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1.
Isr Med Assoc J ; 22(2): 75-78, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32043322

RESUMO

BACKGROUND: The treatment of elderly patients with advanced stage ovarian carcinoma is challenging due to a high morbidity. OBJECTIVES: To evaluate the clinical course and outcome of elderly patients with advanced stage ovarian carcinoma receiving neoadjuvant chemotherapy (NACT). METHODS: A retrospective study of all patients with stage IIIC and IV ovarian carcinoma receiving NACT in one medical center (between 2005 and 2017). The study group criteria age was above 70 years. The control group criteria was younger than 70 years old at diagnosis. Demographics and treatment outcomes were compared between groups. Primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, 105 patients met the inclusion criteria, 71 patients (67.6%) were younger than 70 years and 34 patients (32.4%) older. Rates of interval cytoreduction were significantly higher in younger patients (76.1% vs. 50.0%, P = 0.01). Of those who underwent interval cytoreduction, no difference was found in rates of optimal debulking between groups (83.35% vs. 100%, P = 0.10). Using a Kaplan-Meier survival analysis, no significant differences were observed between groups in PFS or OS, P > 0.05. Among the elderly group alone, patients who underwent interval cytoreduction had significantly longer PFS than those without surgical intervention (0.4 ± 1.7 vs. 19.3 ± 19.4 months, P = 0.001). CONCLUSIONS: Elderly patients with ovarian carcinoma who received NACT undergo less interval cytoreduction than younger patients, with no difference in PFS and OS. However, among the elderly, interval cytoreduction is associated with significantly higher PFS.


Assuntos
Carcinoma Epitelial do Ovário , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos de Citorredução/estatística & dados numéricos , Neoplasias Ovarianas , Fatores Etários , Idoso , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Intervalo Livre de Doença , Feminino , Humanos , Israel/epidemiologia , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
3.
Lancet ; 394(10214): 2084-2095, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31791688

RESUMO

BACKGROUND: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. METHODS: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. INTERPRETATION: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Idoso , Grupo com Ancestrais do Continente Asiático , Carboplatina/administração & dosagem , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Carcinoma Epitelial do Ovário/patologia , Quimioterapia Adjuvante , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Procedimentos Cirúrgicos de Citorredução , Grupo com Ancestrais do Continente Europeu , Neoplasias das Tubas Uterinas/patologia , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Neoplasias Peritoneais/patologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais
4.
Medicine (Baltimore) ; 98(46): e17896, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725636

RESUMO

Ubiquitin-conjugating enzyme E2C (UBE2C) is considered to play an important role in the tumorigenesis of many cancers and promote cell cycle progression. Kangai 1 (KAI1) is considered as a suppressor gene of tumor metastasis. However, the clinicopathological significance and their each relationship of UBE2C and KAI1 in epithelial ovarian carcinoma (EOC) are not widely reported. The purpose of this study is to detect the expression of UBE2C and KAI1 in EOC and their clinical significance.The expression of UBE2C and KAI1 in 180 cases of EOC tissues, 60 cases of normal ovarian epithelial tissues, and 60 cases of ovarian benign tumor tissues were detected by immunohistochemistry. Patients data were also collected.Positive expression of UBE2C in EOC (38.9%) was significantly higher than that both in the normal group (0%) and benign tumors group (10.0%). Furthermore, the expression of UBE2C was positively associated with grades of differentiation, implants, lymph node metastasis (LNM), as well as the International Federation of Gynecology and Obstetrics (FIGO) stages. Positive expression of KAI1 in EOC (25.0%) was significantly lower than that both in the normal group (100%) and benign tumors group (75.0%). And the expression of KAI1 was inversely associated with grades of differentiation, implants, LNM, and FIGO stages. Kaplan-Meier survival analyses demonstrated that UBE2C positive expression for patients with EOC had unfavorably overall survival (OS) time when compared with negative UBE2C for patients. And KAI1 positive expression for patients had favorably OS time when compared with negative KAI1 for patients. Multivariate analysis showed that positive expression of UBE2C and KAI1, implants, and FIGO stages were considered as independently prognostic factors for OS in patients with EOC. Moreover, UBE2C expression was significantly higher in high grade serous adenocarcinoma (SA) when compared with low grade SA; and KAI1 expression was significantly lower in high grade SA when compared with low grade SA. High grade SA patients had higher rates of implants, LNM, and high FIGO stages when compared with low grade SA. High grade SA patients had unfavorably OS time when compared with low grade SA.UBE2C and KAI1 should be considered as potential biomarkers of EOC prognosis.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Proteína Kangai-1/biossíntese , Neoplasias Ovarianas/patologia , Enzimas de Conjugação de Ubiquitina/biossíntese , Biomarcadores Tumorais , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Neoplasias Ovarianas/mortalidade , Prognóstico
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1065-1070, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640948

