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During heart failure, gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function. However, it is unknown if the expression of fMyBP-C expression in the heart is a pathological or compensatory response. We aim to elucidate the cardiac consequence of either increased or knockout of fMyBP-C expression. To determine the sufficiency of fMyBP-C to cause cardiac dysfunction, we generated cardiac-specific fMyBP-C over-expression mice. These mice were further crossed into a cMyBP-C null model to assess the effect of fMyBP-C in the heart in the complete absence of cMyBP-C. Finally, fMyBP-C null mice underwent transverse aortic constriction (TAC) to define the requirement of fMyBP-C during heart failure development. We confirmed the upregulation of fMyBP-C in several models of cardiac disease, including the use of lineage tracing. Low levels of fMyBP-C caused mild cardiac remodeling and sarcomere dysfunction. Exclusive expression of fMyBP-C in a heart failure model further exacerbated cardiac pathology. Following 8 weeks of TAC, fMyBP-C null mice demonstrated greater protection against heart failure development. Mechanistically, this may be due to the differential regulation of the myosin super-relaxed state. These findings suggest that the elevated expression of fMyBP-C in diseased hearts is a pathological response. Targeted therapies to prevent upregulation of fMyBP-C may prove beneficial in the treatment of heart failure. Significance Statement: Recently, the sarcomere - the machinery that controls heart and muscle contraction - has emerged as a central target for development of cardiac therapeutics. However, there remains much to understand about how the sarcomere is modified in response to disease. We recently discovered that a protein normally expressed in skeletal muscle, is present in the heart in certain settings of heart disease. How this skeletal muscle protein affects the function of the heart remained unknown. Using genetically engineered mouse models to modulate expression of this skeletal muscle protein, we determined that expression of this skeletal muscle protein in the heart negatively affects cardiac performance. Importantly, deletion of this protein from the heart could improve heart function suggesting a possible therapeutic avenue.
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The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfrα CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1ß increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1ß also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1ß induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1ß induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling.
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Corazón , Hipertensión Arterial Pulmonar , Animales , Humanos , Ratones , Ratas , Fibroblastos/metabolismo , Fibrosis , Miofibroblastos/metabolismoRESUMEN
BACKGROUND: Cardiac fibroblasts are the main non-myocyte population responsible for extracellular matrix (ECM) production. During perinatal development, fibroblast expansion coincides with the transition from hyperplastic to hypertrophic myocardial growth. Therefore, we investigated the consequences of fibroblast loss at the time of cardiomyocyte maturation by depleting fibroblasts in the perinatal mouse. METHODS AND RESULTS: We evaluated the microenvironment of the perinatal heart in the absence of fibroblasts and the potential functional impact of fibroblast loss in regulation of cardiomyocyte cell cycle arrest and binucleation. Cre-mediated expression of diphtheria toxin A in PDGFRα expressing cells immediately after birth eliminated 70-80% of the cardiac fibroblasts. At postnatal day 5, hearts lacking fibroblasts appeared similar to controls with normal morphology and comparable numbers of endothelial and smooth muscle cells, despite a pronounced reduction in fibrillar collagen. Immunoblotting and proteomic analysis of control and fibroblast-deficient hearts identified differential abundance of several ECM proteins. In addition, fibroblast loss decreased tissue stiffness and resulted in increased cardiomyocyte mitotic index, DNA synthesis, and cytokinesis. Moreover, decellularized matrix from fibroblast-deficient hearts promoted cardiomyocyte DNA replication. While cardiac architecture was not overtly affected by fibroblast reduction, few pups survived past postnatal day 11, suggesting an overall requirement for PDGFRα expressing fibroblasts. CONCLUSIONS: These studies demonstrate the key role of fibroblasts in matrix production and cardiomyocyte cross-talk during mouse perinatal heart maturation and revealed that fibroblast-derived ECM may modulate cardiomyocyte maturation in vivo. Neonatal depletion of fibroblasts demonstrated that although hearts can tolerate reduced ECM composition, fibroblast loss eventually leads to perinatal death as the approach simultaneously reduced fibroblast populations in other organs.
