1 variation. We believe these cases represent another novel subtype of DICER1-associated tumor. This new entity, which we propose to call DICER1-associated presacral malignant teratoid neoplasm, may be difficult initially to distinguish from immature teratoma, but recognizing it as an entity can prompt appropriate classification as an aggressive malignancy and facilitate appropriate genetic counseling, DICER1 germline variant testing, screening, and education.

3.
J Clin Oncol ; 37(8): 668-676, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30715996

RESUMO

PURPOSE: DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of neoplasm incidence accounting for competing risks ("cumulative incidence") of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation. PATIENTS AND METHODS: We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors ("neoplasms," excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival. RESULTS: We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers. CONCLUSION: This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.

4.
Pediatr Blood Cancer ; 66(5): e27628, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30677214

RESUMO

Pleuropulmonary blastoma (PPB) is a rare pediatric tumor. The central nervous system (CNS) is the most common site of extrathoracic metastasis. The prognosis of PPB patients with CNS metastases is dismal: most patients die within one year after recurrence. Here, we describe two patients diagnosed with PPB who developed intracranial recurrences shortly after the end of their initial treatment and were successfully treated by gross total resection, radiotherapy, and chemotherapy. Both patients are in complete remission four and three years after recurrence. Although an optimal regimen remains to be determined, these cases demonstrate that PPB with CNS metastases is potentially curable.

5.
Ophthalmology ; 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30339877

RESUMO

PURPOSE: To characterize the ocular phenotype of DICER1 syndrome. DESIGN: Prospective, single-center, case-control study. PARTICIPANTS: One hundred three patients with an identified germline pathogenic DICER1 variant (DICER1 carriers) and 69 family control participants underwent clinical and ophthalmic examination at the National Institutes of Health between 2011 and 2016. METHODS: All participants were evaluated with a comprehensive ophthalmic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, and a dilated fundus examination. A subset of patients returned for a more detailed evaluation including spectral-domain OCT, color fundus photography, fundus autofluorescence imaging, visual field testing, full-field electroretinography, and genetic testing for inherited retinal degenerative diseases. MAIN OUTCOME MEASURES: Visual acuity and examination findings. RESULTS: Most DICER1 carriers (97%) maintained a visual acuity of 20/40 or better in both eyes. Twenty-three DICER1 carriers (22%) showed ocular abnormalities compared with 4 family controls (6%; P = 0.005). These abnormalities included retinal pigment abnormalities (n = 6 [5.8%]), increased cup-to-disc ratio (n = 5 [4.9%]), optic nerve abnormalities (n = 2 [1.9%]), epiretinal membrane (n = 2 [1.9%]), and drusen (n = 2 [1.9%]). Overall, we observed a significant difference (P = 0.03) in the rate of retinal abnormalities in DICER1 carriers (n = 11 [11%]) versus controls (n = 1 [1.5%]). One patient demonstrated an unexpected diagnosis of retinitis pigmentosa with a novel variant of unknown significance in PRPF31, and 1 showed optic nerve elevation in the setting of increased intracranial pressure (ICP) of unclear cause. Three patients (3%) demonstrated DICER1-related ciliary body medulloepithelioma (CBME), 2 of which were identified during routine examination, a higher rate than that reported previously. CONCLUSIONS: Ophthalmologists should be aware of the ophthalmic manifestations of DICER1 syndrome, and individuals and families should be counseled on the potential signs and symptoms. We recommend that children with a germline pathogenic variant in DICER1, especially those younger than 10 years, undergo annual dilated ophthalmic examination, looking for evidence of CBME, signs of increased ICP, and perhaps changes in the retinal pigment epithelium.

