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1.
Medicine (Baltimore) ; 100(39): e27352, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596142

RESUMO

INTRODUCTION: Recent studies have reported a connection between non-coding RNAs such as circular RNAs (circRNAs) and the prognosis of various cancers. However, the mechanism of circRNA in ovarian cancer and cervical cancer has not been consistent. We evaluated the diagnostic and prognostic roles of circRNAs in ovarian and cervical cancer by meta-analysis. METHODS: Pooled hazard ratios with 95% confidence intervals were to estimate overall survival. Diagnostic efficacy was estimated by sensitivity, specificity and area under curve. RESULTS: By searching PubMed, Embase, the Web of Science databases, and other sources, we obtained a total of 22 studies with 2059 patients from Asia population. High expression levels of oncogenic circRNAs were significantly associated with poor prognoses both in ovarian and cervical cancer. However, elevated expression levels of tumor-suppressor circRNAs were linked with favorable survival time in ovarian cancer. As for diagnostic role, the area under the curve value in ovarian cancer and cervical cancer is 0.89 and 0.93, respectively. CONCLUSIONS: CircRNAs have the prospect of becoming a promising biomarker for diagnosis and prognosis of ovarian and cervical cancer. Accordingly, circRNAs might be novel indicators and targets of therapy for ovarian and cervical cancer.


Assuntos
Neoplasias Ovarianas/epidemiologia , RNA Circular/biossíntese , Neoplasias do Colo do Útero/epidemiologia , Biomarcadores Tumorais , Feminino , Humanos , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , RNA Circular/sangue , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/mortalidade
2.
Medicine (Baltimore) ; 100(40): e27473, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622876

RESUMO

BACKGROUND: FOXP4-AS1 expression participates in multiple signal pathways and has been previously reported in colorectal cancer, cervical cancer, and other cancer cells. However, its role on prognosis and immune infiltrates in ovarian serous cystadenocarcinoma (OVs) remains unclear. The purpose of our study was to investigate the expression of FOXP4-AS1 in OVs and its association with immune infiltrates, and determined its prognostic roles in OVs. METHODS: Using The Cancer Genome Atlas (TCGA) database, we retrieved FOXP4-AS1 expression and clinical information for 376 patients with OVs. Wilcoxon rank sum test was used to compare the expression of FOXP4-AS1 in OVs and normal ovarian tissue. Logistic regression was used to analyze the relationship between clinicopathologic features and FOXP4-AS1. Gene Set Enrichment Analysis (GSEA), and single sample Gene Set Enrichment Analysis (ssGSEA) was conducted to investigate the enrich pathways and functions and quantify the extent of immune cells infiltration for FOXP4-AS1. Kaplan-Meier method was used to generate survival curves, and Cox regression was used to analyze the relationship between FOXP4-AS1 and survival rate. RESULTS: High FOXP4-AS1 expression was significantly correlated with tumor FIGO stage (P = .026). Multivariate survival analysis showed that FOXP4-AS1was an independent prognostic marker for overall survival (OS; hazard ratio [HR]: 0.638; 95% confidence interval [CI]:0.467-0.871; P = .001) and disease-specific survival (DSS; HR: 0.649; CI: 0.476-0.885; P = .006). GSEA showed that High FOXP4-AS1 expression may active programmed cell death 1 (PD-1) signaling, the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) pathway, the B cell receptor signaling pathway, apoptosis, fibroblast growth factor receptor (FGFR) signaling, and the Janus-activated kinase signal transducers and activators of transcription (JAK-STAT) signaling pathway. FOXP4-AS1 expression was negatively correlated with markers of immune cells, including aDC, cytotoxic cells and neutrophils. CONCLUSION: High FOXP4-AS1 expression has the potential to be a prognostic molecular marker of favorable survival in OVs.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , RNA Longo não Codificante/biossíntese , Biomarcadores Tumorais , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico
3.
Medicine (Baltimore) ; 100(35): e27130, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477158