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Proteómica , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas , Animales , Matriz Extracelular/metabolismo , Femenino , Fibroblastos/metabolismo , Ratones , Miocitos Cardíacos/metabolismo , Embarazo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
The limited ability of mammalian adult cardiomyocytes to proliferate following an injury to the heart, such as myocardial infarction, is a major factor that results in adverse fibrotic and myocardial remodeling that ultimately leads to heart failure. The continued high degree of heart failure-associated morbidity and lethality requires the special attention of researchers worldwide to develop efficient therapeutics for cardiac repair. Recently, various strategies and approaches have been developed and tested to extrinsically induce regeneration and restoration of the myocardium after cardiac injury have yielded encouraging results. Nevertheless, these interventions still lack adequate success to be used for clinical interventions. This review highlights and discusses both cell-based and cell-free therapeutic approaches as well as current advancements, major limitations, and future perspectives towards developing an efficient therapeutic method for cardiac repair.
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Infarto del Miocardio/patología , Comunicación Paracrina , Animales , Tratamiento Basado en Trasplante de Células y Tejidos , Exosomas/metabolismo , Exosomas/trasplante , Humanos , Infarto del Miocardio/terapia , Comunicación Paracrina/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
Ex vivo culture of the adult mammalian cardiomyocytes (CMs) presents the most relevant experimental system for the in vitro study of cardiac biology. Adult mammalian CMs are terminally differentiated cells with minimal proliferative capacity. The post-mitotic state of adult CMs not only restricts cardiomyocyte cell cycle progression but also limits the efficient culture of CMs. Moreover, the long-term culture of adult CMs is necessary for many studies, such as CM proliferation and analysis of gene expression. The mouse and the rat are the two most preferred laboratory animals to be used for cardiomyocyte isolation. While the long-term culture of rat CMs is possible, adult mouse CMs are susceptible to death and cannot be cultured more than five days under normal conditions. Therefore, there is a critical need to optimize the cell isolation and long-term culture protocol for adult murine CMs. With this modified protocol, it is possible to successfully isolate and culture both adult mouse and rat CMs for more than 20 days. Moreover, the siRNA transfection efficiency of isolated CM is significantly increased compared to previous reports. For adult mouse CM isolation, the Langendorff perfusion method is utilized with an optimal enzyme solution and sufficient time for complete extracellular matrix dissociation. In order to obtain pure ventricular CMs, both atria were dissected and discarded before proceeding with the disassociation and plating. Cells were dispersed on a laminin coated plate, which allowed for efficient and rapid attachment. CMs were allowed to settle for 4-6 h before siRNA transfection. Culture media was refreshed every 24 h for 20 days, and subsequently, CMs were fixed and stained for cardiac-specific markers such as Troponin and markers of cell cycle such as KI67.
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Envejecimiento/fisiología , Miocitos Cardíacos/citología , Transfección/métodos , Animales , Desdiferenciación Celular , Proliferación Celular , Separación Celular , Células Cultivadas , Medios de Cultivo/farmacología , Ratones , Miocardio/citología , Ratas , Suspensiones , Factores de TiempoRESUMEN
Pericytes are cells that reside adjacent to microvasculature and regulate vascular function. Pericytes gained great interest in the field of wound healing and regenerative medicine due to their multipotential fate and ability to enhance angiogenesis. In burn wounds, scarring and scar contractures are the major pathologic feature and cause loss of mobility. The present study investigated the influence of burn wound environment on pericytes during wound healing. Pericytes isolated from normal skin and tangentially excised burn eschar tissues were analyzed for differences in gene and protein expression using RNA-seq., immunocytochemistry, and ELISA analyses. RNA-seq identified 443 differentially expressed genes between normal- and burn eschar-derived pericytes. Whereas, comparing normal skin pericytes to normal skin fibroblasts identified 1021 distinct genes and comparing burn eschar pericytes to normal skin fibroblasts identified 2449 differential genes. Altogether, forkhead box E1 (FOXE1), a transcription factor, was identified as a unique marker for skin pericytes. Interestingly, FOXE1 levels were significantly elevated in burn eschar pericytes compared to normal. Additionally, burn wound pericytes showed increased expression of profibrotic genes periostin, fibronectin, and endosialin and a gain in contractile function, suggesting a contribution to scarring and fibrosis. Our findings suggest that the burn wound environment promotes pericytes to differentiate into a myofibroblast-like phenotype promoting scar formation and fibrosis.
