RESUMO
In mammalian skin, multiple types of resident cells are required to create a functional tissue and support tissue homeostasis and regeneration. The cells that compose the epithelial stem cell niche for skin homeostasis and regeneration are not well defined. Here, we identify adipose precursor cells within the skin and demonstrate that their dynamic regeneration parallels the activation of skin stem cells. Functional analysis of adipocyte lineage cells in mice with defects in adipogenesis and in transplantation experiments revealed that intradermal adipocyte lineage cells are necessary and sufficient to drive follicular stem cell activation. Furthermore, we implicate PDGF expression by immature adipocyte cells in the regulation of follicular stem cell activity. These data highlight adipogenic cells as skin niche cells that positively regulate skin stem cell activity, and suggest that adipocyte lineage cells may alter epithelial stem cell function clinically.
Assuntos
Adipócitos/citologia , Folículo Piloso/citologia , Pele/citologia , Células-Tronco/citologia , Adipogenia , Animais , Feminino , Humanos , Masculino , Camundongos , Modelos Animais , Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
Pseudomonas aeruginosa arylsulfatase (PAS) hydrolyzes sulfate and, promiscuously, phosphate monoesters. Enzyme-catalyzed sulfate transfer is crucial to a wide variety of biological processes, but detailed studies of the mechanistic contributions to its catalysis are lacking. We present linear free energy relationships (LFERs) and kinetic isotope effects (KIEs) of PAS and analyses of active site mutants that suggest a key role for leaving group (LG) stabilization. In LFERs PASWT has a much less negative Brønsted coefficient (ßleaving groupobs-Enz = -0.33) than the uncatalyzed reaction (ßleaving groupobs = -1.81). This situation is diminished when cationic active site groups are exchanged for alanine. The considerable degree of bond breaking during the transition state (TS) is evidenced by an 18Obridge KIE of 1.0088. LFER and KIE data for several active site mutants point to leaving group stabilization by active site K375, in cooperation with H211. 15N KIEs and the increased sensitivity to leaving group ability of the sulfatase activity in neat D2O (Δßleaving groupH-D = +0.06) suggest that the mechanism for S-Obridge bond fission shifts, with decreasing leaving group ability, from charge compensation via Lewis acid interactions toward direct proton donation. 18Ononbridge KIEs indicate that the TS for PAS-catalyzed sulfate monoester hydrolysis has a significantly more associative character compared to the uncatalyzed reaction, while PAS-catalyzed phosphate monoester hydrolysis does not show this shift. This difference in enzyme-catalyzed TSs appears to be the major factor favoring specificity toward sulfate over phosphate esters by this promiscuous hydrolase, since other features are either too similar (uncatalyzed TS) or inherently favor phosphate (charge).
Assuntos
Arilsulfatases/metabolismo , Fosfatos/química , Sulfatos/química , Arilsulfatases/genética , Catálise , Domínio Catalítico , Hidrólise , Cinética , Organofosfatos/química , Compostos Organofosforados/química , Fosfatos/metabolismo , Pseudomonas aeruginosa/metabolismo , Especificidade por Substrato/genética , Especificidade por Substrato/fisiologia , Sulfatases/química , Sulfatos/metabolismoRESUMO
Integration of morphological, immunohistochemical, and molecular methods is often necessary for the precise diagnosis and optimal clinical management of sarcomas. We have validated and implemented a clinical molecular diagnostic assay, MSK- Fusion Solid, for detection of gene fusions in solid tumors, including sarcomas. Starting with RNA extracted from formalin-fixed paraffin-embedded tumor material, this targeted RNA sequencing assay utilizes anchored multiplex PCR to detect oncogenic fusion transcripts involving 62 genes known to be recurrently rearranged in solid tumors including sarcomas without prior knowledge of fusion partners. From 1/2016 to 1/2018, 192 bone and soft tissue tumors were submitted for MSK- Fusion Solid analysis and 96% (184/192) successfully passed all the pre-sequencing quality control parameters and sequencing steps. These sarcomas encompass 24 major tumor types, including 175 soft tissue tumors and 9 osteosarcomas. Ewing and Ewing-like sarcomas, rhabdomyosarcoma, and sarcoma-not otherwise specified were the three most common tumor types. Diagnostic in-frame fusion transcripts were detected in 43% of cases, including 3% (6/184) with novel fusion partners, specifically TRPS1-PLAG1, VCP-TFE3, MYLK-BRAF, FUS-TFCP2, and ACTB-FOSB, the latter in two cases of pseudomyogenic hemangioendothelioma, representing a novel observation in this sarcoma. Our experience shows that this targeted RNA sequencing assay performs in a robust and sensitive fashion on RNA extracted from most routine clinical specimens of sarcomas thereby facilitating precise diagnosis and providing opportunities for novel fusion partner discovery.