RESUMO

ABSTRACT: Bevacizumab (BV) plus chemotherapy is broadly used in advanced ovarian cancer (OC). However, the efficacy of BV-based regimens for advanced OC patients is not satisfactory. Therefore, it is urgent to explore the predictive genetic biomarkers for BV.Tumor tissues from advanced OC patients receiving BV-based regimens were analyzed with a 150-gene targeted panel for next generation sequencing. The associations between gene alterations or clinicopathology features and progression-free survival (PFS) were analyzed by Kaplan-Meier curves or Cox regression. The association of the genetic alteration in potential predictive genes and expressions of 11 vascular endothelial growth factor-related genes were analyzed in The Cancer Genome Atlas cohort using 292 OC cases.Sixty two Chinese advanced OC patients treated with BV-based therapy were included. The median PFS of was 6.9 months, and objective response rate was 14.5%. In multivariate Cox regression analysis, the status of endothelial growth factor receptor (EGFR) (hazard ratio = 6.39, 95% confidence interval [CI] 2.25-18.13, P < .001) and human epidermal growth factor receptor 2 (HER2) (hazard ratio = 3.58, 95% CI 1.27-10.08, P = .016) were significantly correlated with PFS. MYC Proto-Oncogene amplification seemed to have a positive trend (hazard ratio = 0.21, 95% CI 0.05-1.02, P = .052). Moreover, EGFR and HER2 alterations were not prognostic factors of overall survival for OC in The Cancer Genome Atlas OC cohort. The vascular endothelial growth factor-related signature analysis indicated vascular endothelial factor A expression was upregulated with EGFR alterations (P = .034) which may be involved in BV resistance, and HER2 alterations were associated with hypoxia inducible factor 1 subunit alpha overexpression significantly (P = .029).EGFR or HER2 alterations are negative predictors of PFS for OC patient treated with BV plus chemotherapy. Therefore, the clinicians may consider to use alternative regimens such as anti-EGFR or anti-HER2 targeted therapy instead of BV-based regimens on these patients when standard care fail.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Genes erbB-1 , Genes erbB-2 , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Variantes Farmacogenômicos , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Cancer Invest ; 39(10): 893-901, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34486892

RESUMO

In this retrospective analysis of 36 patients with recurrent ovarian cancer (ROC) treated with platinum pemetrexed doublet ± bevacizumab, the median age was 54.5 years (47-60) and 33 (91.7%) had serous histology. The overall response rate [ORR = complete (CR)+partial (PR) response] was 83.3%. At a median follow-up of 16 months, the median PFS was 13.8 months (95% CI: 10.849-20.580) and median OS 30.6 months, (95% CI: 21.46 months-NR). The incidence of Grade 3/4 anemia, thrombocytopenia, neutropenia and non-hematological toxicity was 19.4%, 3.9%, 16.6%, and 8.3%. Platinum pemetrexed chemotherapy in ROC is safe and effective treatment option.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Pemetrexede/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/mortalidade , Pemetrexede/efeitos adversos , Estudos Retrospectivos
5.
Medicine (Baltimore) ; 100(32): e26849, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397893

RESUMO

ABSTRACT: This study aimed to investigate the effect of molecular targeted agents (MTAs) in chemo on platinum-resistant recurrent ovarian cancer (ROC). We performed this meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements. Randomized controlled trials reporting data about platinum-resistant ovarian cancer treated by MTAs were included. The endpoints for the present study included overall survival and progression-free survival. We analyzed 9 randomized controlled trials including 3631 patients with ROC. The pooled analysis indicated that a combination of MTAs with chemo could markedly increase objective response rate in those patients (P = .012). Nevertheless, the survival rate of those patients was not markedly changed (P = .19). Besides, the combination of MTAs with chemo dramatically aggravated the occurrence of adverse events (P < .05). Moreover, it resulted in the termination of treatment (P = .044) in those patients, but it had no effect on fatal adverse events (P = .16). Our results indicated that the combination of MTAs with chemo notably improved objective response rate in patients with platinum-resistant ROC, but its benefit did not translate into survival benefits.


Assuntos
Antineoplásicos , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas , Antineoplásicos/classificação , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Análise de Sobrevida
6.
Cancer Sci ; 112(10): 4220-4233, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34363722

RESUMO

The ascites that develops in advanced OC, both at diagnosis and upon recurrence, is a rich source of multicellular spheroids/aggregates (MCSs/MCAs), which are the major seeds of tumor cell dissemination within the abdominal cavity. However, the molecular mechanism by which specific ascites-derived tumor cells survive and metastasize remains largely unknown. In this study, we elucidated cancer stem cell (CSC) properties of ascites-derived MCSs, concomitant with enhanced malignancy, induced EMT, and low KLF9 (Krüppel-like factor 9) expression, compared with PTCs. KLF9 was also downregulated in OC cell line-derived spheroids and the CD117+ CD44+ subpopulation in MCSs. Functional experiments demonstrated that KLF9 negatively modulated stem-like properties in OC cells. Mechanistic studies revealed that KLF9 reduced the transcriptional expression of Notch1 by directly binding to the Notch1 promoter, thereby inhibiting the function of slug in a CSL-dependent manner. Clinically, expression of KLF9 was associated with histological grade and loss of KLF9 predicts poor prognosis in OC.