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Platelet-derived growth factor receptor α (PDGFRα), a receptor tyrosine kinase required for cardiac fibroblast development, is uniquely expressed by fibroblasts in the adult heart. Despite the consensus that PDGFRα is expressed in adult cardiac fibroblasts, we know little about its function when these cells are at rest. Here, we demonstrate that loss of PDGFRα in cardiac fibroblasts resulted in a rapid reduction of resident fibroblasts. Furthermore, we observe that phosphatidylinositol 3-kinase signaling was required for PDGFRα-dependent fibroblast maintenance. Interestingly, this reduced number of fibroblasts was maintained long-term, suggesting that there is no homeostatic mechanism to monitor fibroblast numbers and restore hearts to wild-type levels. Although we did not observe any systolic functional changes in hearts with depleted fibroblasts, the basement membrane and microvasculature of these hearts were perturbed. Through in vitro analyses, we showed that PDGFRα signaling inhibition resulted in an increase in fibroblast cell death, and PDGFRα stimulation led to increased levels of the cell survival factor activating transcription factor 3. Our data reveal a unique role for PDGFRα signaling in fibroblast maintenance and illustrate that a 50% loss in cardiac fibroblasts does not result in lethality.NEW & NOTEWORTHY Platelet-derived growth factor receptor α (PDGFRα) is required in developing cardiac fibroblasts, but a functional role in adult, quiescent fibroblasts has not been identified. Here, we demonstrate that PDGFRα signaling is essential for cardiac fibroblast maintenance and that there are no homeostatic mechanisms to regulate fibroblast numbers in the heart. PDGFR signaling is generally considered mitogenic in fibroblasts, but these data suggest that this receptor may direct different cellular processes depending on the cell's maturation and activation status.
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Fibroblastos/metabolismo , Ventrículos Cardíacos/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Adulto , Animales , Apoptosis , Bencimidazoles/farmacología , Linaje de la Célula , Supervivencia Celular , Células Cultivadas , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Humanos , Mesilato de Imatinib/farmacología , Masculino , Ratones Noqueados , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasa/metabolismo , Piperidinas/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/deficiencia , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Transducción de SeñalRESUMEN
Transcription factor 21 (Tcf21) is a basic helix-loop-helix transcription factor required for mesenchymal development in several organs. Others have demonstrated that Tcf21 is expressed in embryonic lung mesenchyme and that loss of Tcf21 results in a pulmonary hypoplasia phenotype. Although recent single-cell transcriptome analysis has described multiple mesenchymal cell types in the lung, few have characterized the Tcf21 expressing population. To explore the Tcf21 mesenchymal lineage, we traced Tcf21-expressing cells during embryogenesis and in the adult. Our results showed that Tcf21 progenitor cells at embryonic day (E)11.5 generated a subpopulation of fibroblasts and lipofibroblasts and a limited number of smooth muscle cells. After E15.5, Tcf21 progenitor cells exclusively become lipofibroblasts and interstitial fibroblasts. Lipid metabolism genes were highly expressed in perinatal and adult Tcf21 lineage cells. Overexpression of Tcf21 in primary neonatal lung fibroblasts led to increases in intracellular neutral lipids, suggesting a regulatory role for Tcf21 in lipofibroblast function. Collectively, our results reveal that Tcf21 expression after E15.5 delineates the lipofibroblast and a population of interstitial fibroblasts. The Tcf21 inducible Cre mouse line provides a novel method for identifying and manipulating the lipofibroblast.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Pulmón/citología , Pulmón/metabolismo , Adipocitos/citología , Adipocitos/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular , Linaje de la Célula/genética , Células Cultivadas , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Metabolismo de los Lípidos/genética , Pulmón/embriología , Masculino , Mesodermo/citología , Mesodermo/embriología , Mesodermo/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , EmbarazoRESUMEN
Cardiac fibrosis, denoted by the deposition of extracellular matrix, manifests with a variety of diseases such as hypertension, diabetes, and myocardial infarction. Underlying this pathological extracellular matrix secretion is an expansion of fibroblasts. The mouse is now a common experimental model system for the study of cardiovascular remodeling and elucidation of fibroblast responses to cardiac growth and stress is vital for understanding disease processes. Here, using diverse but fibroblast specific markers, we report murine fibroblast distribution and proliferation in early postnatal, adult, and injured hearts. We find that perinatal fibroblasts and endothelial cells proliferate at similar rates. Furthermore, regardless of the injury model, fibroblast proliferation peaks within the first week after injury, a time window similar to the period of the inflammatory phase. In addition, fibroblast densities remain high weeks after the initial insult. These results provide detailed information regarding fibroblast distribution and proliferation in experimental methods of heart injury.