RESUMO

OBJECTIVE: To isolate tumor stem-like cells from human epithelial ovarian cancer SKOV3 cells and explore their role in the formation of vascularization mimicry (VM). METHODS: SKOV3 cells were passaged to the 7th generation by suspension culture in serum-free medium, and the percentages of CD133- and CD117-positive cells in the 1st, 3rd, 5th and 7th generations were analyzed using flow cytometry. The proliferative activity of the cells sorted from the 7th generation SKOV3 cells was assessed with colony formation assay. A three-dimensional cell culture model was established to compare the ability of VM formation between the sorted cells and the parental SKOV3 cells. The expression levels of matrix metalloproteinases-2 (MMP-2) and MMP-9 in the two groups were detected using real-time PCR and Western blotting. RESULTS: Some SKOV3 cells formed typical cell spheres with suspension growth in serum-free medium and were passaged to the 7th generation. Flow cytometry revealed that the percentage of CD133-positive cells increased with cell passaging. The cloning efficiency of the sorted cells was significantly higher than that of the parental SKOV3 cells (50.33% vs 5.33%, P < 0.001). The VM formation ability of the sorted cells was stronger than that of the parental SKOV3 cells in the three-dimensional cell culture system. RT-PCR and Western blotting showed that the expression levels of MMP-2 and MMP-9 were significantly higher in the 7th passage cells than in the parental cells (P < 0.05). CONCLUSIONS: The sorted cells from SKOV3 cells cultured in serum-free medium exhibit biological properties of tumor stem cells with strong VM formation ability, suggesting their role in VM formation.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Células-Tronco Neoplásicas/citologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo
7.
Gynecol Oncol ; 155(3): 393-399, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31653510

RESUMO

OBJECTIVE: Early-phase data have demonstrated induction of antibody responses to a polyvalent vaccine conjugate (Globo-H, GM2, MUC1-TN, TF) with adjuvant OPT-821. We sought to determine if this combination decreases the hazard of progression or death compared to OPT-821 alone in patients with ovarian cancer in second/third clinical complete remission following chemotherapy. Secondary and translational objectives were overall survival (OS), safety, and immunogenicity. METHODS: From 2010-2013, patients were randomized (1:1) to receive OPT-821±vaccine-KLH conjugate subcutaneously at weeks 1, 2, 3, 7, 11, and then every 12 weeks (total 11). Dose delay or reduction was not permitted. Patients were removed for pre-defined dose-limiting toxicity. RESULTS: Of 171 patients randomized, 170 were treated. Most had disease of serous histology (85%), stage 3 disease at diagnosis (77%), and had received 2 prior regimens (68%). 32% received >6 treatment cycles [median 6, each arm (p = 0.33)]. 77% discontinued due to progression, 4% due to toxicity, and 1 due to myeloid dysplastic syndrome (MDS). Maximum toxicities included grade 4 MDS and depression/personality change (1 each, unlikely related), as well as grade 3 gastrointestinal disorders and others (n = 21, 4 related). Lesser adverse events were injection site reactions (82%) and fever (11%). Estimated HR for progression-free survival (PFS) of the vaccine + OPT-821 to OPT-821 arm was 0.98 (95% CI: 0.71-1.36). At a median follow-up of 60 months, median OS was 47 and 46 months, respectively. CONCLUSIONS: Vaccine + OPT-821 compared to OPT-821 alone was modestly immunogenic and did not prolong PFS or OS. Multi-remission patients are a viable, well-defined population for exploring innovative consolidation and maintenance approaches. TRIAL REGISTRATION: NCT00857545.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Carcinoma Epitelial do Ovário/terapia , Neoplasias das Tubas Uterinas/terapia , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Vacinas Conjugadas/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Método Duplo-Cego , Neoplasias das Tubas Uterinas/imunologia , Neoplasias das Tubas Uterinas/patologia , Feminino , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologia
8.
Mol Carcinog ; 58(11): 2161-2174, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31486135

