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1.
AAPS PharmSciTech ; 20(8): 317, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605252

RESUMO

The present work aims to develop folate-targeted paclitaxel liposome (F-PTX-LIP), which will selectively target tumor cells overexpressing folate receptor (FR) and leave normal cells. Liposomes were prepared by thin-film hydration method followed by post-insertion of synthesized ligand 1,2-distearoyl-sn-glycero-phosphoethanolamine-polyethyleneglycol 2000-folic acid (DSPE-PEG2000-FA) on the outer surface of the liposome. The synthesized ligand was evaluated for in vivo acute toxicity in Balb/c mice. Developed liposomal formulations were characterized using transmission electron microscopy (TEM) and small-angle neutron scattering (SANS). We have investigated the effect of ligand number on cell uptake and cytotoxicity by confocal laser scanning microscopy (CLSM), competitive inhibition and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Compared to lung adenocarcinoma cells (A549), uptake in human ovarian carcinoma cells (SKOV3) was 2.2- and 1.2-fold higher for liposome with 480 and 240 ligand number respectively. Competitive inhibition experiment shows that prior incubation of SKOV3 cells with free folic acid significantly reduced the cell uptake of F-PTX-LIP with 480 ligand number (480 F-PTX-LIP) by 2.6-fold. 480 F-PTX-LIP displays higher cytotoxicity than free drug and PTX liposome. Moreover, it specifically targets the cells with higher folate receptor expression. Optimized 480 F-PTX-LIP formulation can be potentially useful for the treatment of folate receptor-positive tumors.


Assuntos
Ácido Fólico/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Ligantes , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Ovarianas/química , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem
2.
Georgian Med News ; (290): 20-25, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322508

RESUMO

Borderline ovarian tumors (BOTs) represent particular challenge for diagnosis and clinical management as they are characterized with the features of both benign cystadenomas and malignant carcinomas. The aim of our study was to investigate histomorphological and immunohistochemical characteristics of ovarian serous-papillary borderline tumors, compared to serous cystadenomas and low- and high-grade serous carcinomas. Altogether, 80 formalin fixed and paraffin embedded tissue specimens, distributed in four groups, including serous cystadenoma (group I), serous BOTs (group II), Low (group III) and high (group IV) grade serous carcinomas, were investigated by standard immunohistochemistry, using antibodies against CK7 CK20, WT1, Vimentin, CDX2, CEA, ER, cyclin D1, BCL2, E-cadherin, calretinin, СA125, Ki67, P53. Study results showed, that ovarian serous BOTs are characterized with slightly increase proliferative potential compared to benign cystadenomas, whilst apoptotic potential is retained with the difference from malignant serous carcinomas. p53 mutation is not present, as well as the expression of Vimentin. Overall, ovarian serous BOTs are characterized with highly variable immunohistochemical phenotype and the use of multiple immunohistochemical markers are recommended for the differential diagnosis from low grade serous carcinomas and benign cystadenomas.


Assuntos
Biomarcadores Tumorais/análise , Cistadenocarcinoma Seroso/patologia , Cistadenoma Seroso/química , Cistadenoma Seroso/patologia , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Proteínas WT1/análise
3.
Clin Transl Oncol ; 21(10): 1432-1439, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31025168

RESUMO

INTRODUCTION: Goblet cell carcinoma (GCC) is an appendicular neoplasia representing less than 5% of all appendicular tumors, found in 0.3-0.9% of the appendectomies, 35-58% of all appendicular neoplasms, and less than 14% of malign appendix tumors. The most frequent clinical presentation is abdominal pain associated with a picture of acute appendicitis. MATERIALS AND METHODS: We present 3 clinical cases of appendix GCC, 2 subjected to cytoreductory surgery plus intraperitoneal hyperthermic chemotherapy and a third, who is currently receiving neoadjuvant treatment with a good response to chemotherapy and who will be offered the same treatment as the first two patients. Given the unpredictable behavior of these tumors, the use of molecular markers could help us to predict their behavior and prognosis. In this context, the TP73 gene would make an interesting putative marker. ∆Np73 has been described as overexpressed in a great variety of tumor types including colon cancer and this up-regulation is associated with a poor prognosis. To evidence its role in this malignancy, we evaluate here the status of ∆Np73 in the primary tumor and normal counterpart tissues, in the metastatic implants and in healthy areas of the peritoneum from the appendicular GCC patients. In addition, we checked the expression levels of this p73 variant in the tumor and normal tissue of 26 patients with colon cancer. RESULTS: Remarkably, 2 patients showed significant ∆Np73 down-regulation in both the primary tumor and the implants. Case 1 presented a fourfold decrease of levels in the primary tumor and 20-fold decrease in the implants. Case 2 showed a seven- and fourfold down-regulation in the primary tumor and implants, respectively. However, Case 3 showed an up-regulation of 53- and threefold in the primary tumor and implants, respectively. CONCLUSION: Goblet cell carcinoma of the appendix is very rate. It tends to seed throughout the peritoneum, making aggressive surgical cytoreduction and chemotherapy viable treatment options. Investigation into the molecular basis of these tumors may improve the diagnosis, prognosis and therapeutic decisions regarding these patients. ∆Np73 seems a good candidate for further analysis in longer series.