Assuntos
Ascite/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Receptor Notch1/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Esferoides Celulares/patologia , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Fatores de Transcrição Kruppel-Like/fisiologia , Gradação de Tumores , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais , Esferoides Celulares/metabolismo
7.
Front Immunol ; 12: 645839, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349753

RESUMO

Background: Ovarian cancer (OC) has the highest mortality rate among gynecologic malignancy. Hypoxia is a driver of the malignant progression in OC, which results in poor prognosis. We herein aimed to develop a validated model that was based on the hypoxia genes to systematically evaluate its prognosis in tumor immune microenvironment (TIM). Results: We identified 395 hypoxia-immune genes using weighted gene co-expression network analysis (WGCNA). We then established a nine hypoxia-related genes risk model using least absolute shrinkage and selection operator (LASSO) Cox regression, which efficiently distinguished high-risk patients from low-risk ones. We found that high-risk patients were significantly related to poor prognosis. The high-risk group showed unique immunosuppressive microenvironment, lower antigen presentation, and higher levels of inhibitory cytokines. There were also significant differences in somatic copy number alterations (SCNAs) and mutations between the high- and low-risk groups, indicating immune escape in the high-risk group. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms showed that low-risk patients are significantly responsive to programmed cell death protein-1 (PD-1) inhibitors. Conclusions: In this study, we highlighted the clinical significance of hypoxia in OC and established a hypoxia-related model for predicting prognosis and providing potential immunotherapy strategies.


Assuntos
Neoplasias Ovarianas/mortalidade , Hipóxia Tumoral/fisiologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Nomogramas , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Prognóstico , Microambiente Tumoral
8.
Cancer Sci ; 112(11): 4627-4640, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34464482

RESUMO

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Mitocôndrias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/mortalidade , Animais , Cromossomos Humanos Par 17 , Resistencia a Medicamentos Antineoplásicos/genética , Transporte de Elétrons , Feminino , Dosagem de Genes , Humanos , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Commun ; 12(1): 4230, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244494

RESUMO

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXß2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXß2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXß2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXß2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.


Assuntos
Processamento Alternativo , Carcinoma Epitelial do Ovário/genética , Proteínas da Matriz Extracelular/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas da Matriz Extracelular/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Ovário/cirurgia , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Medicine (Baltimore) ; 100(28): e26574, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260536

RESUMO

BACKGROUND: Ovarian cancer is one of the lethal gynecological diseases in women. However, using tumor microenvironment related genes to identify prognostic signature of ovarian cancer has not been discussed in detail. METHODS: The mRNA profiles of 386 ovarian cancer patients were retrieved from The Cancer Genome Atlas. Univariate Cox regression and LASSO Cox regression analyses were performed and 14 optimized prognostic genes related to tumor microenvironment were identified. RESULTS: The multivariate Cox hazards regression showed risk score was an independent prognostic signature for ovarian cancer. Nomogram model could reliably predict the patients' survival. Furthermore, M1 macrophages, M2 macrophages, and follicular helper T cells, differentially expressed between the high- and low-risk groups, were found to be associated with the risk score. CONCLUSION: CTL-associated antigen 4 (CTLA4) and indoleamine 2,3-Dioxygenase 1 (IDO1), which were previously shown to be important immune checkpoints, probably contribute to the immunosuppressive microenvironment aberration. This study may shed light on the prognosis of ovarian cancer.


Assuntos
Neoplasias Ovarianas/genética , Microambiente Tumoral/fisiologia , Fatores Etários , Idoso , Biomarcadores Tumorais , Antígeno CTLA-4/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nomogramas , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Células T Auxiliares Foliculares/metabolismo , Macrófagos Associados a Tumor/metabolismo
11.
Anticancer Res ; 41(8): 4157-4161, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281887

