RESUMO
INTRODUCTION: Epithelial ovarian cancer (EOC) is the fourth most common malignancy among Malaysian women. This study aims to evaluate the outcomes of EOC, fallopian tube cancer and primary peritoneal serous carcinoma (PPSC) between a centre managed by both clinical oncologists and gynaecologic oncologists, Institut Kanser Negara (IKN) and a centre managed solely by gynaecologic oncologists, Hospital Ampang (HA). MATERIALS AND METHODS: This retrospective cohort study involved data review of all the newly diagnosed patients with EOC, fallopian tube cancer and PPSC who received treatment in IKN and HA from January 2015 to December 2019, with follow-up continuing until December 2022. The primary outcome is overall survival (OS) and the secondary outcome is progression free survival (PFS) rates; estimated using the Kaplan-Meier method and compared using the logrank test. Another secondary outcome is to determine the prognostic factors affecting the OS of patients from these two cohorts using Cox regression analysis. RESULTS: A total of 256 patients from both centres were recruited (106 and 150 patients from IKN and HA respectively) and at the time of diagnosis, more than half of the patients were diagnosed with advanced stage disease (67.5% and 62% from IKN and HA respectively). The median OS for patients with EOC was significantly longer for HA compared to IKN (69 months vs 39 months, p < 0.042). There was no significant difference in the median PFS for both centres. Furthermore, when the comparison was made based on the disease staging, there was no difference in the median OS and median PFS. Multivariate analysis identified that patients aged between 41 and 60 years (Hazard ratio [HR]: 2.83; 95% CI: 1.11, 7.25, p = 0.030), patients with medical illness (HR 1.51; 95% CI: 1.04, 2.21, p = 0.033), patients with advanced-stage disease (HR: 3.63; 95% CI: 2.20, 6.00, p < 0.001) and patients with ECOG ≥ 1 (HR: 2.00; 95%CI: 1.38, 2.91, p < 0.001) as independent risk factors for adverse outcome. Meanwhile, optimal surgery is found to be a protective factor (HR 0.60; 95% CI: 0.41, 0.89, p = 0.011). Patients with optimal surgery had reduced the risk of adverse outcome. CONCLUSION: Our findings confirmed that the median OS was significantly longer for patients with EOC in HA compared to IKN. However, there was no significant difference in the median OS based on the disease staging; therefore, we could not establish the non-inferiority outcome between the two centres. Furthermore, there was no significant difference in median PFS for both centres. This could be due to small sample size to be able to detect any difference. In addition, it could also be contributed by the different treatment options available and unequal volume of patients treated in both centres. Thus, further study with larger sample size and longer time period is needed to provide better guidance and treatments for the patients.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias das Tubas Uterinas , Neoplasias Peritoneais , Humanos , Feminino , Neoplasias das Tubas Uterinas/mortalidade , Neoplasias das Tubas Uterinas/terapia , Neoplasias das Tubas Uterinas/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Peritoneais/terapia , Neoplasias Peritoneais/mortalidade , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/terapia , Carcinoma Epitelial do Ovário/patologia , Idoso , Adulto , Malásia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico , Cistadenocarcinoma Seroso/terapia , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologiaRESUMO
OBJECTIVE: This study presents the development and validation of a nomogram aimed at predicting platinum-sensitivity and survival outcomes in women with advanced epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Data from a retrospective cohort of women diagnosed with stage III/IV EOC between Jan 2011 and Dec 2021 treated at our institute were collected. Clinical and pathological characteristics were analyzed using logistic regression analysis to identify independent predictors of platinum-sensitivity. Impact on progression-free (PFS) and overall survival (OS) was determined by Kaplan-Meier and Cox regression analysis. A nomogram was constructed based on the significant predictors, and its performance was evaluated using calibration, discrimination, and validation analyses. RESULTS: Of the 210 patients, 139 (66.19%) had platinum-sensitive and 71 (33.81%) were platinum-resistant disease. On multivariate analysis, platinum-resistance correlated with neoadjuvant chemotherapy (OR 2.15; 95% CI 1.10-4.21), clear cell/mucinous histology (OR 5.04; 95% CI 2.20-11.54), and sub-optimal debulking status (OR 3.37; 95% CI 1.44-7.91). Median PFS and OS were also significantly shorter for patients with neoadjuvant chemotherapy (23 vs. 10 months and 69 vs. 29 months, respectively), clear cell/mucinous histology (15 vs. 3 months and 63 vs. 11 months, respectively), and suboptimal debulking (26 vs. 5 months and 78 vs. 24 months, respectively). The nomogram demonstrated good predictive accuracy for platinum-sensitivity in the cohort as indicated by high concordance index of 0.745. Calibration plots showed excellent agreement and internal validation further confirmed the reliability of the nomogram's performance. CONCLUSION: A novel predictive nomogram based on type of initial treatment, histology, and debulking status was developed, which provides a friendly and reliable tool for predicting platinum-sensitivity and survival outcomes in women with advanced EOC. Its application may assist clinicians in individualizing treatment decisions.