Assuntos
Adenocarcinoma/química , Neoplasias do Apêndice/química , Biomarcadores Tumorais/análise , Células Caliciformes/química , Neoplasias Ovarianas/química , Neoplasias Peritoneais/química , Proteína Tumoral p73/análise , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/terapia , Colo/química , Neoplasias do Colo/química , Procedimentos Cirúrgicos de Citorredução , Regulação para Baixo , Feminino , Humanos , Hipertermia Induzida , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/secundário , Neoplasias Peritoneais/secundário , Peritônio/química
4.
Ginekol Pol ; 90(1): 1-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30756364

RESUMO

OBJECTIVES: Peroxiredoxins (PRDXs) constitute a family of antioxidant enzymes which are also involved in the process of carcinogenesis. They are composed of six identified isoforms (PRDX-1-6) and are supposed to play different roles in tumor progression, depending on type of cancer and member of the PRDX family. The aim of the study was to assess the prog- nostic value of PRDXs in ovarian cancer. MATERIAL AND METHODS: a dataset of patients with ovarian cancer from The Cancer Genome Atlas was analyzed. Expression of PRDX-1 to 6 mRNA was evaluated in 260 samples. The prognostic value of PRDXs was assessed using the Cox regression model which included the following clinical and pathological data: age, clinical stage, tumor grade, and residual disease. RESULTS: Within the PRDXs family, only higher expression of PRDX-5 was associated with worse overall survival both, in unselected patients and > 50-year-olds. PRDX-5 expression and residual disease were independent negative prognostic factors of patient survival. CONCLUSIONS: PRDX-5 is a negative predictor of survival in ovarian cancer.


Assuntos
Neoplasias Ovarianas , Peroxirredoxinas , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Peroxirredoxinas/análise , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Prognóstico
5.
Ginekol Pol ; 90(1): 11-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30756366

RESUMO

OBJECTIVES: The main aims of the study were to investigate the expression of vimentin and its correlation with the overall survival (OS) of patients with malignant ovarian tumors, and the correlation between vimentin expression and tumor stroma characteristics. MATERIAL AND METHODS: The study focused on 94 malignant ovarian tumors that had been collected from women who were treated in the Department of Gynecology and Oncology of the Lukaszczyk Oncological Center, Bydgoszcz, Poland. Vimentin expression was assessed in both the cancer cells (expression intensity and quantitative analysis) and the tumor stroma (expression intensity). Vimentin expression was analyzed according to both stromal cellularity and the clinicopatho- logical features of the disease. RESULTS: Both high cancer cell vimentin expression intensity and high quantitative vimentin expression (up to and includ- ing 30% of cells) indicated a significantly prolonged OS. Low vimentin stromal expression was associated with prolonged OS, although the difference did not reach the level of significance. High tumor cell vimentin expression intensity was as- sociated with significantly higher vimentin stromal expression. High vimentin expression in the tumor stroma indicated a significantly higher cellularity of the tumor stroma. Vimentin expression in cancer cells and the tumor stroma were not dependent on the histopathological type, the tumor grade or the FIGO stageof the disease. CONCLUSIONS: High cancer cell vimentin expression is associated with an improved OS of patients with malignant ovar- ian tumors. The expression of vimentin in ovarian malignancies may influence the structure of the tumor stroma.


Assuntos
Neoplasias Ovarianas , Vimentina , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/química , Ovário/metabolismo , Ovário/patologia , Prognóstico , Microambiente Tumoral , Vimentina/análise , Vimentina/metabolismo
6.
Int J Gynecol Pathol ; 38(5): 449-458, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30028355