Assuntos
Actinas/genética , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Proteínas Proto-Oncogênicas c-fos/genética , Sarcoma/genética , Análise de Sequência de RNA , Neoplasias de Tecidos Moles/genética , Adolescente , Adulto , Idoso , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Feminino , Predisposição Genética para Doença , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Sarcoma/patologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapiaRESUMO
A cutaneous melanocytic tumor with morphologic overlap with clear cell sarcoma, but defined by CRTC1-TRIM11 gene fusion, was recently described in a series of five adult patients. Here, we expand the clinicopathologic features of this entity by four additional cases which include pediatric presentation, exophytic growth, and propensity to occur on the head. Patients (2F; 2M) had a median age of 41 years (range 11-59). Sites of involvement included leg, ear, and face. Tumors were circumscribed, unencapsulated, mostly limited to the dermis, and varied from 5 to 35 mm. One case was exophytic. Lesional cells were arranged in nests and fascicles, and were monomorphic and fusiform with moderate pale to clear cytoplasm, occasional nuclear pseudo-inclusions, and small to prominent nucleoli. Mitotic rate was variable (rare to 12/10 HPF, median 3/10 HPF). The pediatric case showed increased nuclear pleomorphism, tumor necrosis, and mitotic figures. All cases showed strong, diffuse nuclear staining for SOX10, but were negative or focal for S100 protein, HMB45 and Melan-A expression. Cases were positive by FISH technique and/or RNA sequencing for a TRIM11 rearrangement/fusion, and negative for EWSR1 rearrangement. This series is presented to aid in further characterization of this novel melanocytic tumor.
Assuntos
Melanócitos , Proteínas de Fusão Oncogênica , Sarcoma de Células Claras , Neoplasias Cutâneas , Fatores de Transcrição , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Adulto , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Nucléolo Celular/patologia , Criança , Citoplasma/genética , Citoplasma/metabolismo , Citoplasma/patologia , Feminino , Humanos , Antígeno MART-1/genética , Antígeno MART-1/metabolismo , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/metabolismo , Sarcoma de Células Claras/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
This case-series describes the 6 human infections with Onchocerca lupi, a parasite known to infect cats and dogs, that have been identified in the United States since 2013. Unlike cases reported outside the country, the American patients have not had subconjunctival nodules but have manifested more invasive disease (eg, spinal, orbital, and subdermal nodules). Diagnosis remains challenging in the absence of a serologic test. Treatment should be guided by what is done for Onchocerca volvulus as there are no data for O. lupi. Available evidence suggests that there may be transmission in southwestern United States, but the risk of transmission to humans is not known. Research is needed to better define the burden of disease in the United States and develop appropriately-targeted prevention strategies.
Assuntos
Doenças Transmissíveis Emergentes , Doenças do Cão/epidemiologia , Onchocerca/isolamento & purificação , Oncocercose , Zoonoses , Adolescente , Animais , Gatos , Criança , Pré-Escolar , Doenças Transmissíveis Emergentes/diagnóstico , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/parasitologia , Doenças Transmissíveis Emergentes/transmissão , Efeitos Psicossociais da Doença , Doenças do Cão/diagnóstico , Doenças do Cão/parasitologia , Cães , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Onchocerca/genética , Oncocercose/diagnóstico , Oncocercose/parasitologia , Oncocercose/transmissão , Oncocercose/veterinária , Sudoeste dos Estados Unidos/epidemiologia , Estados Unidos/epidemiologia , Zoonoses/diagnóstico , Zoonoses/epidemiologia , Zoonoses/parasitologia , Zoonoses/transmissãoRESUMO
Obesity has been associated with high bone mineral density (BMD) but a greater propensity to fracture. Some obese individuals have increased marrow adipose tissue (MAT), but the impact of MAT on bone turnover remains controversial, as do changes in BMD associated with a high fat diet (HFD). In this study we hypothesized that MAT volume would increase in response to HFD but would be independent of changes in BMD. Hence, we fed C57BL/6J (B6) male mice at 3 weeks of age either a high fat diet (60 kcal %) or regular diet (10 kcal %) for 12 weeks (n = 10/group). We measured MAT volume by osmium staining and micro-CT (µCT) as well as bone parameters by µCT, histomorphometry, and dual-energy X-ray absorptiometry. We also performed a short-term pilot study using 13-week-old B6 males and females fed a HFD (58 kcal %) for 2 weeks (n = 3/sex). Both long- and short-term HFD feedings were associated with high MAT volume, however, femoral trabecular bone volume fraction (BV/TV), bone formation rate and cortical bone mass were not altered in the long-term study. In the short-term pilot study, areal BMD was unchanged after 2 weeks of HFD. We conclude that, for B6 mice fed a HFD starting at wean or 13 weeks of age, MAT increases whereas bone mass is not altered. More studies are needed to define the mechanism responsible for the rapid storage of energy in the marrow and its distinction from other adipose depots.