Assuntos
Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos , Nomogramas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Idoso , Adulto , Estadiamento de Neoplasias , Terapia Neoadjuvante/métodos , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Progressão , Platina/uso terapêutico , Antineoplásicos/uso terapêutico , Estimativa de Kaplan-MeierRESUMO
Background: Ovarian surface epithelial cancer (OSEC) are an entity in which, according to genomics and pathology data accumulated in the last couple of decades, several different nosological entities with distinct etiologies are aggregated. In ovarian cancer, surgery is the pivot of treatment, to which medical oncological treatment is added by recommendation in most cases. Material and Methods: This is a single centre sample of 263 cases with OSEC operated from January 2014 until December 2021 with a 28-month period of follow-up, until 30th April 2024. OSEC surgical procedures in stages IIB to III and IV of the disease are complex interventions in order to have the R0/optimal cytoreduction achieved, so we summarised and coded them as follows: 1 = biopsy (of the tumour/peritoneum); 2 = bilateral/unilateral adnexectomy (BA/UA) total hysterectomy (TH) omentectomy +- peritoneal biopsies; 3 = (2) with total hysterectomy with bilateral adnexectomy (THBA) +- by extraperitoneal/subperitoneal route+peritonectomies (exclusively diaphragmatic) and electrocauterization of peritoneal carcinomatous lesions; 4 = (3) with visceral (multiple) resections +- stoma; 5 = (4) with diaphragmatic peritonectomies/stripping/partial resection of the diaphragm; 6 = palliative surgery. Results: Debulking surgery (DS) was carried out for n = 182 patients with no residual tissue = R0 being registered in n = 41. Results for patients with residual tissue (n = 141) after DS recorded the following findings: 1 cm (49% cases), 1.1-2 cm (29%) and 2 cm (22%). Recorded results for endometrial ovarian carcinoma (EC) n = 27 shown a tumour free survival probability estimate (%) at 60 months of 66% as both surgery and platinum based chemotherapy are efficient. For clear cell ovarian carcinoma (CCC) n = 7 recorded results shown a tumour free estimate (%) at 60 months of 14%, being known the controversy as to whether or not paclitaxel is an active drug for CCC. Major complications were recorded in 25 patients with a fatality ratio of 5/25. Conclusion: Considering OSEC is a relatively rare disease and the importance of collecting substantial numbers of samples by histotypes to further knowledge about ovarian cancer it comes crucial to establish collaborative endeavour of tertiary centers with standardised and quality control strategies.
Assuntos
Procedimentos Cirúrgicos de Citorredução , Histerectomia , Estadiamento de Neoplasias , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Resultado do Tratamento , Histerectomia/métodos , Procedimentos Cirúrgicos de Citorredução/métodos , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/mortalidade , Pessoa de Meia-Idade , Seguimentos , Idoso , Romênia/epidemiologia , Adulto , Estudos Retrospectivos , Omento/cirurgia , BiópsiaRESUMO
Low grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to.