RESUMO

TP53 gene mutations are known to manifest in distinct p53 immunohistochemical staining patterns; overexpression, wild-type, and null. These stratified staining patterns are routinely utilized in subtyping ovarian cancer subtypes. Three ovarian cancer cell lines were used in the construction of an immunohistochemical p53 expression pattern control panel that highlight respective TP53 mutation status. The cell line control panel sections demonstrated consistent clean and easily interpretable p53 immunohistochemical staining. Procured resection, biopsy, and cytologic specimens were submitted along with either standard control tissue or a p53 cell line control panel to pathologists of varying experience for interrater reliability analysis. Individual interrater reliability was near-perfect and was improved with the p53 cell line control panel when compared with the tissue control. The cell line control panel demonstrated decreased misinterpretation of null expression pattern as wild-type. Next-generation sequencing analysis was performed on the cell lines and select cases, in which there was discordance in p53 expression pattern interpretation. Next-generation sequencing analysis demonstrated low-frequency variant mutations in some cases in which there was reviewer discordance. This study suggests the addition of a p53 cell line expression pattern control panel could potentially increase p53 interpretation accuracy for ovarian cancer subtypes. We developed a cell line-based p53 control panel that has the potential to increase individual interrater reliability for p53 immunohistochemical expression pattern determination, support immunohistochemical optimization, and direct submission of difficult to interpret p53 staining cases to next-generation sequencing.


Assuntos
Neoplasias Ovarianas/química , Proteína Supressora de Tumor p53/análise , Linhagem Celular Tumoral , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Mutação
7.
Int J Gynecol Pathol ; 38(5): 479-484, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30085941

RESUMO

We report the first case of an ovarian pericytoma with t(7;12). An 11-year-old child presented with abdominal pain and distension. A suprapubic mass was detected on examination and radiological investigations revealed a 16.5 cm solid-cystic ovarian mass. Histologically, the tumor was composed of spindle cells with S100-protein, Bcl-2, and CD10 reactivity on immunohistochemistry. Alpha fetoprotein, calretinin, alpha-inhibin, WT1, smooth muscle actin, caldesmon, desmin, cytokeratins, chromogranin, synaptophysin, EMA, Sox10, CD117, CD31, CD34, and CD68 were all negative. Molecular tests showed t(7;12)(p22;q13), resulting in the fusion of the ACTB with GLI1 genes and a diagnosis of pericytoma with t(7;12) of the ovary was made. We discuss the difficulties in diagnosing this lesion in the ovary and highlight the importance on molecular tests in characterizing challenging cases, especially primary ovarian spindle cell mesenchymal tumors.


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 7 , Neoplasias Ovarianas/genética , Translocação Genética , Criança , Feminino , Humanos , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia
8.
Rapid Commun Mass Spectrom ; 33(4): 381-391, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30468547

RESUMO

RATIONALE: Identification of subregions under different pathological conditions on cancerous tissue is of great significance for understanding cancer progression and metastasis. Infrared matrix-assisted laser desorption electrospray ionization mass spectrometry (IR-MALDESI-MS) can be potentially used for diagnostic purposes since it can monitor spatial distribution and abundance of metabolites and lipids in biological tissues. However, the large size and high dimensionality of hyperspectral data make analysis and interpretation challenging. To overcome these barriers, multivariate methods were applied to IR-MALDESI data for the first time, aiming at efficiently resolving mass spectral images, from which these results were then used to identify normal regions within cancerous tissue. METHODS: Molecular profiles of healthy and cancerous hen ovary tissues were generated by IR-MALDESI-MS. Principal component analysis (PCA) combined with color-coding built a single tissue image which summarizes the high-dimensional data features. Pixels with similar color indicated similar composition. PCA results from healthy tissue were further used to test each pixel in cancerous tissue to determine if it is healthy. Multivariate curve resolution-alternating least squares (MCR-ALS) was used to obtain major spatial features existing in ovary tissues, and group molecules with the same distribution patterns simultaneously. RESULTS: PCA as the predominating dimensionality reduction approach captured over 90% spectral variances by the first three PCs. The PCA images show the cancerous tissue is more chemically heterogeneous than healthy tissue, where at least four regions with different m/z profiles can be differentiated. PCA modeling assigns top regions of cancerous tissue as healthy-like. MCR-ALS extracted three and four major compounds from healthy and cancerous tissue, respectively. Evaluating similarities of resolved spectra uncovered the chemical components that were distinct in some regions on cancerous tissue, serving as a supplementary way to differentiate healthy and cancerous regions. CONCLUSIONS: Two unsupervised chemometric methods including PCA and MCR-ALS were applied for resolving and visualizing IR-MALDESI-MS data acquired from hen ovary tissues, improving the interpretation of mass spectrometry imaging results. Then possible normal regions were differentiated from cancerous tissue sections. No prior knowledge is required using either chemometric method, so our approach is readily suitable for unstained tissue samples, which allows one to reveal the molecular events happening during disease progression.