Assuntos
Tecido Adiposo/crescimento & desenvolvimento , Medula Óssea/metabolismo , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Metabolismo Energético , Feminino , Fêmur/efeitos dos fármacos , Fêmur/crescimento & desenvolvimento , Humanos , Leptina/metabolismo , Masculino , Camundongos , Obesidade/patologia , Osteogênese/efeitos dos fármacosRESUMO
BACKGROUND: Cutaneous infection with the mite Sarcoptes scabiei var. hominis is associated with epidermal and dermal changes. After noting superficial fibrin thrombi in two biopsies with scabies mites, we comprehensively reviewed the histopathologic findings in scabietic infections to determine the frequency of this finding. METHODS: Twenty five biopsies of scabies infection were retrieved from the archives of our institution; only cases containing scabietic mite parts or scybala were included. The microscopic features were documented. RESULTS: Nearly half (40%) of the cases showed fibrin thrombi within vessels of the superficial dermis. Other frequent findings included dermal eosinophils (88% of cases), epidermal spongiosis (76% of cases), lymphocyte atypia (64%), a superficial and deep infiltrate (52% of cases), dermal neutrophils (52%) and endothelial cell swelling (52%). Half of the cases contained polarizable mite elements. Less commonly encountered features included extravasated erythrocytes (44%), dermal edema (32%), pink 'pigtails'(28%), intraepidermal pustules (24%), plasma cells (20%) and vasculitis (4%). CONCLUSIONS: The pathologic characteristics of scabietic infection are wide-ranging. Spongiosis, superficial and deep inflammation, and dermal eosinophils and neutrophils are seen in the majority of cases. Superficial fibrin thrombi are not uncommon in scabietic infection, and may provide a helpful diagnostic clue when mites are not visible on initial sections.
Assuntos
Sarcoptes scabiei , Escabiose/sangue , Escabiose/patologia , Trombose/parasitologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Eosinófilos/patologia , Feminino , Fibrina/metabolismo , Humanos , Lactente , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Escabiose/parasitologia , Pele/parasitologia , Pele/patologia , Trombose/patologia , Vasculite/parasitologia , Vasculite/patologia , Adulto JovemRESUMO
Obesity is characterized by an expansion of white adipose tissue mass that results from an increase in the size and the number of adipocytes. However, the mechanisms responsible for the formation of adipocytes during development and the molecular mechanisms regulating their increase and maintenance in adulthood are poorly understood. Here, we report the use of leptin-luciferase BAC transgenic mice to track white adipose tissue (WAT) development and guide the isolation and molecular characterization of adipocytes during development using DNA microarrays. These data reveal distinct transcriptional programs that are regulated during murine WAT development in vivo. By using a de novo cis-regulatory motif discovery tool (FIRE), we identify two early gene clusters whose promoters show significant enrichment for NRF2/ETS transcription factor binding sites. We further demonstrate that Ets transcription factors, but not Nrf2, are regulated during early adipogenesis and that Ets2 is essential for the normal progression of the adipocyte differentiation program in vitro. These data identify ETS2 as a functionally important transcription factor in adipogenesis and its possible role in regulating adipose tissue mass in adults can now be tested. Our approach also provides the basis for elucidating the function of other gene networks during WAT development in vivo. Finally these data confirm that although gene expression during adipogenesis in vitro recapitulates many of the patterns of gene expression in vivo, there are additional developmental transitions in pre and post-natal adipose tissue that are not evident in cell culture systems.
