Uterine sarcomas: clinical presentation and MRI features

Uterine sarcomas are a rare heterogeneous group of tumors of mesenchymal origin, accounting for approximately 8% of uterine malignancies. They comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated endometrial sarcoma, and adenosarcoma. Compared with the more common endometrial carcinomas, uterine sarcomas behave more aggressively and are associated with a poorer prognosis. Due to their distinct clinical and biological behavior, the International Federation of Gynecology and Obstetrics introduced a new staging system for uterine sarcomas in 2009, categorizing uterine carcinosarcoma as a variant of endometrial carcinoma, rather than a pure sarcoma. Magnetic resonance imaging (MRI) has a developing role in the assessment of these malignancies. Features such as tumor localization, irregular or nodular margins, necrosis, rapid growth, intense contrast enhancement, and restriction at diffusion-weighted imaging can suggest the diagnosis and help differentiate from more common leiomyomas and endometrial carcinoma. MRI is therefore extremely useful in preoperative detection and staging and, consequently, in determination of appropriate management. This pictorial review aims to discuss the clinical features of uterine sarcomas, as well as their most common appearances and distinct characteristics in MRI.

Efeitos ginecológicos do "tamoxifeno": contributo da radiologia

O “Tamoxifeno” (TAM) é a terapêutica anti-estrogénica de escolha nas doentes com cancro da mama. Os efeitos proliferativos do TAM em idade pós-menopausa têm sido associados a hiperplasia, pólipos, carcinoma e sarcoma do endométrio. As doentes tratadas com TAM têm também maior incidência de leiomiomas, adenomiose e endometriose, assim como maior risco de quistos do ovário. O método de primeira linha na vigilância das mulheres sob TAM é a ecografia transvaginal (US-TV). O endométrio apresenta-se frequentemente espessado e com áreas quísticas, aspectos passíveis de melhor caracterização por histerossonografia e ressonância magnética. Nas imagens ponderadas em T2, um endométrio espessado e heterogéneo com captação de aspecto reticulado e a opacificação da interface endométrio-miométrio associam-se a lesões de pior prognóstico (pólipos, hiperplasia atípica e neoplasia). O conhecimento dos efeitos ginecológicos do TAM e da sua tradução radiológica promove o diagnóstico precoce e adequado encaminhamento destas doentes.

Inmunoterapia autóloga con células dendríticas en modelos caninos con tumor venéreo transmisible

La inmunoterapia autóloga utiliza células del mismo cuerpo para estimular y restaurar las defensas naturales del sistema inmunológico. Algunas de las células que han sido utilizado en años recientes son: linfocitos infiltrantes de tumor, linfocitos T citotóxicos, células asesinas activadas por linfocinas y células dendríticas (CD). Las CD son células especializadas y su función es el capturar, procesar y presentar antígenos a los linfocitos para iniciar una respuesta inmune. El tumor venéreo transmisible (TVT), también conocido como sarcoma infeccioso o tumor de Sticker, es un cáncer transmisible en perros que afecta mayormente los genitales externos y se transmite durante el coito. En este trabajo se implementó por primera vez un modelo de TVT en el órgano genital (vagina) de los pacientes y se les administró la inmunoterapia autóloga con CD específicas contra el tumor. Para estudiar esta terapia se utilizaron tres grupos experimentales: el tumor sin tratamiento, el tumor tratado con sangre completa autóloga, y el tumor tratado con CD autólogas específicas para el TVT. Por último se evaluó la capacidad inmunológica del extracto tumoral total (ETT) del tumor como método de prevención in vivo. Para el tratamiento autólogo con las CD, se esperó que el tumor midiese 3cm, se realizó un cultivo primario de las células de TVT y se les extrajo el 4% de su peso corporal de sangre a los pacientes para realizar una diferenciación de los monocitos a CD. Para evaluar el efecto de la inmunoterapia autóloga con CD se observaron los efectos secundarios, el tamaño tumoral, las poblaciones de linfocitos, los niveles de IFN-γ en sangre y los linfocitos infiltrantes de tumor por histopatología. Los monocitos se diferenciaron a CD y se les realizó un análisis fenotípico mediante citometría de flujo. Los monocitos mostraron una expresión de CD14+ de 80.1%, CD80+ de 15.6%, CD83+ de 0.4% y un DLA II de1.8%. En las CD se obtuvo una expresión de 8.7% para CD14+, 80.3% para CD80+, 76.4% para CD83+ y 86.5% para DLA II y 62% en la prueba de fagocitosis. La terapia no mostró ningún efecto secundario en nuestro grupo experimental y hubo una regresión tumoral del 100% para la semana doce. Se encontró un aumento de expresión celular en sangre de CD4+ de 29%, de CD8+ de 34% y de IFN-γ de 120 pg/mL. Nuestros resultados demuestran que la inmunoterapia autóloga con CD específicas inducen una regresión del TVT en caninos.