Assuntos
Galinhas , Neoplasias Ovarianas/veterinária , Doenças das Aves Domésticas/diagnóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Galinhas/metabolismo , Feminino , Análise dos Mínimos Quadrados , Análise Multivariada , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Ovário/química , Ovário/patologia , Doenças das Aves Domésticas/patologia , Análise de Componente Principal
9.
Rapid Commun Mass Spectrom ; 33(1): 97-106, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30376198

RESUMO

RATIONALE: Development of therapy-resistant cancer is a major problem in clinical oncology, and there is an urgent need for novel markers identifying development of the resistant phenotype. Lipidomics represents a promising approach to discriminate lipid profiles of malignant phenotype cells. Alterations in phospholipid distribution or chemical composition have been reported in various pathologies including cancer. Here we were curious whether quantitative differences in phospholipid composition between cisplatin-resistant and -sensitive model cancer cell lines could be revealed by mass spectrometric means. METHODS: The phospholipid contents of cell membranes of the cancer cell lines CCRF-CEM and A2780, both responsive and resistant to cisplatin, were analyzed by solid-phase extraction (SPE) and electrospray ionization mass spectrometry (ESI-MS and tandem mass spectrometry (MS/MS)). Extracts were obtained by disruption of cells with a dounce tissue grinder set followed by centrifugation. To minimize the enzymatic activity, phospholipids were extracted from cell extracts by SPE immediately after the cell lysis and analyzed by MS. Both supernatant and pellet fractions of cell extracts were analyzed. RESULTS: A phospholipid profile specific for cell lines and their phenotypes was revealed. We have documented by quantitative analysis that phosphocholines PC P-34:0, PC 34:1, PC 20:2_16:0, LPC 18:1 and LPC 16:0 PLs were present in the 200-400 µM concentration range in CCRF-CEM cisplatin-responsive cells, but absent in their cisplatin-resistant cells. Similarly, PC 34:1, LPC 18:1 and LPC 16:0 were increased in cisplatin-responsive A2780 cells, and PC 20:2_16:0 was downregulated in cisplatin-resistant A2780 cells. CONCLUSIONS: In this work we showed that the ESI-MS analysis of the lipid content of the therapy-resistant and -sensitive cells can clearly distinguish the phenotypic pattern and determine the potential tumor response to cytotoxic therapy. Lipid entities revealed by mass spectrometry and associated with development of therapy resistance can thus support molecular diagnosis and provide a potential complementary cancer biomarker.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fosfolipídeos/análise , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Fosfolipídeos/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Extração em Fase Sólida , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
10.
Lab Invest ; 99(4): 483-498, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30487595

RESUMO

Polyploid giant cancer cells (PGCCs) are key contributors to cancer heterogeneity, and the formation of PGCCs is associated with changes in the expression of cell-cycle-related proteins. This study investigated the intracellular localization and expression level of multiple cell-cycle-related proteins in PGCCs derived from BT-549 and HEY cells. In addition, the formation of PGCCs and the clinicopathological significance of cell-cycle-related proteins in human breast and ovarian cancer were examined. The expression levels of cell-cycle-related proteins, including cyclin B1, CDC25B, CDC25C, and other cell cycle phosphoproteins, including Chk2, and Aurora-A kinase, were determined using immunostaining and western blotting both in vitro and in vivo. Migration, invasion, and proliferation in control cells, cyclin B1 knockdown cells and their PGCCs following CoCl2 treatment were compared. In addition, human breast and ovarian cancer samples were collected to determine the correlation of number of PGCCs, expression of cell-cycle-related proteins, and tumor pathologic grade and metastasis. Our results confirm that cyclin B1 was localized in the cytoplasm of PGCCs and in the nuclei of their budding daughter cells. The phosphorylated proteins Chk2 and Aurora-A kinase regulated the expression and subcellular localization of cyclin B1, CDC25B, and CDC25C. The rate of positive cytoplasmic staining of cyclin B1 and positive nuclear staining of both CDC25B and CDC25C increased with increase in tumor grade and lymph node metastasis. Cell-cycle-related proteins, including cyclin B1, CDC25B, and CDC25C play an important role in regulating the formation of PGCCs. The inhibition of cyclinB1 and CoCl2 treatment significantly promoted cell proliferation, invasion, and migration abilities. The subcellular localization of these cell-cycle-related proteins was regulated by other cell cycle phosphoproteins, and was associated with pathologic grade and metastasis of tumors in cases of human breast and ovarian cancer.