RESUMO

BACKGROUND/AIM: A higher number of neoadjuvant chemotherapy (NACT) cycles translate to a lower risk of morbidity and mortality, but few studies have analyzed the prognostic impact of >4 cycles of NACT. PATIENTS AND METHODS: Overall, 52 patients [31 patients, NACT plus interval debulking surgery (IDS); 21 patients, NACT alone owing to progressive disease] who underwent NACT between January 2008 and December 2014 were evaluated. RESULTS: In total, 6, 7-10, and 11-18 cycles of NACT were performed in 52.3%, 27.3%, and 20.5% of the patients, respectively. The median overall survival was 76.0 months (range=36.0-94.0 months), and the median progression-free survival was 26.0 months (range=18.0-54.0 months) in the NACT plus IDS group. CONCLUSION: At least six cycles of NACT plus IDS are associated with a lower rate of multi-organ resection and a high rate of complete resection or optimal (<1 cm) following IDS.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Idoso , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Peritoneais/mortalidade , Prognóstico , Estudos Retrospectivos
12.
J Egypt Natl Canc Inst ; 33(1): 16, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34241710

RESUMO

BACKGROUND: P D-L1 is expressed in tumor cells and plays a crucial role in tumor immune escape. Tumor-infiltrating lymphocytes (TILs) as CD8 T cells contribute to reduced tumor growth. Few studies investigated the prognostic effect of PD-L1 and CD8 TILs in ovarian high-grade serous carcinoma (HGSC). In the present study, we analyzed the expression of PD-L1 and CD8 TILs in HGSC by immunohistochemistry, and results were correlated to prognosis. It was carried on 54 cases of ovarian HGSC who attended the Oncology Centre, Mansoura University, Egypt, from 2012 till 2019. RESULTS: Nearly 60% of cases showed positive PD-L1 expression in tumor cells. Regarding the clinicopathological characteristics, higher PD-L1 expression was found among patients with residual tumor (82.4%) compared to patients with no residual tumor (54.5%), with marginal statistical significance (p 0.07). PD-L1 was significantly associated with CD8 TILs expression. Higher PD-L1 expression was found among tumors with low expression of CD8 TILs with statistically significant difference (p≤0.001). Disease-free survival (DFS) was significantly lower among the group with positive expression of PD-L1 compared to the group with negative expression of PD-L1 (p 0.01), while overall survival (OS) was not associated with PD-L1 expression. On the other hand, the overall survival (OS) in patients with high CD8 expression was significantly higher than patients with low CD8 expression (p 0.043), while DFS was not significantly different among both CD8 TILS groups. CONCLUSIONS: PD-L1 and CD8 TILs may become a promising therapeutic target for patients with ovarian HGSC. More studies are needed to further validate their prognostic effect. Precise identification of patients who will benefit from PD-L1 checkpoint blockade and TILs adaptive immunotherapy is mandatory.


Assuntos
Antígeno B7-H1 , Linfócitos T CD8-Positivos/imunologia , Carcinoma , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/terapia , Adulto , Antígeno B7-H1/análise , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma/mortalidade , Carcinoma/terapia , Egito , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/química , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Prognóstico , Receptor de Morte Celular Programada 1 , Análise de Sobrevida
13.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207103

RESUMO

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates. This paper reviews the role of immunotherapy in ovarian cancer as well as novel therapeutics and study designs involving tumor biomarkers that increase the likelihood of success with immunotherapy in ovarian cancer.


Assuntos
Imunoterapia , Neoplasias Ovarianas/terapia , Medicina de Precisão , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/mortalidade , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Resultado do Tratamento
14.
Cochrane Database Syst Rev ; 7: CD005343, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34328210