6.
Pediatr Nephrol ; 33(12): 2281-2288, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30178239

RESUMO

BACKGROUND: The DICER1 syndrome is a tumor-predisposition disorder caused by germline pathogenic variation in DICER1 and is associated with cystic nephroma and other renal neoplasms. Dicer1 mouse and rare human DICER1 syndrome case reports describe structural kidney and collecting system anomalies. We investigated renal function and the frequency of structural abnormalities of the kidney and collecting system in individuals with germline loss-of-function variants in DICER1. METHODS: In this family-based cohort study, prospectively ascertained germline DICER1-mutation carriers (DICER1-carriers) and unaffected family controls were evaluated at the National Institutes of Health Clinical Center with renal ultrasound and comprehensive laboratory testing. Two radiologists reviewed the imaging studies from all participants for structural abnormalities, cysts, and tumors. RESULTS: Eighty-nine DICER1-carriers and 61 family controls were studied. Renal cysts were detected in 1/33 DICER1-carrier children without history of cystic nephroma. Similar proportions of adult DICER1-carriers (8/48; 17%) and controls (11/50; 22%) had ultrasound-detected renal cysts (P = 0.504). 8/89 (9%) DICER1-carriers harbored ultrasound-detected structural abnormalities of varying severity within the collecting system or kidney, nephrolithiasis, or nephrocalcinosis. None of the family controls (0/61) had similar findings on ultrasound (P = 0.02). No meaningful differences in renal laboratory values between DICER1-carriers and unaffected family controls were observed. CONCLUSIONS: Our report is the first to systematically characterize renal function and anatomy in a large prospective cohort of DICER1-carriers and DICER1-negative family controls. DICER1-carriers may be at increased risk of structural anomalies of the kidney or collecting system. The role for DICER1 in renal morphogenesis merits additional investigation.

7.
Clin Cancer Res ; 24(10): 2251-2261, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29343557

RESUMO

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma, and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing and surveillance and treatment recommendations. Attendees from North America, Europe, and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology, and clinical research. Recommendations are provided for genetic testing; prenatal management; and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, and central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated. Clin Cancer Res; 24(10); 2251-61. ©2018 AACR.

8.
Gynecol Oncol ; 147(3): 521-527, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29037807

RESUMO

BACKGROUND: Ovarian sex cord-stromal tumors (OSCST) include juvenile granulosa cell tumors (JGCT), Sertoli-Leydig cell tumor (SLCT) and gynandroblastoma (GAB) among others. These ovarian sex cord-stromal tumors as well as other tumors including pleuropulmonary blastoma (PPB) may be associated with DICER1 mutations. We sought to describe the clinical and genetic findings from the first 107 individuals enrolled in the International Ovarian and Testicular Stromal Tumor Registry. METHODS: Medical and family history were obtained for individuals consecutively enrolled in the International Ovarian and Testicular Stromal Tumor Registry. Pathology was centrally reviewed. DICER1 sequencing was performed on blood and tumor tissue. RESULTS: Of the 107 participants, 49 had SLCT, 25 had JGCT and 5 had GAB. Nearly all (36/37) SLCTs and 4/4 GAB tested had a DICER1 mutation in an RNase IIIb domain hotspot; approximately half of these individuals had a predisposing germline DICER1 mutation. Metachronous SLCTs were seen in 3 individuals with germline DICER1 mutations. Other DICER1-associated conditions were seen in 19% of patients with SLCT or GAB. Three children of women with SLCT were diagnosed with PPB based on genetic testing and clinical screening during the course of this study. All were diagnosed with PPB in its earliest and most curable form (Type I), were treated with surgery alone, and are alive without evidence of disease. CONCLUSIONS: Recognition of the distinct genetic basis for a group of these tumors improves precise classification in difficult cases and promotes mutation-based screening and early detection.


Assuntos
RNA Helicases DEAD-box/genética , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Tumor de Células de Sertoli-Leydig/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Lactente , Pessoa de Meia-Idade , Mosaicismo , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Prognóstico , Sistema de Registros , Tumor de Células de Sertoli-Leydig/enzimologia , Tumor de Células de Sertoli-Leydig/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/enzimologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Adulto Jovem
9.
Int J Cancer ; 141(10): 2030-2036, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28748527