Assuntos
Neoplasias da Mama , Proteínas de Ciclo Celular/metabolismo , Ciclina B1/metabolismo , Neoplasias Ovarianas , Fosfatases cdc25/metabolismo , Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Proteínas de Ciclo Celular/análise , Linhagem Celular Tumoral , Ciclina B1/análise , Feminino , Humanos , Espaço Intracelular/metabolismo , Processos Neoplásicos , Neoplasias Ovarianas/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/fisiopatologia , Poliploidia , Fosfatases cdc25/análise
11.
Biochem Biophys Res Commun ; 508(2): 646-653, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30527804

RESUMO

Armadillo-related proteins function in both signal transduction and cell adhesion, it also plays a central role in tumorigenesis. Plakophilin 3 (PKP3) is a member of the armadillo protein family. PKP3 has demonstrated a role in melanoma, breast cancer, gastric cancer, and other kind of cancers; however its role in ovarian cancer was not fully understood. In this study we explored the function and mechanisms of PKP3 in ovarian cancer. An elevated level of PKP3 was found in ovarian cancer tissues compared with normal tissues. PKP3 also modulate cellular proliferation and invasion in ovarian cancer. The ability of cellular proliferation, formation, and invasion was significantly decreased after the silencing of PKP3 in SKOV3 cells. While an over-expression of PKP3 in A2780 cells up-regulates the ability of cellular proliferation, formation, and invasion. As for the mechanism of PKP3, mTOR pathway was activated to regulate autophagy according to the interaction of PKP3 with the upstream of MAPK pathway. The result of this study support PKP3 as the oncogene candidate and a potential target for the treatment of ovarian cancer.


Assuntos
Autofagia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Placofilinas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Movimento Celular , Células Cultivadas , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Invasividade Neoplásica , Neoplasias Experimentais/química , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/química , Placofilinas/análise , Placofilinas/genética
12.
J Gynecol Oncol ; 29(6): e93, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30207101

RESUMO

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Ovarianas/terapia , Anticorpos Monoclonais/imunologia , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/análise , Antígeno B7-H1/imunologia , Quebras de DNA , Feminino , Humanos , Tolerância Imunológica , Imunoterapia/métodos , Mutação , Neoplasias/imunologia , Nivolumabe/uso terapêutico , Neoplasias Ovarianas/química , Neoplasias Ovarianas/imunologia , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Resultado do Tratamento , Proteínas Supressoras de Tumor/genética
13.
J Ovarian Res ; 11(1): 64, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30071867

RESUMO

BACKGROUND: Ovarian cancer is the most lethal of gynecological malignancies. Fourier Transform Infrared (FTIR) spectroscopy has gradually developed as a convenient, inexpensive and non-destructive technique for the study of many diseases. In this study, FTIR spectra of normal and several heterogeneous ovarian cancer cell lines as well as ovarian cancer tissue samples were compared in the spectral region of 4000 cm- 1 - 600 cm- 1. METHODS: Cell samples were collected from human ovarian surface epithelial cell line (HOSEpiC) and five ovarian cancer cell lines (ES2, A2780, OVCAR3, SKOV3 and IGROV1). Validation spectra were performed on normal and cancerous tissue samples from 12 ovarian cancer patients. FTIR spectra were collected from a NICOLET iN10 MX spectrometer and the spectral data were analyzed by OMNIC 8.0 software. RESULTS: Spectral features discriminating malignant tissues from normal tissues were integrated by cell line data and tissue data. In particular changes in cancerous tissues, the decrease in the amount of lipids and nucleic acids were observed. Protein conformation and composition were also altered in some cancer cells. The band intensity ratio of 1454/1400 was higher in normal cells/tissues and lower in cancer cells/tissues. CONCLUSION: The spectral features revealed the important molecular characteristics about ovarian cancer cells/tissues. These findings demonstrate the possible diagnostic use of FTIR spectroscopy, providing the research model and evidences, and supporting the future study on more tissue samples to establish a data bank of spectra features for the possible discrimination of ovarian cancers.


Assuntos
Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico , Ovário/química , Ovário/citologia , Ovário/patologia , Espectroscopia de Infravermelho com Transformada de Fourier
14.
Diagn Pathol ; 13(1): 57, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30131069

RESUMO

BACKGROUND: The expression of high temperature requirement factor A1 (Htra1) has been reported to be decreased in ovarian carcinoma, but its prognostic effect remains undetermined. METHODS: We evaluated the impact of HtrA1 downregulation in tumoral tissues on cancer progression and death in women with serous ovarian carcinoma. HtrA1 staining was performed on tissue microarrays (TMA) comprised of tumor samples from a cohort of 106 women who were diagnosed with primary high-grade serous ovarian carcinoma and receiving standard treatment at the Québec University Hospital between 1993 and 2006. HtrA1 expression was assessed visually (percentage of positive nuclei) and by digital image analysis (percentage of positive area). Cox regression multivariate models included standard prognostic factors and were used to estimate adjusted hazard ratios (aHR) for progression or death in the cohort. RESULTS: By visual analysis, a low percentage of HtrA1-positive nuclei (< 10% vs ≥10%) tend to be associated with a lower risk of progression (aHR = 0.71; 95% Confidence interval (CI) = 0.46-1.09; P = 0.11) and mortality (aHR = 0.65; 95% CI = 0.41-1.04; P = 0.07). Low nuclear HtrA1 expression assessed by digital image analysis (< median % vs ≥ median %) showed a significant association with lower risk of progression (aHR = 0.62; 95% CI = 0.40-0.95; p = 0.03) and death (aHR = 0.60; 95% CI = 0.38-0.95; p = 0.03). CONCLUSION: Altogether, our results demonstrate that nuclear downregulation of HtrA1 is associated with a better prognosis in women with high grade serous ovarian carcinoma.