Assuntos
Cistadenocarcinoma Seroso , Ensaios de Triagem em Larga Escala , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológicoRESUMO
BACKGROUND: Epithelial ovarian cancer, especially high grade serous ovarian cancer (HGSOC) is by far, the most lethal gynecological malignancy with poor prognosis and high relapse rate. Despite of availability of several therapeutic interventions including poly-ADP ribose polymerase (PARP) inhibitors, HGSOC remains unmanageable and identification of early detection biomarkers and therapeutic targets for this lethal malady is highly warranted. Aberrant expression of protein kinase C iota (PKCί) is implicated in many cellular and physiological functions involved in tumorigenesis including cell proliferation and cell cycle deregulation. METHODS AND RESULTS: Two high grade serous ovarian cancer cells SKOV3 and COV362 were employed in this study. PKCί was genetically knocked down or pharmacologically inhibited and several functional and biochemical assays were performed. We report that PKCί is overexpressed in HGSOC cells and patient tissue samples with a significant prognostic value. Pharmacological inhibition of PKCί by Na-aurothiomalate or its shRNA-mediated genetic knockdown suppressed HGSOC cell proliferation, EMT and induced apoptosis. Moreover, PKCί positively regulated GLUT1 and several other glycolytic genes including HK1, HK2, PGK1, ENO1 and LDHA to promote elevated glucose uptake and glycolysis in HGSOC cells. Mechanistically, PKCί drove glycolysis via PI3K/AKT/mTOR signalling. Na-aurothiomalate and highly selective, dual PI3K/mTOR inhibitor dactolisib could serve as novel anti-glycolytic drugs in HGSOC. CONCLUSION: Taken together, our results indicate PKCί/PI3K/AKT/mTOR signalling cascade could be a novel therapeutic target in a lethal pathology like HGSOC.
Assuntos
Proliferação de Células , Glicólise , Isoenzimas , Neoplasias Ovarianas , Fosfatidilinositol 3-Quinases , Proteína Quinase C , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Feminino , Humanos , Apoptose/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Regulação Neoplásica da Expressão Gênica , Isoenzimas/metabolismo , Isoenzimas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteína Quinase C/metabolismo , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: The main challenge in treating ovarian cancer is chemotherapy resistance. Previous studies have shown that PAK2 is highly expressed in various cancers. This research investigates whether increased PAK2 expression contributes to chemo-resistance and poor prognosis in ovarian cancer. METHODS: Initially, bioinformatics analysis was used to assess the importance of PAK2 mRNA up-regulation in ovarian cancer. This was then validated using tissue microarray to confirm PAK2 protein expression and localization in clinical samples. Univariate and multivariate logistic regression analyses were carried out to identify potential risk factors for chemo-resistance in serous epithelial ovarian cancer (EOC), while multivariate Cox regression and Kaplan-Meier analysis were conducted to ascertain prognostic factors for overall survival (OS) and disease-free survival (DFS) in patients with serous EOC. In vitro experiments were conducted to verify if inhibiting PAK2 expression could increase A2780/Taxol cells' sensitivity to paclitaxel, as shown by evaluating cell proliferation, apoptosis, transwell, and clone formation. Additionally, the interaction between PAK2, lnc-SNHG1, and miR-216b-5p was verified using RIP and luciferase reporter assays. Rescue experiments were undertaken to examine the influence of the lnc-SNHG1/miR-216b-5p/PAK2 axis on the development of paclitaxel resistance in A2780/Taxol cells. RESULTS: The bioinformatics analysis indicated a notable increase in PAK2 expression in ovarian malignant tumors compared to adjacent tissues, particularly in patients with stage III-IV disease compared to those with stage I-II disease (P = 0.0056). Elevated levels of PAK2 were linked to reduced OS in ovarian cancer patients, although no significant association was observed with DFS. Immunohistochemistry findings further supported these results, showing positive PAK2 protein expression in chemo-resistant serous EOC tissues, predominantly localized in the cytoplasm, which correlated with poorer OS and DFS outcomes. In vitro experiments demonstrated that the downregulation of PAK2 in A2780/Taxol cells led to a reduction in colony formation, an increase in apoptosis, and a diminished capacity for cell invasion. Subsequent analysis confirmed that lnc-SNHG1 functions as a competitive endogenous RNA (ceRNA) by interacting with miR-216b-5p and regulating PAK2 expression. Rescue experiments demonstrated that lnc-SNHG1 induces resistance to paclitaxel in A2780/Taxol cells by modulating the miR-216b-5p/PAK2 axis. CONCLUSIONS: PAK2 shows promise as a predictor of chemotherapy resistance and poor outcomes in ovarian cancer, indicating its potential use as a treatment target to overcome this resistance.