Adenocarcinoma pleomórfico de células giganates de vías biliares(osteoclastoma like)

Las células gigante tipo osteoclásticas (CGTO) del páncreas son una entidad poco frecuente descrito originalmente por Rosaien 1968, caracterizado por osteoclastos, que son células gigantes mononucleares idénticas a las células del estroma observadas en tumores óseos. Desde entonces, hay pocos informes de los tumores que contienen células gigantes en otras localizaciones anatómicas. Las CGTO se pueden distinguir de las células gigantes tipo pleomórficas (CGTP), debido a la falta de un marcado pleomorfismo nuclear asociado. A menudo, un carcinoma de páncreas histológicamente reconocibles acompaña CGTO, dando lugar a un mal resultado. Formas puras de CGTO presentan un mejor pronóstico porque se necesita mucho tiempo para desarrollar metástasis, pero esta forma es muy raros, con pocos casos reportados en la literatura Inglésa. La mayoría de veces se discute el diagnóstico de benignidad de estos tumores basados en la evaluación de inmunohistoquímica. El presente caso se trata de una paciente de sexo femenino de 56 años de edad con cuadro caracterizado por dolor tipo cólico que mejora con antiespasmódicos, de varios meses de evolución, con periodos de remisión y exacerbación. A examen físico presenta: en piel y mucosas ligero tinte subictérico, a nivel abdominal: abdomen doloroso de forma difusa sin viseromegalias o masas palpables

Evaluation of the antioxidant activity and antitumor activity of marine invertebrates extracts

Dissertação de Mestrado, Biologia Marinha, Faculdade de Ciências e Tecnologias, Universidade do Algarve, 2014

Identificação morfológica de organismos semelhantes à anaplasmataceae em monócitos de surubim híbrido (Pseudoplatystoma reticulatum x P. corruscans) – relato de caso

The aim of this study was to report the occurrence of Anaplasmataceae-like organisms in monocytes from the hybrid surubim catfish. During the hematological evaluation of fish infected by Pseudomonas sp. in a fish farm located in the State of Mato Grosso do Sul we observed into the monocytes the presence of numerous pleomorphic inclusions of various sizes, rough in appearance which presented basophilic staining. These inclusions were similar to elementary bodies, initial bodies and morule of the bacteria from Anaplasmataceae family, often diagnosed in domestic mammals. This is the first report of its occurrence possibly belonging to the family of Anaplasmataceae in cultured fish in Brazil. Additional studies are necessary for molecular characterization of this bacteria, pathogenic potential, life cycle and impact on the intensive production of fish.

The Herpesvirus Nuclear Egress Complex Component, UL31, is Recruited to Sites of DNA Damage Through Poly(ADP-RIBOSE) Binding

Thesis (Master, Biomedical & Molecular Sciences) -- Queen's University, 2016-08-23 15:03:30.807

Establishment of antibody panels and histochemical techniques in routine tumor diagnosis in Veterinary Pathology