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Fibroblastos/patología , Corazón/crecimiento & desarrollo , Remodelación Ventricular , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colágeno/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Femenino , Fibroblastos/efectos de los fármacos , Corazón/efectos de los fármacos , Isoproterenol/farmacología , Masculino , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Presión , Receptores Adrenérgicos beta/metabolismo , Remodelación Ventricular/efectos de los fármacosRESUMEN
Cardiac fibrosis remains an important health concern, but the study of fibroblast biology has been hindered by a lack of effective means for identifying and tracking fibroblasts. Recent advances in fibroblast-specific lineage tags and reporters have permitted a better understanding of these cells. After injury, multiple cell types have been implicated as the source for extracellular matrix-producing cells, but emerging studies suggest that resident cardiac fibroblasts contribute substantially to the remodeling process. In this review, we discuss recent findings regarding cardiac fibroblast origin and identity. Our understanding of cardiac fibroblast biology and fibrosis is still developing and will expand profoundly in the next few years, with many of the recent findings regarding fibroblast gene expression and behavior laying down the groundwork for interpreting the purpose and utility of these cells before and after injury. (Circ J 2016; 80: 2269-2276).
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Fibroblastos/metabolismo , Regulación de la Expresión Génica , Cardiopatías/metabolismo , Miocardio/metabolismo , Animales , Fibroblastos/patología , Fibrosis , Cardiopatías/patología , Humanos , Miocardio/patologíaRESUMEN
Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo. Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin(+) myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21(+) tissue-resident fibroblasts.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Moléculas de Adhesión Celular/metabolismo , Infarto del Miocardio/patología , Miocardio/patología , Miofibroblastos/metabolismo , Animales , Biomarcadores/metabolismo , Moléculas de Adhesión Celular/genética , Femenino , Integrasas , Masculino , Ratones , Ratones Transgénicos , Miocardio/metabolismo , TamoxifenoRESUMEN
The use of mouse genetic tools to track and manipulate fibroblasts has provided invaluable in vivo information regarding the activities of these cells. Recently, many new mouse strains have been described for the specific purpose of studying fibroblast behavior. Colorimetric reporter mice and lines expressing Cre are available for the study of fibroblasts in the organs prone to fibrosis, including heart, kidney, liver, lung, and skeletal muscle. In this review we summarize the current state of the models that have been used to define tissue resident fibroblast populations. While these complex genetic reagents provide unique insights into the process of fibrosis, they also require a thorough understanding of the caveats and limitations. Here, we discuss the specificity and efficiency of the available genetic models and briefly describe how they have been used to document the mechanisms of fibrosis.