Assuntos
Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Ovarianas , Paclitaxel , Quinases Ativadas por p21 , Humanos , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/genética , Feminino , Resistencia a Medicamentos Antineoplásicos/genética , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Prognóstico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/mortalidade , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Proliferação de Células , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Apoptose/efeitos dos fármacos , Regulação para CimaRESUMO
Standard of care genetic testing has undergone significant changes in recent years. The British Gynecological Cancer Society and the British Association of Gynecological Pathologists (BGCS/BAGP) has re-assembled a multidisciplinary expert consensus group to update the previous guidance with the latest standard of care for germline and tumor testing in patients with ovarian cancer. For the first time, the BGCS/BAGP guideline group has incorporated a patient advisor at the initial consensus group meeting. We have used patient focused groups to inform discussions related to reflex tumor testing - a key change in this updated guidance. This report summarizes recommendations from our consensus group deliberations and audit standards to support continual quality improvement in routine clinical settings.
Assuntos
Carcinoma Epitelial do Ovário , Testes Genéticos , Neoplasias Ovarianas , Humanos , Feminino , Testes Genéticos/métodos , Testes Genéticos/normas , Reino Unido , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/diagnóstico , Sociedades Médicas , ConsensoRESUMO
BACKGROUND: Cytoreductive surgery is critical for optimal tumor clearance in advanced epithelial ovarian cancer (EOC). Despite best efforts, some patients may experience R2 (>1 cm) resection, while others may not undergo surgery at all. We aimed to compare outcomes between advanced EOC patients undergoing R2 resection and those who had no surgery. METHODS: Retrospective data from 51 patients with R2 resection were compared to 122 patients with no surgery between January 2015 and December 2019 at a UK tertiary referral centre. Progression-free survival (PFS) and overall survival (OS) were the study endpoints. Principal Component Analysis and Term Frequency - Inverse Document Frequency scores were utilized for data discrimination and prediction of R>2 cm from computed tomography pre-operative reports, respectively. RESULTS: No statistical significance was observed, except for age (73 vs 67 years in the no- surgery vs R2 group, P: .001). Principal Components explained 34% of data variances. Reasons for no surgery included age, co-morbidities, patient preference, refractory disease, patient deterioration or disease progression, and absence of measurable intra- abdominal disease). The median PFS and OS were 12 and 14 months for no-surgery, vs 14 and 26 months for R2 (P: .138 and P: .001, respectively). Serous histology and performance status independently predicted PFS in both no-surgery and R2 cohorts. In the no-surgery cohort, serous histology independently predicted OS, while in the R2 cohorts, both serous histology and adjuvant chemotherapy were independent prognostic features for OS. The bi-grams "abdominopelvic ascites" and "solid omental" were amongst those best discriminating between R>2 cm and R1-2 cm. CONCLUSIONS: R2 resection and no-surgery cohorts displayed unfavourable prognosis with a notable degree of uniformity. When cytoreduction results in suboptimal results, the survival benefit may still be higher compared to those who underwent no surgery.