RESUMO

Metabolic reprogramming (including the Warburg effect) is a hallmark of cancer, yet the association between the altered metabolism and chemoresistance remains elusive. Hexokinase II (HKII) is a key metabolic enzyme and is upregulated in multiple cancers. In this study, we examined the impact of targeting metabolism via silencing of HKII on chemoresistance in ovarian cancer (OVCA). In addition, the regulatory molecular mechanism of tumor metabolism was examined using gain- and loss-of-function approaches in epithelial OVCA cell lines of various histological subtypes. We demonstrated that cisplatin (CDDP)-induced p53-mediated HKII downregulation is a determinant of chemosensitivity in OVCA. Silencing of HKII sensitized chemoresistant OVCA cells to apoptosis in a p53-dependent manner. As a negative regulator, p53 suppressed HKII transcription by promoter binding and decreased glycolysis. Pyruvate dehydrogenase kinase-1 (PDK1) is a key regulator of cell proliferation involved in Akt signaling axis. Our Gene Expression Profiling Interactive Analysis (GEPIA) and molecular studies also revealed that PDK1, an upstream activator strongly correlates with HKII expression and regulates its metabolic activity. Finally, we demonstrated that the clinically approved drug metformin sensitizes chemoresistant OVCA cells to CDDP via PDK1-HKII pathway. Collectively, our data implicate that p53--PDK1-HKII axis is a central regulatory component of metabolism conferring chemoresistance in OVCA.


Assuntos
Carcinoma Epitelial do Ovário/tratamento farmacológico , Hexoquinase/genética , Proteína Supressora de Tumor p53/genética , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Proliferação de Células/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hexoquinase/antagonistas & inibidores , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
9.
Gynecol Oncol ; 155(2): 213-219, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31477282

RESUMO

OBJECTIVE: Optimizing the counselling of women ≤40years with epithelial ovarian cancer (EOC) by investigating the role of young age and tumour characteristics on overall survival (OS). METHODS: A retrospective population-based study was done using data of EOC patients diagnosed between 1990 and 2014 registered in the Netherlands Cancer Registry. Descriptive statistics were performed to analyse clinical and tumour characteristics. Five- and 10-year OS rates were calculated using Kaplan Meier curves. To determine prognostic factors, univariable and multivariable survival analyses were performed. RESULTS: 1407 women ≤40years and 29,022 women >40years old were included. OS was higher for the younger women compared to older group (5-year survival of 65.6% vs. 32.7%, 10-year survival of 57.5% vs. 22.5%, respectively). The younger women had more often a mucinous (36.4%), well-differentiated (31.8%) tumour in early stage of disease (49.9%). Serous tumours (43.0%), high-grade (36.0%) and stage III (47.1%) were most frequently found in the older women. Histology, grade, stage, incidence year, and age group are independent prognostic factors for survival. OS of the young women for several combinations of tumour characteristics were calculated. CONCLUSIONS: Age is an independent prognostic factor for OS in EOC patients. Counselling on prognosis could be more individualised in young EOC patients using the tumour characteristics histology, stage and grade.