RESUMO

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). SEARCH METHODS: We searched the following databases up to 9 October 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in each included trial. We extracted data of overall (OS) and progression-free survival (PFS), adverse events, surgically-related mortality and morbidity and quality of life outcomes.  We used GRADE methods to determine the certainty of evidence. MAIN RESULTS: We identified 2227 titles and abstracts through our searches, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1774 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the four studies where data were available and found little or no difference with regard to overall survival (OS) (Hazard Ratio (HR) 0.96, 95% CI 0.86 to 1.08; participants = 1692; studies = 4; high-certainty evidence) or progression-free survival in four trials where we were able to pool data (Hazard Ratio 0.98, 95% CI 0.88 to 1.08; participants = 1692; studies = 4; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were variably and incompletely reported across studies. There are probably clinically meaningful differences in favour of NACT compared to PDS with regard to overall postoperative serious adverse effects (SAE grade 3+): 6% in NACT group, versus 29% in PDS group, (risk ratio (RR) 0.22, 95% CI 0.13 to 0.38; participants = 435; studies = 2; heterogeneity index (I2) = 0%; moderate-certainty evidence). NACT probably results in a large reduction in the need for stoma formation: 5.9% in NACT group, versus 20.4% in PDS group, (RR 0.29, 95% CI 0.12 to 0.74; participants = 632; studies = 2; I2 = 70%; moderate-certainty evidence), and probably reduces the risk of needing bowel resection at the time of surgery: 13.0% in NACT group versus 26.6% in PDS group (RR 0.49, 95% CI 0.30 to 0.79; participants = 1565; studies = 4; I2 = 79%; moderate-certainty evidence). NACT reduces postoperative mortality: 0.6% in NACT group, versus 3.6% in PDS group, (RR 0.16, 95% CI 0.06 to 0.46; participants = 1623; studies = 5; I2 = 0%; high-certainty evidence). QoL on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scale produced inconsistent and imprecise results in three studies (MD -0.29, 95% CI -2.77 to 2.20; participants = 524; studies = 3; I2 = 81%; very low-certainty evidence) but the evidence is very uncertain and should be interpreted with caution. AUTHORS' CONCLUSIONS: The available high to moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT probably reduces the risk of serious adverse events, especially those around the time of surgery, and reduces the risk of postoperative mortality and the need for stoma formation. These data will inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário , Procedimentos Cirúrgicos de Citorredução/métodos , Terapia Neoadjuvante/métodos , Neoplasias Ovarianas , Viés , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/cirurgia , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/mortalidade , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/mortalidade , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Cuidados Pré-Operatórios , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
15.
Obstet Gynecol ; 138(2): 261-271, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237756

RESUMO

OBJECTIVE: To examine the effects of intraoperative ovarian capsule rupture on progression-free survival and overall survival in women who are undergoing surgery for early-stage ovarian cancer. DATA SOURCES: MEDLINE using PubMed, EMBASE (Elsevier), ClinicalTrials.gov, and Scopus (Elsevier) were searched from inception until August 11, 2020. METHODS OF STUDY SELECTION: High-quality studies reporting survival outcomes comparing ovarian capsule rupture to no capsule rupture among patients with early-stage epithelial ovarian cancer who underwent surgical management were abstracted. Study quality was assessed with the Newcastle-Ottawa Scale, and studies with scores of at least 7 points were included. TABULATION, INTEGRATION, AND RESULTS: The data were extracted independently by multiple observers. Random-effects models were used to pool associations and to analyze the association between ovarian capsule rupture and oncologic outcomes. Seventeen studies met all the criteria for inclusion in the meta-analysis. Twelve thousand seven hundred fifty-six (62.6%) patients did not have capsule rupture and had disease confined to the ovary on final pathology; 5,532 (33.7%) patients had intraoperative capsule rupture of an otherwise early-stage ovarian cancer. Patients with intraoperative capsule rupture had worse progression-free survival (hazard ratio [HR] 1.92, 95% CI 1.34-2.76, P<.001), with moderate heterogeneity (I2=41%, P=.07) when compared with those without capsule rupture. Pooled results from these studies showed a worse overall survival (HR 1.48, 95% CI 1.15-1.91, P=.003), with moderate heterogeneity (I2=53%, P=.02) when compared with patients without intraoperative capsule rupture. This remained significant in a series of sensitivity analyses. CONCLUSION: This systematic review and meta-analysis of high-quality observational studies shows that intraoperative ovarian capsule rupture results in decreased progression-free survival and overall survival in women with early-stage ovarian cancer who are undergoing initial surgical management. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021216561.


Assuntos
Complicações Intraoperatórias , Neoplasias Ovarianas/cirurgia , Ovário/lesões , Intervalo Livre de Progressão , Ruptura , Progressão da Doença , Feminino , Humanos , Neoplasias Ovarianas/mortalidade , Taxa de Sobrevida
16.
Exp Cell Res ; 406(1): 112742, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34302857

RESUMO

BACKGROUND: Mutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer (HGSOC). METHODS: We identified BRCA2 BRC domain mutations by sequencing PCR-amplified amplicons of genomic DNA isolated from tumor tissues and peripheral blood leukocytes (PBL)in 113 patients with advanced EOC, and assessed platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). RESULTS: 21.23% (24 of 113) cases with somatic missense mutation but not germline mutation were identified. Among 24 cases with mutation, 33.3% (8 of 24) cases with nonsense mutation (C-terminal truncation) significantly prolonged median PFI (37 vs 8 months,P = 0.000), PFS (43 vs 14 months, p = 0.000) and OS (56 vs 31 months, P = 0.002); 66.7% (16 of 24) cases with missense mutation also prolonged median PFI (15 vs 8 months, P = 0.044), PFS (21 vs 14 months, P = 0.049) and OS (38 vs 31 months, P = 0.037), compared to those without any mutation. CONCLUSIONS: Somatic mutations in BRCA2 BRC domain confer a higher sensitivity to platinum-based therapy and are associated with a favourable survival in HGSOC.