The study examined outcomes in advanced epithelial ovarian cancer (EOC) patients who underwent either R2 (suboptimal) surgical resection or received no surgery at all at a UK tertiary referral center. Sophisticated machine learning methodolgies were used to analyze data patterns and predict the extent of resection (>2 cm) from pre-operative CT reports. Reasons for not undergoing surgery included older age, presence of other medical conditions, patient preference, progressive disease, patient decline, or lack of detectable intra-abdominal disease. Factors like serous histology and performance status iinfluenced the risk of recurrence in both groups, while serous histology and adjuvant chemotherapy predicted the risk of death in the R2 group. Word sequences like "omental disease" and "reduced bulk" helped differentiate between R>2 cm and less extensive resections (R1-2 cm). In summary, both R2 resection and no-surgery groups had poor outcomes, but patients who underwent R2 resection generally had better survival compared to those who received no surgery, even when complete tumor removal was not achieved.
Assuntos
Carcinoma Epitelial do Ovário , Procedimentos Cirúrgicos de Citorredução , Neoplasias Ovarianas , Humanos , Feminino , Idoso , Estudos Retrospectivos , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Procedimentos Cirúrgicos de Citorredução/métodos , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , AdultoRESUMO
Protein lactylation has a poor prognosis in malignant tumors, but its impact on the prognosis of epithelial ovarian cancer (EOC) remains unknown. We analyzed 112 patients with EOC. Immunohistochemical staining was used to detect the level of pan lactylation (Pan Kla) and histone H3K18 lactylation (H3K18la) in the EOC tissues and normal ovarian tissues. The result showed that the protein lactylation level in EOC was higher than in normal tissues. Then, we analyzed the relationship between overall survival (OS), progression-free survival (PFS) of EOC, and lactylation. The result showed that patients with high histone H3K18la levels had poorer OS (p=0.028) and PFS (p<0.001). Multivariate Cox regression analysis of PFS showed histone H3K18la was an independent risk factor (p=0.001). In addition, we found that both histone H3K18la and Pan Kla in the cytoplasm were associated with platinum recurrence time (p=0.002/p=0.003). The results also indicated that the H3K18la level was related to a tumor stage (p=0.037). Furthermore, we explored the effects of lactylation on the metastasis of ovarian cancer. The results indicated a significant increase in migration in the promoter group compared to the negative control group and inhibitor group. In conclusion, high histone H3K18la level is associated with poor prognosis in EOC. Protein lactylation may have a significant impact on EOC and could potentially be used as a target for EOC therapy in the future.
Assuntos
Carcinoma Epitelial do Ovário , Histonas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/mortalidade , Histonas/metabolismo , Prognóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Pessoa de Meia-Idade , Idoso , Adulto , Biomarcadores Tumorais/metabolismoRESUMO
BACKGROUND: Ovarian cancer exhibits a significant prevalence and incidence on a global scale. Low-grade or high-grade epithelial-type ovarian cancer can be classified by using the dualistic model. Inflammation has been associated with AKNA protein by cancer researchers. The potential of AKNA as a cancer biomarker is supported by its significance and association with ovarian carcinoma. Uninvestigated is this enormous potential. AIM: This study examines the correlation between AKNA expression in low-grade and high-grade ovarian tumors and its utility as a predictive biomarker for ovarian cancer. METHODS: This study examined a total of thirty-one samples, which were classified into three groups: cyst, low-grade, and high-grade ovarian carcinoma. The departmental archive was accessed for the following information: age, tumor size, nuclear grade, mitosis, ovary volume, implant tumor status, lymph vascular invasion status, lymph node metastasis, and tumor-infiltrating lymphocyte. The expression of AKNA was determined using IHC staining. The information was collected and analyzed via analysis of variance. RESULTS: The AKNA H-score shows the mean difference between all three groups (P < 0.001). Cysts had the highest AKNA expression, followed by low-grade and high-grade ovarian carcinoma. CONCLUSION: Higher-grade ovarian cancer expressed less AKNA compared to cysts or low-grade forms of the disease. This considerable difference suggests that AKNA might predict ovarian cancer tumor grade.