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Fibroblastos/patología , Fibrosis/diagnóstico , Fibrosis/genética , Integrasas/genética , Pulmón/patología , Patología Molecular , Animales , Fibrosis/patología , Humanos , Ratones TransgénicosRESUMEN
RATIONALE: Accurate knowledge of the cellular composition of the heart is essential to fully understand the changes that occur during pathogenesis and to devise strategies for tissue engineering and regeneration. OBJECTIVE: To examine the relative frequency of cardiac endothelial cells, hematopoietic-derived cells, and fibroblasts in the mouse and human heart. METHODS AND RESULTS: Using a combination of genetic tools and cellular markers, we examined the occurrence of the most prominent cell types in the adult mouse heart. Immunohistochemistry revealed that endothelial cells constitute >60%, hematopoietic-derived cells 5% to 10%, and fibroblasts <20% of the nonmyocytes in the heart. A refined cell isolation protocol and an improved flow cytometry approach provided an independent means of determining the relative abundance of nonmyocytes. High-dimensional analysis and unsupervised clustering of cell populations confirmed that endothelial cells are the most abundant cell population. Interestingly, fibroblast numbers are smaller than previously estimated, and 2 commonly assigned fibroblast markers, Sca-1 and CD90, under-represent fibroblast numbers. We also describe an alternative fibroblast surface marker that more accurately identifies the resident cardiac fibroblast population. CONCLUSIONS: This new perspective on the abundance of different cell types in the heart demonstrates that fibroblasts comprise a relatively minor population. By contrast, endothelial cells constitute the majority of noncardiomyocytes and are likely to play a greater role in physiological function and response to injury than previously appreciated.
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Células Endoteliales/metabolismo , Fibroblastos/metabolismo , Corazón , Células Madre Hematopoyéticas/metabolismo , Adulto , Animales , Biomarcadores/metabolismo , Recuento de Células , Diferenciación Celular , Linaje de la Célula , Separación Celular/métodos , Femenino , Citometría de Flujo , Regulación de la Expresión Génica , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Humanos , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , FenotipoRESUMEN
Solitary benign cecal ulcer is a non-usual finding without characteristic clinical or radiological performance. Because ofits little frequency and its clinical symptoms often suspicious for the presence of severe diseases like are malignancies, acute abdomen or lower gastrointestinal bleeding, this finding is only rarely diagnosed preoperatively. Definitive diagnosis is almost always made pathologically. In this case report we describe clinical, radiological and pathological findings in our patient with difficulties caused by a solitary benign cecal ulcer.
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Enfermedades del Ciego/diagnóstico , Úlcera/diagnóstico , Anciano , Femenino , HumanosRESUMEN
INTRODUCTION: Ductal carcinoma in situ (DCIS) is the disease with increasing incidence. Nowadays, approximately 80% DCIS are diagnosed via mammography and represent more than 20% of all types of breast cancer. The acceptance of surgical procedures with this type of breast carcinoma is controversial as primary diagnosis of non-invasive carcinoma is often underestimated and in the end, histopathological examination reveals invasive carcinoma with biological potential to metastasize. In cases of "risk" patient groups with DCIS, several studies report lymph node metastases. The aim of the study has been to assess the incidence of sentinel lymph node metastatic involvement in high-risk patient group with DCIS and in ductal carcinoma in situ with microinvasion (DCISMI), to note the incidence of invasive carcinoma in definitive histopathology in patients with pre-operative diagnosis of DCIS and to analyze some predictors of invasivity. STUDY TYPE AND PATIENT GROUP: In retrospective analysis, we evaluated the setting of 119 patients who have been operated on at our Clinic from January, 1st 2008 until December, 31th 2010 for the diagnosis of DCIS. Prospectively, we have created the setting of 44 patients with high-risk DCIS with sentinel lymph node biopsy (SLNB) performed. METHODS AND RESULTS. Metastatic involvement of sentinel lymph node in high-risk DCIS has been found in 4 cases (9.0%)--in 1 patient (2.2%) with correct diagnosis of DCIS and in 3 patients (6.8%) with invasive carcinoma according to final histopathology. In the patient with DCIS, a micrometastasis of 0.4 mm was found in one sentinel lymph node. After complete axillary dissection, non-sentinel axillary lymph nodes metastatic involvement was not demonstrated (14/0). In 6 cases (5.0%), we identified DCISMI and did not find metastasis in sentinel lymph node. In the high-risk DCIS group, in 4 patients (9.0%) DCISMI and in 12 patients (27.2%) invasive carcinoma was found after definitive histopathologic examination. In this group, the overall ratio of invasive lesions was 36.2%. As for predictors of invasivity, high-grade carcinoma (OR 4.2; 95% CI 1,40-12,58) has more than 4-fold higher influence and lesion size