Assuntos
Biomarcadores Tumorais/análise , Serina Peptidase 1 de Requerimento de Alta Temperatura A/análise , Interpretação de Imagem Assistida por Computador , Imuno-Histoquímica , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Ovarianas/química , Idoso , Núcleo Celular/química , Núcleo Celular/patologia , Estudos de Coortes , Regulação para Baixo , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo , Análise Serial de Tecidos , Resultado do Tratamento
15.
Zhonghua Bing Li Xue Za Zhi ; 47(7): 517-521, 2018 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-29996316

RESUMO

Objective: To describe the clinicopathologic features, diagnosis and differential diagnosis of ovarian carcinoid tumors. Methods: A retrospective chart review was performed of all patients diagnosed with primary ovarian carcinoid tumors at Fudan University Shanghai Cancer Centre from 2007 to 2017. Results: The histologic analysis of these carcinoid tumors revealed 3 were insular, 1 was trabecular, 1 was mucinous, and 10 were strumal. Histologic features of insular and trabecular carcinoid were similar to other parts of the neuroendocrine tumor. Strumal carcinoid was composed of thyroid tissue intimately admixed with carcinoid tumor, showing trabecular pattern. Mucinous carcinoid was resembles Krukenberg tumor. Most ovarian carcinoid tomours were diffusely positive with at least one neuroendocrine marker, especially synaptophysin (14/14) and CD56(9/10). The median follow-up time was 53 months, 1 patient with squamous-cell carcinoma of cervixrecur rence in vaginal after 37 months, and only 1 patient died of disease. The remaining patients were disease-free survival. Conclusions: Primary carcinoid of the ovary is a very rare low grade malignant monodermal teratomas and somatic-type tumours arising from a dermoid. The diagnosis and differential diagnosis mainly relies on the histopathologic characteristics and the immuno-phenotype. Primary ovarian carcinoid almost always exhibit a benign clinical behavious except mucinous carcinoid.


Assuntos
Tumor Carcinoide/patologia , Neoplasias Ovarianas/patologia , Estruma Ovariano/patologia , Tumor Carcinoide/química , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patologia , China , Diagnóstico Diferencial , Intervalo Livre de Doença , Feminino , Humanos , Tumor de Krukenberg/patologia , Neoplasias Ovarianas/química , Estudos Retrospectivos , Estruma Ovariano/química , Sinaptofisina/análise , Teratoma/química , Teratoma/patologia , Glândula Tireoide/patologia
16.
Virchows Arch ; 473(2): 165-175, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29926183

RESUMO

Causes of peritoneal carcinomatosis (PC) in patients with a history of breast carcinoma include both metastatic breast carcinoma (MBC) and primary peritoneal/ovarian carcinoma (PPOC). The origin of PC is important to determine the appropriate treatment strategy. Cytological examination of the peritoneal fluid (PF), which may be the first diagnostic approach to PC, is of distinct value in confirming the presence of malignant cells and determining the origin of PC. We analyzed the clinicopathological and cytomorphological characteristics of 33 patients with a history of breast carcinoma whose PF cytology contained malignant cells. Cases showing positive immunoreactivity for PAX8 and a lack of GATA3 expression were considered as PPOC. Sixteen patients developed PC caused by PPOC. PPOC patients were characterized by early-stage primary breast carcinoma, absence of non-peritoneal MBC before PC, and normal serum levels of CEA and CA15-3. Fourteen PPOC patients had pathogenic germline BRCA mutations. Cytological examination revealed that most of the PPOC cases had a dominant papillary arrangement of the tumor cells with severe nuclear pleomorphism, occasional bizarre nuclei, and atypical mitotic figures. Patients with PPOC who underwent cytoreductive surgery had a significantly longer survival time compared to those who did not, or MBC patients. In patients with a history of breast carcinoma presenting with PC, the presence of early-stage primary breast carcinoma, no prior non-peritoneal MBC, and a dominant papillary cellular arrangement pattern in the PF cytology were independent predictors of PPOC. Cytoreductive surgery significantly improved survival for patients with PPOC.