Assuntos
Adipogenia/genética , Tecido Adiposo Branco/embriologia , Tecido Adiposo Branco/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Proteína Proto-Oncogênica c-ets-2/metabolismo , Células 3T3-L1 , Animais , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteína Proto-Oncogênica c-ets-2/genéticaRESUMO
Pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, has been linked to distinct diseases involving adipose or bone tissue, the metabolic syndrome, and osteogenesis imperfecta (OI) type VI. Since mesenchymal stem cell (MSC) differentiation into adipocytes vs. osteoblasts can be regulated by specific factors, PEDF-directed dependency of murine and human MSCs was assessed. PEDF inhibited adipogenesis and promoted osteoblast differentiation of murine MSCs, osteoblast precursors, and human MSCs. Blockade of adipogenesis by PEDF suppressed peroxisome proliferator-activated receptor-γ (PPARγ), adiponectin, and other adipocyte markers by nearly 90% compared with control-treated cells (P<0.001). Differentiation to osteoblasts by PEDF resulted in a common pathway that involved PPARγ suppression (P<0.01). Canonical Wnt-ß-catenin signaling results in a MSC differentiation pattern analogous to that seen with PEDF. Thus, adding PEDF enhanced Wnt-ß-catenin signal transduction in human MSCs, demonstrating a novel Wnt agonist function. In PEDF knockout (KO) mice, total body adiposity was increased by >50% compared with controls, illustrating its systemic role as a negative regulator of adipogenesis. Bones from KO mice demonstrated a reduction in mineral content recapitulating the OI type VI phenotype. These results demonstrate that the human diseases associated with PEDF reflect its ability to modulate MSC differentiation.
Assuntos
Adipogenia , Adiposidade , Densidade Óssea , Proteínas do Olho/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fatores de Crescimento Neural/metabolismo , Serpinas/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Proteínas do Olho/genética , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/genética , Osteoblastos/citologia , Osteoblastos/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Serpinas/genética , Proteínas Wnt/metabolismo , Via de Sinalização WntRESUMO
A 2-year-old African American, Hispanic boy presented with well-defined, violaceous, annular dermal plaques without scale over the upper extremities, face, lower extremities, and buttocks. The clinical presentation and laboratory studies were consistent with a diagnosis of subacute cutaneous lupus erythematous (SCLE). SCLE presenting in childhood is exceedingly rare, with only eight cases previously reported. It is important to clinically differentiate SCLE from other eruptions more common to children, such as atopic dermatitis, urticarial drug eruptions, and psoriasis vulgaris, because progression to systemic lupus erythematous (SLE) may occur. SLE needs to be closely followed. We present the first case (to our knowledge) of SCLE in a child of African American or Hispanic descent and provide a table of other documented pediatric presentations of SCLE for comparison.
Assuntos
Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Cutâneo/patologia , Pele/patologia , Biópsia , Pré-Escolar , Diagnóstico Diferencial , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
Lichen sclerosus is a debilitating and chronic disease that typically affects the anogenital area, although it can also be found on extragenital locations such as the shoulders, neck, trunk, breasts, and arms. Facial involvement is rare, but there have been a few reported cases of extragenital lichen sclerosus affecting the infraorbital area. To our knowledge, there are 7 documented cases of extragenital lichen sclerosus affecting the eyelid in medical literature. This is a novel case and documented report of a patient with extragenital lichen sclerosus located on the eyelid with eyelash margin involvement.
RESUMO
We describe an 11-month-old boy with an unusually large presternal mass present since birth. The large size, fluctuant properties, transillumination, compressibility, and imaging of this lesion were characteristic of a lymphatic malformation. Although four treatments with sclerotherapy markedly reduced its size, it was not until definitive treatment with surgical excision and the final pathology report that we arrived at the ultimate diagnosis of dermoid cyst. Dermoid cysts, although appearing along embryologic lines of closure, are rarely presternal. They are usually small, thick walled, and filled with sebaceous or keratinous fluid, which typically allows for clinical diagnosis, and show characteristic features on magnetic resonance imaging (MRI) and ultrasound. However, this case illustrates that dermoid cysts can appear in somewhat atypical locations, and imaging is not always diagnostic, so dermoid cyst should remain a part of the differential diagnosis for any lesion presenting midsternally, regardless of the size and imaging characteristics.