Assuntos
Carcinoma Epitelial do Ovário/mortalidade , Neoplasias Ovarianas/mortalidade , Adulto , Distribuição por Idade , Idoso , Carcinoma Epitelial do Ovário/patologia , Aconselhamento , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Neoplasias Ovarianas/patologia , Prognóstico , Sistema de Registros , Estudos Retrospectivos
10.
Gynecol Oncol ; 155(1): 58-62, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31402165

RESUMO

OBJECTIVE: To evaluate the impact of an evidence-based triage algorithm to decide between primary debulking surgery (PDS) and neoadjuvant chemotherapy followed by interval debulking surgery (NACT/IDS) for advanced epithelial ovarian cancer (EOC). METHODS: Surgical morbidity and mortality (M/M) after PDS for stage IIIC-IV EOC at Mayo Clinic after implementation of the triage algorithm (contemporary cohort, 2012-July 2016) were compared to that of a historic PDS cohort (2003-2011). RESULTS: Mean age of the 232 women who met inclusion criteria in the contemporary cohort was 63.9 years. We observed a 71% decrease in 90-day mortality from 8.9% to 2.6% (P = 0.002) between the contemporary and historic cohorts. Accordion grade 3+ postoperative complications within 30 days after surgery decreased from 22.3% to 18.3% (P = 0.19). Among those with a grade 3+ complication, 90-day mortality rates decreased from 28.3% in the historic cohort to 2.4% in the contemporary cohort (P < 0.001) suggesting patients were better able to tolerate complex surgery. When compared to the historic PDS cohort, oncologic outcomes were also improved in the contemporary PDS cohort. Complete as well as optimal (residual disease ≤1 cm) cytoreduction rates increased (45.5% vs. 62.5% and 84.5% vs. 95.3%, respectively, P < 0.001), and the proportion of women starting chemotherapy within 42 days of surgery increased (57.4% vs. 69.8%, P = 0.001). Three-year overall survival was 53% in the historic cohort and 66% in the contemporary cohort (P < 0.001). CONCLUSIONS: Use of the Mayo triage algorithm for EOC was associated with reduced 90-day mortality after PDS and improved oncologic outcomes. Surgical risk assessment is a critical aspect of treatment planning in the primary management of EOC and should be incorporated into practice.


Assuntos
Algoritmos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Triagem/métodos , Idoso , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Quimioterapia Adjuvante , Estudos de Coortes , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Análise de Sobrevida
11.
Gynecol Oncol ; 155(1): 69-74, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31409486

RESUMO

OBJECTIVE: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. METHOD: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV. RESULTS: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606). CONCLUSION: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.


Assuntos
Tecido Adiposo/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Adiposidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/patologia , Obesidade/fisiopatologia , Neoplasias Ovarianas/diagnóstico por imagem , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Tomografia Computadorizada por Raios X
13.
Expert Opin Investig Drugs ; 28(9): 771-785, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449760

RESUMO

Introduction: Molecular analyzes including molecular descriptor/phenotype interactions have led to better characterization of epithelial ovarian cancer patients, including a definition of a BRCA wild-type (BRCAwt) phenotype. Understanding how and when to use agents targeted against dependent BRCAwt pathways or other molecular events at disease progression is an important translational and therapeutic direction in ovarian cancer research. Areas covered: In this overview, we provide definitions and descriptions of a BRCAwt genotype and phenotype. We discuss novel investigational drugs that hold promise for the treatment of BRCAwt ovarian cancer, including inhibitors of poly(ADP-ribose) polymerase, ribonucleotide reductase, DNA protein kinase-catalytic subunit, ataxia-telangiectasia-mutated kinase (ATM), ataxia-telangiectasia mutated and Rad3-related kinase (ATR), CHK 1/2, cyclin kinases, glutaminase-1, WEE1 kinase, as well as tumor microenvironment and angiogenesis inhibitors. This article explores the known and the emerging areas of clinical research on patients with BRCAwt ovarian cancer. Expert opinion: Discovery of molecular changes tied to annotated disease information, along with an expanding array of pathway targets and targeted therapeutic agents, creates optimism and opportunity for women with ovarian cancer. Using precision oncology approaches, clinical researchers are, and will be, poised to select more effective treatments for ovarian cancer patients.


Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Drogas em Investigação/farmacologia , Feminino , Humanos , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
14.
Eur J Radiol ; 118: 187-193, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31439240

RESUMO

PURPOSE: To investigate the potential of ESWAN in differentiating borderline epithelial ovarian tumors (BEOTs) from malignant epithelial ovarian tumors (MEOTs). METHOD: Thirty-four patients with 37 lesions were enrolled, including 14 BEOTs and 23 MEOTs. The magnitude, phase, R2* and T2* maps were analyzed by two observers. The regions of interest were drawn along the boundaries of tumors on the slice with maximal solid area, according to fat suppression T2WI and T1WI. The consistency among the three measurements taken by two observers was tested by intra-class correlation coefficients. Agreement of average values measured by two observers was evaluated by Bland-Altman plots. All the data of BEOTs and MEOTs were compared using the independent-sample t test. The receiver operating characteristic curve was used to evaluate the diagnostic performance. RESULTS: No statistical differences were observed in the magnitude and phase values between two tumor groups. The R2* value of BEOTs was lower than that of MEOTs (P < 0.001), whereas the T2* value of BEOTs was higher than that of MEOTs (P = 0.01). The area under the curve of R2* values was 0.894 and the corresponding cutoff value was 7.50 Hz, with the sensitivity, specificity and accuracy of 85.7%, 82.6% and 86.5%, respectively. The AUC of T2* values was 0.776 and the corresponding cutoff value was 143.73 ms with the sensitivity, specificity and accuracy of 71.4%, 82.6% and 78.4%, respectively. CONCLUSIONS: R2* and T2* values can be used for quantificationally differentiating BEOTs from MEOTs and the R2* has better diagnostic performance.


Assuntos
Carcinoma Epitelial do Ovário/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Angiografia por Ressonância Magnética/métodos , Neoplasias Ovarianas/diagnóstico por imagem , Adolescente , Adulto , Idoso , Carcinoma Epitelial do Ovário/patologia , Criança , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/diagnóstico por imagem , Ovário/patologia , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
15.
J Exp Clin Cancer Res ; 38(1): 345, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391118

RESUMO

BACKGROUND: Epithelial ovarian cancer (EOC) is the malignant tumor of the female reproductive system with the highest fatality rate. Tolerance of chemotherapeutic drugs like cisplatin (DDP) occurring in very early stage is one of the important factors of the poor prognosis of epithelial ovarian cancer. Here we aim to study the dysregulation of a particular long noncoding RNA, lncRNA GAS5, and its role in EOC progression. METHODS: The low expression of lncRNA GAS5 in EOC tissues and OC cell lines was determined by microarray analyses and Real-Time qPCR. Flow cytometer assays were used to detect cell cycle and apoptosis of OC cells. CCK8 assay were performed to investigate the DDP sensitivity of OC cells. Western blot was carried out to detect cell growth markers, apoptotic markers, PARP1, E2F4, MAPK pathway protein expression and other protein expression in OC cell lines. The binding of GAS5 and E2F4 were proved by RNA pull-down and RIP assay. The effect of E2F4 on PARP1 were determined by CHIP-qPCR assay and luciferase reporter assay. The effect of lncRNA GAS5 on OC cells was assessed in vitro and in vivo. RESULTS: By microarray (3 EOC tissues νs. 3 normal ovary tissues) and RT- qPCR (53 EOC tissues νs. 10 normal ovary tissues) we identified lncRNA GAS5 to be dramatically low expressed in EOC samples and correlated with prognosis. Compared with sensitive cell lines, GAS5 was also low expressed in DDP resistant OC cell lines, and over-expression of GAS5 significantly enhanced the sensitivity of OC cells to DDP in vivo and in vitro. Meanwhile the over-expression of GAS5 also caused OC cells G0/G1 arrest and apoptosis increase. Mechanistically, GAS5 might regulate PARP1 expression by recruiting the transcription factor E2F4 to its promoter, and then affect the MAPK pathway activity. Due to the 5'TOP structure, GAS5 could be regulated by transcription inhibitor rapamycin in OC cells. CONCLUSION: Here we explored the specific mechanisms of EOC cisplatin resistance and tumor progress due to lncRNA-GAS5, presented the GAS5-E2F4-PARP1-MAPK axis and its role in OC drug-sensitivity and progression for the first time, and the results may provide experimental basis for clinical application.