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Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: The aim of this retrospective matched cohort study was to evaluate the rate of recurrence among women with delayed large flap breast reconstruction after mastectomy for breast cancer. The recurrence rate among women treated at a single hospital was compared with that in an individually matched control group of women with breast cancer who did not have reconstruction after mastectomy. METHODS: Between 1982 and 2001, 125 women with previous invasive breast carcinoma underwent delayed large flap breast reconstruction with pedicled musculocutaneous or microvascular flaps (a median of 32 months after mastectomy). They were matched individually with 182 women with breast cancer who had a mastectomy but did not undergo breast reconstruction. Matching criteria were year of diagnosis, age at diagnosis and treating hospital. Medical records were evaluated until October 2007. Histopathological specimens for all included women were re-evaluated. The endpoint was locoregional or distant breast cancer recurrence. The risk of recurrent disease was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. RESULTS: Median follow-up for the entire cohort was 146 months. The reconstruction group had a 2·08 (95 per cent confidence interval 1·07 to 4·06) times higher risk of recurrent disease than the mastectomy only group. CONCLUSION: Women with breast cancer who had delayed reconstruction with a large flap in this study had a higher risk of recurrent disease than those with mastectomy alone.
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Neoplasias de la Mama/cirugía , Mamoplastia/métodos , Mastectomía/métodos , Recurrencia Local de Neoplasia , Colgajos Quirúrgicos , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Espera VigilanteRESUMEN
We present our experience regarding sentinel lymph node biopsy (SLNB) at St. Elizabeth Institute of Oncology during 48 months. From January 1st, 2006 until December 31st, 2009, we had performed SLNB in 269 patients. Primary tumour size was 0.3-3.5cm including non-invasive breast carcinoma (i.e. TIS, T1 and T2 of TNM classification). Invasive carcinoma accounted for 255 (94.8%) cases, while non-invasive carcinoma for 14 (5.2%) cases. From total of 269 patients with invasive carcinoma, we used validation method in 157 (72.7%). In 255 patients with invasive carcinoma, sentinel node was not identified in 4 (1.6%) cases--in 1 patient with T1 invasive carcinoma and in 3 patients with T2 tumours. False negativity of sentinel node in T1 tumours was 4.3%. The incidence of macrometastases in sentinel nodes was confirmed using standard histopathologic examination with hematoxylin-eosin stain. In negative instances, the examination was then completed with serial sections and immunohistochemistry using cytoskeletal antibodies for confirmation of presence of micrometastases. In 6 (2.4%) cases, we found micrometastase in originally negative sentinel lymph node. Subsequent axillary dissection has not confirmed non-sentinel nodes involvement.
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Neoplasias de la Mama/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias de la Mama/cirugía , Femenino , Humanos , Biopsia del Ganglio Linfático Centinela/métodosRESUMEN
AIM: To survey the histopathological abnormalities in breasts of women who have undergone risk reducing mastectomy and to evaluate the effect of this measure on future breast cancer development. PATIENTS/METHODS: Between August 1995 and October 2006 100 consecutive women with a hereditary increased risk of breast cancer underwent prophylactic mastectomy (PM) at Malmö University Hospital. Fifty of the 100 women had no previous breast cancer. Fifty were BRCA1 or BRCA2 mutation carriers. All breast specimens have been examined histopathologically according to a prospective protocol. Follow-up data was collected from medical records and data in the Regional Cancer Registry. RESULTS: In the PM specimens abnormal lesions were found in 18 women (three with invasive cancers, eight in situ cancers and seven atypical hyperplasia). In previously healthy women lesions were more frequent after the age of 40 than among younger women (p=0.03). BRCA mutation carriers were more likely to present with ADH (atypical ductal hyperplasia)/ALH (atypical lobular hyperplasia) compared to the non-carriers/untested cases (p=0.01). After a median follow-up of 52 months (range 1-136 months) none of the women have developed breast cancer in the area of the prophylactically removed breast. CONCLUSIONS: Prevalent atypical or malignant lesions are relatively a common finding in PM specimens in asymptomatic women with hereditary increased risk of breast cancer. Such findings were significantly more common above age 40 in women without previous breast cancer. The risk of newly formed breast cancer after PM is small. The clinical importance of detecting a premalignant or preinvasive lesion in the breast at PM is still unclear.