RESUMO

The DICER1 syndrome is associated with a variety of rare benign and malignant tumors, including pleuropulmonary blastoma (PPB), cystic nephroma (CN) and Sertoli-Leydig cell tumor (SLCT). The prevalence and penetrance of pathogenic DICER1 variation in the general population is unknown. We examined three publicly-available germline whole exome sequence datasets: Exome Aggregation Consortium (ExAC), 1,000 Genomes (1,000 G) and the Exome Sequencing Project (ESP). To avoid over-estimation of pathogenic DICER1 variation from cancer-associated exomes, we excluded The Cancer Genome Atlas (TCGA) variants from ExAC. All datasets were annotated with snpEff and ANNOVAR and variants were classified into four categories: likely benign (LB), unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). The prevalence of DICER1 P/LP variants was 1:870 to 1:2,529 in ExAC-nonTCGA (53,105 exomes) estimated by metaSVM and REVEL/CADD, respectively. A more stringent prevalence calculation considering only loss-of-function and previously-published pathogenic variants detected in ExAC-nonTCGA, yielded a prevalence of 1:10,600. Despite the rarity of most DICER1 syndrome tumors, pathogenic DICER1 variation is more common than expected. If confirmed, these findings may inform future sequencing-based newborn screening programs for PPB, CN and SLCT, in which early detection improves prognosis.


Assuntos
Biomarcadores/metabolismo , RNA Helicases DEAD-box/genética , Doenças Renais Císticas/genética , Neoplasias Ovarianas/genética , Blastoma Pulmonar/genética , Ribonuclease III/genética , Tumor de Células de Sertoli-Leydig/genética , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Doenças Renais Císticas/epidemiologia , Neoplasias Ovarianas/epidemiologia , Prevalência , Prognóstico , Blastoma Pulmonar/epidemiologia , Tumor de Células de Sertoli-Leydig/epidemiologia , Estados Unidos/epidemiologia
10.
J Clin Endocrinol Metab ; 102(5): 1614-1622, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323992

RESUMO

Context: The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown. Objective: To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome. Design: Family-based cohort study. Setting: National Institutes of Health (NIH) Clinical Center (CC). Participants: The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families. Interventions: Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC. Main Outcome Measures: The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing. Results: By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations. Conclusions: We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.


Assuntos
Adenocarcinoma Folicular/epidemiologia , Carcinoma/epidemiologia , RNA Helicases DEAD-box/genética , Bócio Nodular/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Ribonuclease III/genética , Neoplasias da Glândula Tireoide/epidemiologia , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/cirurgia , Adolescente , Adulto , Carcinoma/genética , Carcinoma/cirurgia , Carcinoma Papilar , Estudos de Casos e Controles , Estudos de Coortes , Família , Feminino , Mutação em Linhagem Germinativa , Bócio Nodular/diagnóstico por imagem , Bócio Nodular/genética , Bócio Nodular/cirurgia , Humanos , Incidência , Masculino , Prevalência , Risco , Análise de Sequência de DNA , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/estatística & dados numéricos , Ultrassonografia , Adulto Jovem
11.
Arch Pathol Lab Med ; 141(1): 43-48, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27681334

RESUMO

CONTEXT: -The placenta is an important component in understanding the fetal response to intrauterine Zika virus infection, but the pathologic changes in this organ remain largely unknown. Hofbauer cells are fetal-derived macrophages normally present in the chorionic villous stroma. They have been implicated in a variety of physiological and pathologic processes, in particular involving infectious agents. OBJECTIVES: -To characterize the fetal and maternal responses and viral localization in the placenta following Zika virus transmission to an 11 weeks' gestation fetus. The clinical course was notable for prolonged viremia in the mother and extensive neuronal necrosis in the fetus. The fetus was delivered at 21 weeks' gestation after pregnancy termination. DESIGN: -The placenta was evaluated by using immunohistochemistry for inflammatory cells (macrophages/monocytes [Hofbauer cells], B and T lymphocytes) and proliferating cells, and an RNA probe to Zika virus. The fetal brain and the placenta were previously found to be positive for Zika virus RNA by reverse transcription-polymerase chain reaction. RESULTS: -The placenta demonstrated prominently enlarged, hydropic chorionic villi with hyperplasia and focal proliferation of Hofbauer cells. The degree of Hofbauer cell hyperplasia gave an exaggerated immature appearance to the villi. No acute or chronic villitis, villous necrosis, remote necroinflammatory abnormalities, chorioamnionitis, funisitis, or hemorrhages were present. An RNA probe to Zika virus was positive in villous stromal cells, presumably Hofbauer cells. CONCLUSIONS: -Zika virus placental infection induces proliferation and prominent hyperplasia of Hofbauer cells in the chorionic villi but does not elicit villous necrosis or a maternal or fetal lymphoplasmacellular or acute inflammatory cell reaction.