Assuntos
Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F4/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , RNA Longo não Codificante/genética , Adolescente , Adulto , Animais , Apoptose , Sítios de Ligação , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Ciclo Celular , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais , Carga Tumoral , Adulto Jovem
16.
Gynecol Oncol ; 154(3): 516-523, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31340883

RESUMO

OBJECTIVE: Endometrioid ovarian carcinomas (EOCs) comprise 5-10% of all ovarian cancers and commonly co-occur with synchronous endometrioid endometrial cancer (EEC). We sought to examine the molecular characteristics of pure EOCs in patients without concomitant EEC. METHODS: EOCs and matched normal samples were subjected to massively parallel sequencing targeting 341-468 cancer-related genes (n = 8) or whole-genome sequencing (n = 28). Mutational frequencies of EOCs were compared to those of high-grade serous ovarian cancers (HGSOCs; n = 224) and EECs (n = 186) from The Cancer Genome Atlas, and synchronous EOCs (n = 23). RESULTS: EOCs were heterogeneous, frequently harboring KRAS, PIK3CA, PTEN, CTNNB1, ARID1A and TP53 mutations. EOCs were distinct from HGSOCs at the mutational level, less frequently harboring TP53 but more frequently displaying KRAS, PIK3CA, PIK3R1, PTEN and CTNNB1 mutations. Compared to synchronous EOCs and pure EECs, pure EOCs less frequently harbored PTEN, PIK3R1 and ARID1A mutations. Akin to EECs, EOCs could be stratified into the four molecular subtypes: 3% POLE (ultramutated), 19% MSI (hypermutated), 17% copy-number high (serous-like) and 61% copy-number low (endometrioid). In addition to microsatellite instability, a subset of EOCs harbored potentially targetable mutations, including AKT1 and ERBB2 hotspot mutations. EOCs of MSI (hypermutated) subtype uniformly displayed a good outcome. CONCLUSIONS: EOCs are heterogeneous at the genomic level and harbor targetable genetic alterations. Despite the similarities in the repertoire of somatic mutations between pure EOCs, synchronous EOCs and EECs, the frequencies of mutations affecting known driver genes differ. Further studies are required to define the impact of the molecular subtypes on the outcome and treatment of EOC patients.


Assuntos
Carcinoma Endometrioide/classificação , Carcinoma Epitelial do Ovário/classificação , Neoplasias Ovarianas/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/classificação , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Análise Mutacional de DNA , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos
17.
Folia Med (Plovdiv) ; 61(2): 296-302, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301662

RESUMO

BACKGROUND: The epithelial-mesenchymal transition (EMT), which is a change in the cell phenotype from epithelial to mesenchymal morphology, is an important step in the invasion process and metastasis of ovarian carcinomas. It is known that the suppression of cell adhesion molecules such as E-cadherin and the expression of mesenchymal markers such as Vimentin are key processes in EMT. There is controversy in the literature about the EMT status of ovarian carcinomas. AIM: To investigate EMT status using immunohistochemical expression of E-cadherin in benign, primary malignant serous ovarian tumors and metastases from them in order to assess their significance in tumor progression. MATERIALS AND METHODS: The study included a retrospective investigation of 217 ovarian epithelial tumors. Ninety-two cases of serous ovarian tumors and metastases were examined for expression of E-cadherin. RESULTS: In our study, the predominant histological subtype in benign ovarian tumors and carcinomas was serous (73% and 61%, respectively). 65% of benign tumors demonstrated EMT negative status. The majority of carcinomas demonstrated EMT positive status (82%), whereas negative EMT status was only observed in 18% of cases. 89% of the metastases showed EMT positive status, whereas only 11% of them showed negative EMT status. In 6 selected cases with positive EMT status we found Vimentin expression in tumor cells. CONCLUSION: Positive EMT status (reduced E-cadherin expression) is a characteristic of ovarian carcinomas and metastases, but not of benign serous ovarian tumors.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Ovarianas/metabolismo , Vimentina/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/secundário , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/patologia , Estudos Retrospectivos
18.
BMC Cancer ; 19(1): 696, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307411