Assuntos
Proteína BRCA2/genética , Cisplatino/uso terapêutico , Cistadenocarcinoma Seroso/genética , Mutação , Neoplasias Ovarianas/genética , Rad51 Recombinase/genética , Adulto , Sequência de Aminoácidos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína BRCA2/metabolismo , Sequência de Bases , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Rad51 Recombinase/metabolismo , Transdução de Sinais , Análise de Sobrevida
17.
Sci Rep ; 11(1): 15154, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312408

RESUMO

Positive ascites cytology is a strong prognostic factor in patients with early-stage ovarian cancer (OvCa). However, limited information is currently available on the impact of positive ascites cytology on patient prognoses under each clinical background. We herein investigated the comprehensive impact of positive ascites cytology on patients with epithelial OvCa and the effectiveness of additional therapeutic interventions, including complete staging surgery and chemotherapy. Among 4730 patients with malignant ovarian neoplasms, retrospectively identified in multiple institutions, 1906 with epithelial OvCa were included. In the investigation of its effects on clinical factors using a multivariate analysis, positive ascites cytology correlated with a poor prognosis. Positive ascites cytology had a significantly worse prognosis than those with negative cytology in all subgroups except for patients with stage IV tumors and a mucinous histology. Chemotherapy may be effective in reducing the negative impact of positive ascites cytology on the prognosis of patients in terms of progression-free and overall survivals, while complete staging surgery did not improve the prognosis of patients with positive ascites cytology. Collectively, our findings suggested that positive ascites cytology had a negative impact on the prognosis of patients with epithelial OvCa, but not those with stage IV tumors or a mucinous histology.


Assuntos
Ascite/patologia , Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/patologia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
18.
J Prev Med Hyg ; 62(1): E174-E184, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34322634

RESUMO

Objective: Ovarian cancer is known as the seventh most common cancer among women, accounting for about 4% of all cancers associated with the females. Method: This is a descriptive cross-sectional study based on cancer incidence data and cancer mortality rates from the Global Cancer Data in 2018. The incidence and mortality rates were estimated and ovarian cancer distribution maps for world countries were drawn. To analyze data, correlation and regression tests were used to evaluate association between its incidence and mortality with human development index (HDI). Results: Results revealed a direct and significant correlation between ovarian cancer incidence (R = 0.409, P < 0.0001) and mortality (R = 0.193, P < 0.05) with HDI. It also projected a direct and significant correlation between incidence with Gross National Income per 1,000 capita (GNI), mean years of schooling (MYS), life expectancy at birth (LEB) and expected years of schooling (EYS) (P < 0.0001). The findings also demonstrated a direct and significant correlation between mortality and GNI, MYS, LEB as well as EYS (P < 0.05). The linear regression model showed that a higher MYS [B = 0.2, CI 95%: (-0.03, 0.5)] can significantly augment the incidence of ovarian cancer while an increased MYS [B = 0.2, CI 95% (0.03, 0.4)] can induce mortality. Conclusions: Given the direct and significant correlation between ovarian cancer incidence and mortality with HDI, attention to risk factors in these countries can be effective in curbing its incidence and mortality.


Assuntos
Países em Desenvolvimento , Saúde Global , Neoplasias Ovarianas , Estudos Transversais , Feminino , Humanos , Incidência , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/mortalidade , Fatores Socioeconômicos
19.
PLoS One ; 16(7): e0255142, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34320033

RESUMO

Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsa-miR-126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsa-miR-506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Thus, the evaluation on independent cohorts will further evaluate the performance of such findings.


Assuntos
MicroRNAs/metabolismo , Neoplasias Ovarianas/genética , RNA Mensageiro/metabolismo , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Bases de Dados Genéticas , Feminino , Redes Reguladoras de Genes/genética , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Taxa de Sobrevida
20.
Eur J Cancer ; 154: 190-200, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34293664

RESUMO

BACKGROUND: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. METHODS: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. RESULTS: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3-11.3), 5.4 (4.8-5.8) and 2.9 (2.8-4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1-22.4) and 8.3 (7.1-10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). CONCLUSIONS: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Nomogramas , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/toxicidade , Piperazinas/toxicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Prognóstico , Intervalo Livre de Progressão
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