In Portugal, Veterinary Pathology is developing rapidly, and in recent years we assist to the emergence of private laboratories and the restructuring of universities,polytechnics and public laboratories.The Portuguese Society of Animal Pathology,through its actions and its associates has been keeping the discussion among its peers in order to standardizethe criteria of description,classification and evaluation of cases which are the subject of our daily work.One of the last challenges is associated with the use of routine histochemical techniques and immunohistochemistry, in an effort to establish standardized panels for tumour diagnosis, which could eventually reduce each analysis cost.For this purpose a simple survey was built, in which all collaborators answered questions about the markers used for carcinoma, sarcoma and round cell tumour diagnosis, as well as general questions related with the subject. We obtained twenty-one answered to the questions, from public and private laboratories.In general, in most cases immunohistochemical and histochemical methods are used for diagnosis.The wide spectrum cytokeratins are universally used to confirm carcinoma, and vimentin for sarcoma. The CD3 marker is used by all laboratories to identify T lymphocytes. For the diagnosis of B-cell lymphoma, the marker used is not consensual. In each laboratory there are different markers for more specific situations and only two labs perform PCR techniques for diagnosis. These data will be presented to promote extended discussion,namely to reach a consensus when different markers are used.

Microenvironment and prognostic factors in bone tumors: IDH mutations in chondrosarcoma

Microenvironment in bone tumors is a dynamic entity composed of cells from different origins (immune cells, stromal cells, mesenchymal stem cells, endothelial cells, pericytes) and vascular structures surrounded by a matrix of different nature (bone, cartilage, myxoid). Interactions between cancer cells and tumor microenvironment (TME) are complex and can change as tumor progress, but are also crucial in determining response to cancer therapies. Chondrosarcoma is the second most frequent bone cancer in adult age, but its treatment still represents a challenge, for the intrinsic resistance to conventional chemotherapy and radiation therapy. This resistance is mainly due to pathological features, as dense matrix, scarce mitoses and poor vascularization, sustained by biological mechanisms only partially delucidated. Somatic mutation in the Krebs cycle enzyme isocytrate dehydrogenase (IDH) have been described in gliomas, acute myeloid leukemia, cholangiocarcinoma, melanoma, colorectal, prostate cancer, thyroid carcinoma and other cancers. In mesenchymal tumors IDH mutations are present in about 50% of central chondrosarcoma. IDH mutations are an early event in chondrosarcoma-genesis, and contribute to the acquisition of malignancy through the block of cellular differentiation, hypoxia induction through HIF stabilization, DNA methylation and alteration of cellular red-ox balance. While in gliomas IDH mutations confers a good prognosis, in chondrosarcoma IDH prognostic role is controversial in different reported series. First aim of this project is to define the prevalence and the prognostic role of IDH mutation in high grade central conventional chondrosarcoma patients treated at Istituto Ortopedico Rizzoli. Second aim is the critical revision of scientific literature to understand better how a genomic event in cancer cell can trigger alteration in the TME, through immune infiltrate reshaping, angiogenesis induction, metabolic and methylation rewiring. Third aim is to screen other sarcoma histotypes for the presence of IDH mutation.

Methods for Biodata Analysis in different Omic Contexts

The world of Computational Biology and Bioinformatics presently integrates many different expertise, including computer science and electronic engineering. A major aim in Data Science is the development and tuning of specific computational approaches to interpret the complexity of Biology. Molecular biologists and medical doctors heavily rely on an interdisciplinary expert capable of understanding the biological background to apply algorithms for finding optimal solutions to their problems. With this problem-solving orientation, I was involved in two basic research fields: Cancer Genomics and Enzyme Proteomics. For this reason, what I developed and implemented can be considered a general effort to help data analysis both in Cancer Genomics and in Enzyme Proteomics, focusing on enzymes which catalyse all the biochemical reactions in cells. Specifically, as to Cancer Genomics I contributed to the characterization of intratumoral immune microenvironment in gastrointestinal stromal tumours (GISTs) correlating immune cell population levels with tumour subtypes. I was involved in the setup of strategies for the evaluation and standardization of different approaches for fusion transcript detection in sarcomas that can be applied in routine diagnostic. This was part of a coordinated effort of the Sarcoma working group of "Alleanza Contro il Cancro". As to Enzyme Proteomics, I generated a derived database collecting all the human proteins and enzymes which are known to be associated to genetic disease. I curated the data search in freely available databases such as PDB, UniProt, Humsavar, Clinvar and I was responsible of searching, updating, and handling the information content, and computing statistics. I also developed a web server, BENZ, which allows researchers to annotate an enzyme sequence with the corresponding Enzyme Commission number, the important feature fully describing the catalysed reaction. More to this, I greatly contributed to the characterization of the enzyme-genetic disease association, for a better classification of the metabolic genetic diseases.