Assuntos
Proliferação de Células , Macrófagos/virologia , Placenta/patologia , Placenta/virologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia , Zika virus/fisiologia , Adulto , Animais , Vilosidades Coriônicas/diagnóstico por imagem , Vilosidades Coriônicas/patologia , Vilosidades Coriônicas/virologia , Feminino , Feto/diagnóstico por imagem , Feto/patologia , Feto/virologia , Idade Gestacional , Interações Hospedeiro-Patógeno , Humanos , Hiperplasia , Macrófagos/patologia , Imagem por Ressonância Magnética , Placenta/diagnóstico por imagem , Gravidez , Ultrassonografia Pré-Natal , Infecção por Zika virus/diagnóstico por imagem
13.
Am Fam Physician ; 94(11): 884-889, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27929271

RESUMO

The results of large clinical trials have led physicians and patients to question the safety of hormone therapy for menopause. In the past, physicians prescribed hormone therapy to improve overall health and prevent cardiac disease, as well as for symptoms of menopause. Combined estrogen/progestogen therapy, but not estrogen alone, increases the risk of breast cancer when used for more than three to five years. Therefore, in women with a uterus, it is recommended that physicians prescribe combination therapy only to treat menopausal symptoms such as vasomotor symptoms (hot flashes) and vaginal atrophy, using the smallest effective dosage for the shortest possible duration. Although estrogen is the most effective treatment for hot flashes, nonhormonal alternatives such as low-dose paroxetine, venlafaxine, and gabapentin are effective alternatives. Women with a uterus who are using estrogen should also take a progestogen to reduce the risk of endometrial cancer. Women who cannot tolerate adverse effects of progestogens may benefit from a combined formulation of estrogen and the selective estrogen receptor modulator bazedoxifene. There is no highquality, consistent evidence that yoga, paced respiration, acupuncture, exercise, stress reduction, relaxation therapy, and alternative therapies such as black cohosh, botanical products, omega-3 fatty acid supplements, and dietary Chinese herbs benefit patients more than placebo. One systematic review suggests modest improvement in hot flashes and vaginal dryness with soy products, and small studies suggest that clinical hypnosis significantly reduces hot flashes. Patients with genitourinary syndrome of menopause may benefit from vaginal estrogen, nonhormonal vaginal moisturizers, or ospemifene (the only nonhormonal treatment approved by the U.S. Food and Drug Administration for dyspareunia due to menopausal atrophy). The decision to use hormone therapy depends on clinical presentation, a thorough evaluation of the risks and benefits, and an informed discussion with the patient.


Assuntos
Dispareunia/terapia , Terapia de Reposição de Estrogênios/métodos , Fogachos/terapia , Menopausa , Doenças Vaginais/terapia , Terapia por Acupuntura , Administração Intravaginal , Aminas/uso terapêutico , Antidepressivos/uso terapêutico , Atrofia , Ácidos Cicloexanocarboxílicos/uso terapêutico , Suplementos Nutricionais , Quimioterapia Combinada , Estrogênios/uso terapêutico , Terapia por Exercício , Feminino , Gabapentina , Humanos , Hipnose , Indóis/uso terapêutico , Paroxetina/uso terapêutico , Progestinas/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/análogos & derivados , Tamoxifeno/uso terapêutico , Vagina , Sistema Vasomotor , Cloridrato de Venlafaxina/uso terapêutico , Ácido gama-Aminobutírico/uso terapêutico
14.
J Oncol Pract ; 12(10): 940-946, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27858560

RESUMO

Ovarian sex cord-stromal tumors are clinically significant heterogeneous tumors that include several pathologic types. These tumors are often found in adolescents and young adults and can present with hormonal manifestations as well as signs and symptoms of a pelvic mass. Serum tumor markers may assist in preoperative diagnosis and surveillance. Several subtypes are associated with genetic predisposition, including those observed in patients with Peutz-Jegher syndrome. Recent studies have elucidated the relationship between Sertoli-Leydig cell tumors and DICER1 mutations. When classified as International Federation of Gynecology and Obstetrics stage Ia, most subtypes may be treated with surgery alone. Higher stage or recurrent tumors have variable prognoses that range from a usually rapid course in poorly differentiated Sertoli-Leydig cell tumor to an often prolonged course in adult granulosa cell tumors. New understanding of the molecular pathogenesis of these tumors may pave the way for novel therapeutics.