Assuntos
Cisto Dermoide/diagnóstico , Anormalidades Linfáticas/diagnóstico , Escleroterapia/métodos , Neoplasias Cutâneas/diagnóstico , Biópsia por Agulha , Cisto Dermoide/congênito , Cisto Dermoide/tratamento farmacológico , Diagnóstico Diferencial , Seguimentos , Humanos , Imuno-Histoquímica , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Medição de Risco , Neoplasias Cutâneas/congênito , Neoplasias Cutâneas/tratamento farmacológico , Esterno , Parede Torácica/patologia , Resultado do TratamentoRESUMO
Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the hypothesis that the cardiomyopathy observed following cardiomyocyte circadian clock disruption may be secondary to chronic activation of cardiac GH/IGF1 signaling. Here, we report that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit increased cardiac GH sensitivity, as evidenced by augmented GH-induced STAT5 phosphorylation (relative to littermate controls) in the heart (but not in the liver). Moreover, Igf1 mRNA levels are approximately 2-fold higher in CBK hearts (but not in livers), associated with markers of GH/IGF1 signaling activation (e.g., p-ERK, p-mTOR, and p-4EBP1) and adverse remodeling (e.g., cardiomyocyte hypertrophy and interstitial fibrosis). Genetic deletion of one allele of the GH receptor (GHR) normalized cardiac Igf1 levels in CBK hearts, associated with a partial normalization of adverse remodeling. This included attenuated progression of cardiomyopathy in CBK mice. Collectively, these observations suggest that excessive cardiac GH/IGF1 signaling contributes toward cardiomyopathy following genetic disruption of the cardiomyocyte circadian clock.
RESUMO
Protein tyrosine phosphatases (PTPs) possess a conserved mobile catalytic loop, the WPD-loop, which brings an aspartic acid into the active site where it acts as an acid/base catalyst. Prior experimental and computational studies, focused on the human enzyme PTP1B and the PTP from Yersinia pestis, YopH, suggested that loop conformational dynamics are important in regulating both catalysis and evolvability. We have generated a chimeric protein in which the WPD-loop of YopH is transposed into PTP1B, and eight chimeras that systematically restored the loop sequence back to native PTP1B. Of these, four chimeras were soluble and were subjected to detailed biochemical and structural characterization, and a computational analysis of their WPD-loop dynamics. The chimeras maintain backbone structural integrity, with somewhat slower rates than either wild-type parent, and show differences in the pH dependency of catalysis, and changes in the effect of Mg2+. The chimeric proteins' WPD-loops differ significantly in their relative stability and rigidity. The time required for interconversion, coupled with electrostatic effects revealed by simulations, likely accounts for the activity differences between chimeras, and relative to the native enzymes. Our results further the understanding of connections between enzyme activity and the dynamics of catalytically important groups, particularly the effects of non-catalytic residues on key conformational equilibria.
RESUMO
BACKGROUND A ventricular septal aneurysm (VSA) is rare and almost always an incidental finding on cardiac imaging. It is rarely an isolated phenomenon and is more commonly associated with other forms of congenital heart disease such a ventricular septal defect (VSD). Differentiating a ventricular septal aneurysm from an aneurysm of the right sinus of Valsalva is crucial as the latter usually has a more aggressive course and may require surgical intervention. Cardiac computed tomography (cardiac CT) or cardiac magnetic resonance imaging (CMR) may help confirm the diagnosis. CASE REPORT We report a case of a 42-year-old obese Japanese man with a past medical history of hyperlipidemia who described occasional effort-related palpitations when climbing stairs over the past few months but no anginal symptoms. Echocardiogram revealed normal left ventricular systolic with a presumed right sinus of Valsalva aneurysm measuring around 1.5 cm. A coronary CTA was obtained to further delineate the aneurysm and revealed normal CT angiographic appearance of a right dominant coronary artery circulation with a small aneurysmal outpouching of the membranous ventricular septum measuring 13×17 mm without any evidence of shunting, along with focal calcification of the medial aspect of the tricuspid annulus. The right sinus of Valsalva appeared normal on coronary CTA. CONCLUSIONS Membranous ventricular septal aneurysm is a rare condition that is almost always an incidental finding on echocardiography and can be mistaken for an aneurysm of the right sinus of Valsalva. Multimodality imaging and high degree of clinical suspicion are needed to accurately diagnose a ventricular septal aneurysm and to achieve favorable outcomes. A VSA usually has a benign course and is rarely a cause of arrythmia, right ventricular outflow obstruction, or valvular insufficiency.