Assuntos
Líquido Ascítico/patologia , Neoplasias da Mama/patologia , Carcinoma/patologia , Segunda Neoplasia Primária/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Adulto , Líquido Ascítico/química , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Antígeno Carcinoembrionário/sangue , Carcinoma/química , Carcinoma/genética , Carcinoma/secundário , Procedimentos Cirúrgicos de Citorredução , Diagnóstico Diferencial , Feminino , Fator de Transcrição GATA3/análise , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mucina-1/sangue , Estadiamento de Neoplasias , Segunda Neoplasia Primária/química , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/cirurgia , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Fator de Transcrição PAX8/análise , Neoplasias Peritoneais/química , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/cirurgia , Valor Preditivo dos Testes , Resultado do Tratamento
17.
Hum Pathol ; 81: 89-95, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29944972

RESUMO

In the female genital tract, extrauterine leiomyomas such as those that arise in the ovary and paraovarian/paratubal regions are rare. Currently, little is known about the background genetic changes in such adnexal leiomyomas. Recent studies have found that the MED12 mutation is common in uterine leiomyomas, which suggests that such mutations may play an oncogenic role in smooth muscle neoplasms in females. Herein, we examined a series of ovarian and other adnexal leiomyomas in terms of MED12 mutational status to investigate possible MED12 involvement in the pathogenesis of extrauterine smooth muscle tumors. We evaluated 10 cases of adnexal leiomyomas (5 ovarian, 3 paraovarian, and 2 paratubal) and 49 cases of ovarian sex cord-stromal tumors as controls. We performed polymerase chain reaction followed by direct sequencing of exon 2 of MED12, and immunohistochemical staining for smooth muscle actin and desmin. We identified somatic MED12 mutations in 90% (9/10) of the adnexal leiomyomas. None of the sex cord-stromal tumors in the control group harbored MED12 mutations. Diffuse immunoreactivity for both smooth muscle actin and desmin was characteristic of adnexal leiomyomas only. Thus, we conclude that ovarian leiomyomas are distinct from sex cord-stromal tumors. MED12 mutations are key molecular features of ovarian and other adnexal leiomyomas. We speculate that the pathogenesis of adnexal leiomyoma is similar to that of its uterine counterpart.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias das Tubas Uterinas/genética , Leiomioma/genética , Complexo Mediador/genética , Mutação , Neoplasias Ovarianas/genética , Actinas/análise , Adulto , Idoso , Biomarcadores Tumorais/análise , Diferenciação Celular , Análise Mutacional de DNA , Desmina/análise , Neoplasias das Tubas Uterinas/química , Neoplasias das Tubas Uterinas/patologia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Leiomioma/química , Leiomioma/patologia , Pessoa de Meia-Idade , Taxa de Mutação , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Fenótipo , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Fatores de Risco , Tóquio
18.
Hum Pathol ; 81: 26-36, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29753846

RESUMO

Identification of the yolk sac tumor (YST) component in germ cell tumors (GCT) may prove challenging, and highly sensitive and specific immunohistochemical markers are still lacking. Preliminary data from the literature suggest that HNF1ß may represent a sensitive marker of YST. The specificity of HNF1ß has not been addressed in GCT. A cohort of 49 YST specimens from 45 patients was designed, occurring either as pure tumors, or as a component of a mixed GCT. Immunohistochemistry was conducted on whole tumor sections using HNF1ß. SALL4, OCT4, CD30, CDX2, Cytokeratin 19, Glypican 3, and GATA3 were used for classification of the GCT components. Patients were mostly male (39/45), aged 14 months to 49 years, with primary testicular tumors (37/39), or primary mediastinal pure YSTs (2/39). All 6 primary tumors occurring in females (6/45) were pure ovarian YSTs; age range was 4 to 72 years. HNF1ß nuclear reactivity was seen in the YST component in all 49 tumors, with a moderate to strong nuclear pattern of staining. Embryonal carcinoma (EC, 0/32) and seminoma (0/6) were negative. Choriocarcinoma (6/6) showed faint focal cytoplasmic reactivity to HNF1ß but no nuclear staining. In teratomas, only enteric-type glands showed nuclear reactivity to HNF1ß (11/16). Therefore, HNF1ß sensitivity in YST component identification was 100% and specificity was 80%. Thus, in our experience, HNF1ß is a sensitive and reliable marker of the YST component in GCT, and allows distinction of YST from intricately admixed EC, especially in the diffuse embryoma pattern.