Assuntos
Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Feminino , Humanos , Masculino , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Tumores do Estroma Gonadal e dos Cordões Sexuais/epidemiologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/terapia , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Neoplasias Testiculares/terapia
15.
Semin Diagn Pathol ; 33(6): 450-461, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27838088

RESUMO

Dr. Louis Dehner is an internationally renowned surgical pathologist who has published multiple textbooks and has authored or co-authored nearly 400 original articles in the medical literature. While many think of him as a pediatric pathologist, he has contributed to the literature across virtually the entire breadth of surgical pathology, and the lung and pleura is no exception. This review will highlight Dr. Dehner׳s contributions to the pulmonary and pleural pathology literature in the areas of infectious disease, medical lung disease and transplant pathology, and a number of neoplasms of the lung and pleura, with the remainder of this manuscript dedicated to the still evolving story of the pleuropulmonary blastoma as the signature contribution of his long and distinguished career.


Assuntos
Pneumopatias/história , Patologia Cirúrgica/história , Doenças Pleurais/história , História do Século XX , História do Século XXI , Humanos , Pneumopatias/patologia , Doenças Pleurais/patologia
17.
N Engl J Med ; 374(22): 2142-51, 2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27028667

RESUMO

The current outbreak of Zika virus (ZIKV) infection has been associated with an apparent increased risk of congenital microcephaly. We describe a case of a pregnant woman and her fetus infected with ZIKV during the 11th gestational week. The fetal head circumference decreased from the 47th percentile to the 24th percentile between 16 and 20 weeks of gestation. ZIKV RNA was identified in maternal serum at 16 and 21 weeks of gestation. At 19 and 20 weeks of gestation, substantial brain abnormalities were detected on ultrasonography and magnetic resonance imaging (MRI) without the presence of microcephaly or intracranial calcifications. On postmortem analysis of the fetal brain, diffuse cerebral cortical thinning, high ZIKV RNA loads, and viral particles were detected, and ZIKV was subsequently isolated.


Assuntos
Encéfalo/anormalidades , Feto/anormalidades , Microcefalia/virologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Adulto , Encéfalo/embriologia , Encéfalo/patologia , Encéfalo/virologia , Surtos de Doenças , Feminino , Humanos , Imagem por Ressonância Magnética , Gravidez , Ultrassonografia Pré-Natal , Viremia , Infecção por Zika virus/epidemiologia
18.
Nat Genet ; 48(3): 273-82, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26829751

RESUMO

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.


Assuntos
Glioma/genética , Proteínas Oncogênicas v-myb/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Criança , Hibridização Genômica Comparativa , Exoma/genética , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Proteínas Oncogênicas v-myb/biossíntese , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Ligação a RNA/biossíntese
19.
Fam Cancer ; 15(1): 105-10, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26289771

RESUMO

Germline DICER1 mutations have been described in individuals with pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumor (SLCT), sarcomas, multinodular goiter, thyroid carcinoma, cystic nephroma and other neoplastic conditions. Early results from the International Ovarian and Testicular Stromal Tumor Registry show germline DICER1 mutations in 48 % of girls and women with SLCT. In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tumors, an additional somatic mutation in the RNase IIIb domain of DICER1 was found. In rare patients, germline intronic mutations in DICER1 that are predicted to cause incorrect splicing can also contribute to the pathogenesis of SLCT.


Assuntos
RNA Helicases DEAD-box/genética , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Neoplasias Testiculares/genética , Adolescente , Sequência de Aminoácidos , Criança , Feminino , Humanos , Íntrons , Masculino , Dados de Sequência Molecular , Mutação , Sistema de Registros
20.
J Clin Endocrinol Metab ; 101(1): 1-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26555935

RESUMO

CONTEXT: DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established. CASE DESCRIPTION: We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings. CONCLUSIONS: This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.


Assuntos
Carcinoma/genética , RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adolescente , Carcinoma/patologia , Carcinoma Papilar , Criança , Éxons/genética , Feminino , Hiperplasia Nodular Focal do Fígado/genética , Hiperplasia Nodular Focal do Fígado/patologia , Humanos , Masculino , Mutação/genética , Mutação de Sentido Incorreto/genética , Linhagem , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia
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