Assuntos
Aneurisma Aórtico , Aneurisma Cardíaco , Comunicação Interventricular , Seio Aórtico , Adulto , Aneurisma Aórtico/diagnóstico por imagem , Diagnóstico Diferencial , Comunicação Interventricular/diagnóstico por imagem , Humanos , Masculino , Seio Aórtico/diagnóstico por imagemRESUMO
Initial clinical reports comparing the delivery of radiotherapy (RT) at distinct times of the day suggest that this strategy might affect toxicity and oncologic outcomes of radiation for multiple human tissues, but the clinical effects on high-grade gliomas (HGG) are unknown. The present study addresses the hypothesis that radiotherapy treatment time of the day (RT-TTD) influences outcome and/or toxic events in HGG. Patients treated between 2009-2018 were reviewed (n = 109). Outcomes were local control (LC), distant CNS control (DCNSC), progression-free survival (PFS), and overall survival (OS). RT-TTD was classified as morning if ≥50% of fractions were delivered before 12:00 h (n = 70) or as afternoon (n = 39) if after 12:00 h. The average age was 62.6 years (range: 14.5-86.9) and 80% were glioblastoma. The median follow-up was 10.9 months (range: 0.4-57.2). The 1y/3y LC, DCNSC, and PFS were: 61.3%/28.1%, 86.8%/65.2%, and 39.7%/10.2%, respectively. Equivalent PFS was found between morning and afternoon groups (HR 1.27; p = .3). The median OS was 16.5 months. Patients treated in the afternoon had worse survival in the univariate analysis (HR 1.72; p = .05), not confirmed after multivariate analysis (HR 0.92, p = .76). Patients with worse baseline performance status and treatment interruptions showed worse PFS and OS. The proportion of patients that developed grade 3 acute toxicity, pseudo progression, and definitive treatment interruptions were 10.1%, 9.2%, and 7.3%, respectively, and were not affected by RT-TTD. In conclusion, for patients with HGG, there was no difference in PFS and OS between patients treated in the morning or afternoon. Of note, definitive treatment interruptions adversely affected outcomes and should be avoided, especially in patients with low performance status. Based on these clinical findings, high-grade glioma cells may not be the best initial model to be irradiated in order to study the effects of chronotherapy.
Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/radioterapia , Ritmo Circadiano , Glioma/radioterapia , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Solitary fibrous tumour (SFT) is well-described in the urinary tract, but malignant examples are rare. We studied our experience with high grade malignant SFT of the prostate to address the degree of histological and immunophenotypical overlap with sarcomatoid carcinoma and prostatic stromal sarcoma. Four cases were identified from the surgical pathology consultation archives. All available H&E stained sections were reviewed. Immunostains for STAT6, CAM5.2, NKX3.1, PAX-8, GATA3, high molecular weight cytokeratin (34BE12), p40, and p63 were performed on available material. Each case was evaluated by three separate SFT prognostic risk models based on clinicopathological features, and for features of 'dedifferentiated SFT'. The patient's ages were 49, 55, 69, and 73 years. Three presented with symptoms of benign prostatic hyperplasia and one with haematuria. Tumour sizes were 5, 9, 13, and 13 cm. Mitotic rate ranged from 6 to 20 mitoses per 10 high power fields, and two cases showed abrupt transition from conventional SFT to areas with marked nuclear pleomorphism/anaplasia (i.e., 'de-differentiation'). Immunophenotypically, all four cases had strong and diffuse nuclear reactivity for STAT6. For other markers, three of three had both focal PR and GATA3 nuclear expression (up to 30% of cells). One case with 'dedifferentiated' features showed expression of multiple epithelial markers, including EMA (focal), high molecular weight cytokeratin (focal), p63, and p40. In summary, malignant SFT may rarely occur in the prostate and may closely mimic sarcomatoid carcinoma or prostatic stromal sarcoma, both histologically and immunophenotypically. Consideration of the diagnostic possibility of malignant SFT, recognition of unexpected GATA3 and PR expression, and utilisation of monoclonal STAT6 immunohistochemistry facilitate appropriate diagnosis at this unusual anatomical site.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma/diagnóstico , Neoplasias da Próstata/diagnóstico , Sarcoma/diagnóstico , Tumores Fibrosos Solitários/diagnóstico , Idoso , Carcinoma/patologia , Feminino , Fator de Transcrição GATA3/metabolismo , Humanos , Imuno-Histoquímica , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Próstata/patologia , Neoplasias da Próstata/classificação , Neoplasias da Próstata/patologia , Fator de Transcrição STAT6/metabolismo , Sarcoma/patologia , Tumores Fibrosos Solitários/classificação , Tumores Fibrosos Solitários/patologiaRESUMO