RESUMO

BACKGROUND: In ovarian cancer, dysregulation of mRNA expression of several components of the family of the kallikrein-related peptidases (KLKs) is observed. In this study, we have analyzed the KLK5 mRNA expression pattern in tumor tissue of patients suffering from high-grade serous ovarian cancer stage FIGO III/IV. Moreover, we have correlated the KLK5 mRNA levels with clinical outcome. METHODS: We assessed the mRNA expression levels of KLK5 in tumor tissue of 138 patients using quantitative PCR (qPCR). The mRNA levels were correlated with KLK5 antigen tumor tissue levels measured by ELISA (available for 41 of the 138 patients), established clinical features as well as patients' outcome, using Chi-square-tests, Mann-Whitney U-tests and Spearman rank calculations as well as Cox regression models, Kaplan-Meier survival analysis and the log-rank test. RESULTS: A highly significant correlation between the mRNA expression levels and protein levels of KLK5 in tumor tissues was observed (rs = 0.683, p < 0.001). In univariate Cox regression analysis, elevated KLK5 mRNA expression was remarkably associated with reduced progression-free survival (PFS; p = 0.047), but not with overall survival (OS). Association of KLK5 mRNA expression with PFS was validated in silico using The Cancer Genome Atlas. For this, Affymetrix-based mRNA data (n = 377) were analyzed applying the Kaplan-Meier Plotter tool (p = 0.027). In multivariable Cox analysis, KLK5 mRNA values revealed a trend towards statistical significance for PFS (p = 0.095), whereas residual tumor mass (0 mm vs. > 0 mm), but not ascites fluid volume (≤500 ml vs. > 500 ml), remained an independent indicator for both OS and PFS (p < 0.001, p = 0.005, respectively). CONCLUSIONS: These results obtained with a homogenous patient group with all patients suffering from advanced high-grade serous ovarian cancer support previous results suggesting elevated KLK5 mRNA levels as an unfavorable marker in ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Calicreínas/metabolismo , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Distribuição de Qui-Quadrado , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Estatísticas não Paramétricas
19.
Oncogene ; 38(32): 6035-6050, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31278368

RESUMO

Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.


Assuntos
Carcinogênese/genética , Carcinoma Epitelial do Ovário/genética , MicroRNAs/fisiologia , Neoplasias Ovarianas/genética , Animais , Antígenos de Neoplasias/genética , Carcinoma Epitelial do Ovário/patologia , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Via de Sinalização Wnt/genética , Proteína Wnt1/genética , Proteína Wnt1/metabolismo
20.
Medicine (Baltimore) ; 98(24): e15876, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192919

RESUMO

BACKGROUND: Lymphocyte-to-monocyte ratio (LMR) was recently proposed as a prognostic factor of ovarian cancer. However, prognostic value of the LMR in ovarian cancer remains inconclusive. The study aimed to assess prognostic value of the LMR in ovarian cancer. METHODS: Seven common databases were comprehensively searched for relevant studies. The analyses were performed for overall survival (OS), progression-free survival (PFS) and clinical parameters. The hazard ratio (HR) and 95% confidence interval (CI) were used to analyze OS and PFS. RESULTS: A total of 2343 patients with ovarian cancer were included in this meta-analysis. The results showed that a low LMR predicted shorter OS (HR = 1.81, 95% CI = 1.38-2.37, P < .01) and PFS (HR = 1.65 95% CI = 1.46-1.85, P < .01) when compared to a high LMR in ovarian cancer. Besides, a low LMR was significantly associated with advanced clinical stage (P < .01), earlier lymph node metastasis (P = .01), higher carbohydrate antigen-125 levels (P < .01), larger residual tumor (P < .01) and worse chemosensitivity (P < .01) when compared to a high LMR in ovarian cancer. CONCLUSION: Low LMR was associated with unfavorable survival in patients with ovarian cancer. LMR could serve as a prognostic biomarker of ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/imunologia , Monócitos/citologia , Neoplasias Ovarianas/imunologia , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Contagem de Leucócitos , Metástase Linfática , Contagem de Linfócitos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , Análise de Sobrevida
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