Assuntos
Biomarcadores Tumorais/análise , Coriocarcinoma/química , Tumor do Seio Endodérmico/química , Fator 1-beta Nuclear de Hepatócito/análise , Neoplasias Complexas Mistas/química , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/química , Neoplasias Testiculares/química , Adolescente , Adulto , Idoso , Carcinoma Embrionário/química , Carcinoma Embrionário/patologia , Criança , Pré-Escolar , Coriocarcinoma/patologia , Diagnóstico Diferencial , Tumor do Seio Endodérmico/patologia , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias Complexas Mistas/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Seminoma/química , Seminoma/patologia , Teratoma/química , Teratoma/patologia , Neoplasias Testiculares/patologia , Adulto Jovem
19.
Histol Histopathol ; 33(8): 859-870, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29569698

RESUMO

Double primary endometrioid endometrial and ovarian carcinomas (DPEEOCs) are the most common multiple gynecological carcinomas. In recent years, gene sequential comparison analysis has strongly supported the opinion that sporadic double endometrioid endometrial and ovarian cancers (DEEOCs) are clonally related in both primary and metastatic tumors. In order to find more clonal evidence for DPEEOC, we investigated cancer stem cells (CSCs). SOX2 and OCT4 are two common factors in CSCs. MicroRNA (miRNA)-145, a small non-coding RNA, has effects in regulating gene expression and tumorigenesis in CSCs. The aim of this study was to assess the involvements of SOX2, OCT4, and miRNA-145 in the tumorigenesis of DPEEOCs. In our study, twenty DPEEOC patients were chosen. Metastatic DEEOCs and normal endometrial and ovarian tissues were also included. The expression of miRNA-145 was detected by real-time quantitative PCR. Immunohistochemical staining was used to measure the expression of OCT4 and SOX2. The results showed that miRNA-145 expression was lower in DPEEOC endometrial tissues and higher in DPEEOC ovarian tissues compared to the corresponding normal tissues. Both SOX2 and OCT4 were over-expressed in cancer tissues compared with that in normal tissues. MiRNA-145, SOX2, and OCT4 were expressed at similar levels in two cancer sites of a given DPEEOC or metastatic DEEOC sample. Besides, metastatic DEEOC sections expressed a higher level of SOX2 and OCT4 compared to the corresponding DPEEOC tissues. Together, these results support the clonality of DPEEOCs. Moreover, SOX2 and OCT4 may have some implication in DPEEOC and metastatic DEEOC diagnosis.


Assuntos
Biomarcadores Tumorais , Carcinoma Endometrioide , Neoplasias do Endométrio , MicroRNAs/genética , Neoplasias Primárias Múltiplas , Fator 3 de Transcrição de Octâmero/análise , Neoplasias Ovarianas , Fatores de Transcrição SOXB1/análise , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/química , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/secundário , Neoplasias do Endométrio/química , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Ann Pathol ; 38(2): 131-136, 2018 Apr.
Artigo em Francês | MEDLINE | ID: mdl-29398147

RESUMO

We report the case of a 15 years old teenage girl presenting with a primary amenorrhea and hypervirilisation symptoms. The clinical assessement found a 16cm wide heterogenous ovarian mass testosteronemia and alpha-foeto protein levels were increased. On gross exam the tumor was solid and cystic, multilocular containing serous and mucinous liquids. Microscopically, there was a sertoli cells rich solid area in which the cells had a trabecular and nested organization with Leydig cells between them and there was also a cystic area made of glandular structures lined with an intestinal muco-secreting epithelium. Next to these area, there were Sertoli cells and an oedematous stroma. The immunostaining showed that the Sertoli cells expressed, among others, the inhibine and the glands expressed the cytokeratins 7 and 20. A Sertoli and Leydig cells tumor of intermediate differentiation with heterologous elements diagnostic was made. This is a rare tumor, representing less than 0.5% of ovary tumors. Well differentiated tumors are not frequent. In one third of the cases, there are hypervirilisation symptoms, the imaging exams will serve to narrow the diagnosis and to do a full work-up to establish an extension. There are several histologic sub types caracterised by the existence of retiforms structures or heterologous elements. There are no specific immunostainings, this will only help to narrow the diagnosis and rule out some hypothesis. There are no guidelines for the management of the patients, indeed each center has its own practices. Those tumors have quite a good prognosis thanks to their early diagnosis at a stade where they are still confined to the ovary.


Assuntos
Neoplasias Ovarianas/diagnóstico , Tumor de Células de Sertoli-Leydig/diagnóstico , Adolescente , Biomarcadores Tumorais , Diferenciação Celular , Feminino , Humanos , Inibinas/análise , Queratina-20/análise , Queratina-7/análise , Proteínas de Neoplasias/análise , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Tumor de Células de Sertoli-Leydig/sangue , Tumor de Células de Sertoli-Leydig/química , Tumor de Células de Sertoli-Leydig/patologia , Testosterona/sangue , alfa-Fetoproteínas/análise
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