CONTEXT.: Metastatic mucinous tumors present a diagnostic challenge for pathologists as tumor histomorphology is often nonspecific and optimal immunoprofiles are still under investigation. OBJECTIVE.: To present a head-to-head comparison of special AT-rich sequence-binding protein 2 (SATB2) and caudal type homeobox 2 (CDX2) expression in a diverse array of primary mucinous tumors. DESIGN.: SATB2 and CDX2 immunohistochemical stains were performed on whole sections from 44 mucinous colorectal carcinomas and 175 noncolorectal mucinous tumors. A nuclear scoring system measuring intensity (0-3+) and percentage staining (0 = <5%, 1 = 5%-49%, 2 = ≥50%) was implemented, producing an additive histologic score (H-score). RESULTS.: SATB2 demonstrated acceptable accuracy at low to moderate expression levels (H-scores of 1-4). With these H-score cutoffs, overall accuracy was greater than 90%. In contrast, CDX2's accuracy rivaled that of SATB2 only at an H-score of 5 (89.0%), as its specificity suffered at lower expression levels (<70.0% at H-scores of 1-4). Using a moderate H-score cutoff of 3 or higher, significant differences for both sensitivity and specificity were identified between SATB2 and CDX2 (P = .01 for sensitivity and P < .001 for specificity), though these stains were near equivalent when each was interpreted as positive at its respective optimal H-score (SATB2 ≥ 3 and CDX2 = 5). CONCLUSIONS.: SATB2 is a more accurate marker of colorectal origin across a variety of expression levels compared with CDX2 when applied to mucinous tumors from a host of primary sites. However, these stains are near equivalent when each is interpreted at its optimal expression level.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Fator de Transcrição CDX2/análise , Neoplasias Colorretais/diagnóstico , Proteínas de Ligação à Região de Interação com a Matriz/análise , Metástase Neoplásica/diagnóstico , Fatores de Transcrição/análise , Adenocarcinoma Mucinoso/patologia , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica/métodos , Metástase Neoplásica/patologia , Sensibilidade e EspecificidadeRESUMO
Special AT-rich sequence-binding protein 2 (SATB2) is an accurate marker for conventional colorectal carcinoma (CRC), although its sensitivity and specificity in mucinous tumors from the colon and other sites remains unknown. The objective of this study is to evaluate the accuracy of SATB2 expression detected by immunohistochemical assay, as a marker of primary CRC in mucinous adenocarcinomas. SATB2 immunohistochemical stains were performed on whole sections from 63 conventional CRCs (controls), 47 mucinous CRCs (mCRC), and 182 noncolorectal mucinous tumors. SATB2 intensity was scored as 1 to 3 based on the estrogen receptor/progesterone receptor grading system, and the percent positive cells was scored in broad categories as follows: 0 (negative)≤5%, 1=5% to 49%, 2≥50%. An optimal sensitivity/specificity pairing (83% and 95%, respectively) was achieved in the mCRCs when the additive intensity and percent score was ≥3 (ie, intensity score+percent score=total score). Defining this total score (histologic score/"H score") as a "positive" result, the sensitivity of SATB2 for conventional CRC was 98% (62/63) versus 83% (39/47) for mCRCs (P=0.02); whereas 5% (9/182) of all noncolorectal mucinous tumors were considered positive. SATB2 especially demonstrated reduced specificity when applied to mucinous gastroesophageal and breast carcinomas, which showed significant expression in 27% and 9% of cases, respectively. In summary, SATB2 is a less sensitive marker of colorectal origin in mCRC compared with conventional CRC and shows significantly reduced specificity in mucinous gastroesophageal and breast primaries.