Nuclear shape instability caused by lamin A deregulation promotes invasiveness in pediatric bone sarcomas: from nucleo-cytoskeleton dynamics to novel therapeutic opportunities

Osteosarcoma (OS) and Ewing sarcoma (EWS) are the two most frequent primary bone tumors, in which metastases remain the most relevant adverse prognostic factor. Lamin A is the main constituent of the nuclear lamina, with a fundamental role in maintaining the connection between nucleus and cytoskeleton (through LINC complex proteins interactions), and its alterations can be implicated in tumor progression. We investigated how nucleo-cytoskeleton dynamics is influenced by lamin A modulation in OS and EWS, demonstrating that both these cancer models had low levels of lamin A, which are linked to a significantly more marked nuclear misshaping. In our in vitro studies, reduced levels of lamin A promoted migratory abilities in these tumors. Moreover, these findings were corroborated by gene expression analyses on EWS patient samples, showing that LMNA levels were significantly lower in metastatic lesions compared to primary tumors and that patients with low LMNA had a significant worse overall survival. We also found that LMNA expression significantly impaired EWS metastases formation in vivo. We demonstrated that low lamin A expression was linked to a severe mislocalization of LINC complex proteins, thus disrupting nucleo-cytoskeleton interactions, with a corresponding gain in malignant properties, which resulted in increased invasiveness. Lamin A overexpression or its accumulation by a statin-based pharmacological treatment allowed us to reconstitute a functional nucleo-cytoskeleton interplay, which resulted in significant downmodulation of ROCK2 and YAP, two crucial drivers of EWS aggressiveness. Our study demonstrated that lamin A is a favorable mediator of nuclear shape stability in bone sarcomas, and its modulation rescues LINC complex protein localization and regulates mechano-signaling pathways, thus promoting a less aggressive cancer phenotype. We also identified statins, already employed in clinical practice, as a tool capable to increase lamin A levels, and to reconstitute functional nucleo-cytoskeletal dynamics, resulting in reduced cellular migration.

Characterization of the molecular mechanisms mediated by the insulin-like growth factor-2 mRNA-binding proteins and Ephrin receptor A2 (EPHA2) signaling in the malignancy of CIC-DUX4 sarcomas

Ewing sarcoma (EWS) and CIC-DUX4 sarcoma (CDS) are pediatric fusion gene-driven tumors of mesenchymal origin characterized by an extremely stable genome and limited clinical solutions. Post-transcriptional regulatory mechanisms are crucial for understanding the development of this class of tumors. RNA binding proteins (RBPs) play a crucial role in the aggressiveness of these tumors. Numerous RBP families are dysregulated in cancer, including IGF2BPs. Among these, IGF2BP3 is a negative prognostic factor in EWS because it promotes cell growth, chemoresistence, and induces the metastatic process. Based on preliminary RNA sequencing data from clinical samples of EWS vs CDS patients, three major axes that are more expressed in CDS have been identified, two of which are dissected in this PhD work. The first involves the transcription factor HMGA2, IGF2BP2-3, and IGF2; the other involves the ephrin receptor system, particularly EphA2. EphA2 is involved in numerous cellular functions during embryonic stages, and its increased expression in adult tissues is often associated with pathological conditions. In tumors, its role is controversial because it can be associated with both pro- and anti-tumoral mechanisms. In EWS, it has been shown to play a role in promoting cell migration and neoangiogenesis. Our study has confirmed that the HMGA2/IGF2BPs/IGF2 axis contributes to CDS malignancy, and Akt hyperactivation has a strong impact on migration. Using loss/gain of function models for EphA2, we confirmed that it is a substrate of Akt, and Akt hyperactivation in CDS triggers ligand-independent activation of EphA2 through phosphorylation of S897. Moreover, the combination of Trabectedin and NVP/BEZ235 partially inhibits Akt/mTOR activation, resulting in reduced tumor growth in vivo. Inhibition of EphA2 through ALWII 41_27 significantly reduces migration in vitro. The project aim is the identification of target molecules in CDS that can distinguish it from EWS and thus develop new targeted therapeutic strategies.