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Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma in Situ , Mamoplastia , Mastectomía , Adulto , Anciano , Proteínas Reguladoras de la Apoptosis , Proteína BRCA1/análisis , Proteína BRCA2/análisis , Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Hiperplasia , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the occurrence of mixed and unclassifiable vulvovaginitis (i.e. those, which fulfill the diagnostic criteria of several diagnostic units or no diagnostic unit) in symptomatic and asymptomatic women. TYPE OF STUDY: Prospective study. METHODS: In 412 women (115 of them asymptomatic) the authors established the diagnosis of vulvovaginitis on the basis of gynecological examination, pH, the amine test and microscopic examination according to Giemsa and Gram. RESULTS: Mycosis was diagnosed in 15.5% women (in 9,6% of asymptomatic ones), lactobacillosis in u 5.6% (in 7.0% of asymptomatic), anaerobic vaginosis in 10.7% (8.7% of asymptomatic), aerobic vaginitis in 7.7% women (4.3% of asymptomatic). U 15.0% mixed infections were diagnosed (in 61% asymptomatic). U 29.4% symptomatic women the diagnostic criteria were not fulfilled for any nosological unit. CONCLUSION: Vulvovaginal mycosis, lactobacillosis, anaerobic vaginosis, aerobic vaginosis were considered as dysmicrobia conditions. The authors demonstrated a high occurrence of more units ("clear" diagnoses to "mixed" diagnoses being in the ratio of 1.62:1). The authors also demonstrated a high occurrence of mixed infections in asymptomatic women (36.0%). On the contrary, in 29.4% of symptomatic women the diagnosis could not be established, the findings being "normal" or "unclassifiable".
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Vulvovaginitis/microbiología , Femenino , Humanos , Micosis/diagnóstico , Micosis/microbiología , Vaginosis Bacteriana/diagnóstico , Vaginosis Bacteriana/microbiología , Vulvovaginitis/diagnósticoRESUMEN
AIM OF THE STUDY: The evaluation of combined and miscellaneous vulvovaginal infections incidence and their treatment with combined vaginal products containing nifuratel and nystatin. DESIGN: Prospective study. SETTING: Gynecologic outpatient department LEVRET, Prague; Laboratories of Microbiology AescuLab, Prague. METHODS: 70 consecutive patients were examined with complaint of vaginal fluor and/or pruritus. We established macroscopic features of fluor, pH, amine test and mounts stained with Giemsa and Gram. We qualified the cases with more diagnostic criteria (mycosis, lactobacillosis, anaerobic vaginosis, aerobic vaginitis) as combined infection, those with no diagnostic criteria as miscellaneous. We treated all patients with vaginal tablets nystatin + nifuratel (Macmiror complex). We prescribed clotrimazol cream, if pruritus was present. We evaluated withdrawals of symptoms and relapses during 3 months after treatment. RESULTS: Combined infection was found in 21 patients from 70 (30%). The most frequent combination was that of mycosis and aerobic vaginitis (13/70, 18.6%) or mycosis and anaerobic vaginosis (4/70, 5.7%); 11 patients fulfilled criteria of no diagnosis. We concluded them as "miscelaneous". The treatment was successful in all cases, 10 women relapsed in 3 months. CONCLUSIONS: Combined vaginal infection findings are present very often (30%), likewise miscellaneous ones (15%) occur. The treatment of these women in successful with vaginal tablets with nystatin + nifuratel.