Assuntos
Biomarcadores Tumorais , Gradação de Tumores , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Adulto , Idoso , Carcinoma Epitelial do Ovário/patologia , Imuno-HistoquímicaRESUMO
Epithelial ovarian carcinoma poses a significant challenge due to its resistance to chemotherapy and propensity for metastasis, thereby reducing the effectiveness of conventional treatments. Hence, the identification of novel compounds capable of augmenting the anti-cancer efficacy of platinum-based chemotherapy is imperative. Oxyresveratrol (OXY), a derivative of resveratrol, has been demonstrated to possess antiproliferative and apoptosis-inducing effects across various cancer cell lines. Notably, OXY appears to exert its effects by inhibiting the PI3K/AKT/mTOR signaling pathway. However, the synergistic potential of OXY in combination with cisplatin against epithelial ovarian cancer has not yet been elucidated. The current study investigated the synergistic effects of OXY and cisplatin on the ovarian cancer cell lines SKOV3 and TOV21G. We found that OXY significantly enhanced cisplatin's ability to reduce cell viability, induce apoptosis, induce cell cycle arrest, and increase the proportion of cells in the sub-G1 phase. Furthermore, OXY treatment alone dose-dependently inhibited the production of anti-apoptotic proteins including Mcl-1, Bcl-xL, and XIAP under EGF activation. Mechanistically, OXY suppressed the PI3K/AKT/mTOR signaling pathway by reducing phosphorylated AKT, while having no discernible effect on the MAPK pathway. These findings highlight OXY's potential to enhance ovarian cancer cell sensitivity to chemotherapy, suggesting its development as a pharmaceutical adjunct for clinical use in combination therapies.
Assuntos
Apoptose , Carcinoma Epitelial do Ovário , Cisplatino , Sinergismo Farmacológico , Neoplasias Ovarianas , Proteínas Proto-Oncogênicas c-akt , Estilbenos , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cisplatino/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Apoptose/efeitos dos fármacos , Estilbenos/farmacologia , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Extratos VegetaisRESUMO
Centrosome amplification is a feature of cancer cells associated with chromosome instability and invasiveness. Enhancing chromosome instability and subsequent cancer cell death via centrosome unclustering and multipolar divisions is an aimed-for therapeutic approach. Here, we show that centrosome amplification potentiates responses to conventional chemotherapy in addition to its effect on multipolar divisions and chromosome instability. We perform single-cell live imaging of chemotherapy responses in epithelial ovarian cancer cell lines and observe increased cell death when centrosome amplification is induced. By correlating cell fate with mitotic behaviors, we show that enhanced cell death can occur independently of chromosome instability. We identify that cells with centrosome amplification are primed for apoptosis. We show they are dependent on the apoptotic inhibitor BCL-XL and that this is not a consequence of mitotic stresses associated with centrosome amplification. Given the multiple mechanisms that promote chemotherapy responses in cells with centrosome amplification, we assess such a relationship in an epithelial ovarian cancer patient cohort. We show that high centrosome numbers associate with improved treatment responses and longer overall survival. Our work identifies apoptotic priming as a clinically relevant consequence of centrosome amplification, expanding our understanding of this pleiotropic cancer cell feature.
Assuntos
Apoptose , Centrossomo , Neoplasias Ovarianas , Humanos , Apoptose/efeitos dos fármacos , Centrossomo/metabolismo , Centrossomo/efeitos dos fármacos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Instabilidade Cromossômica/efeitos dos fármacos , Mitose/efeitos dos fármacos , Proteína bcl-X/metabolismo , Proteína bcl-X/genética , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Análise de Célula Única/métodosRESUMO
BACKGROUND: Extensive surgery on advanced-stage epithelial ovarian cancer is associated with increased postoperative morbidity, which may cause a delay in or omission of chemotherapy. We examined postoperative complications and their effects on adjuvant treatment in patients undergoing primary debulking surgery (PDS). METHODS: Stage IIIC-IV epithelial ovarian cancer patients who underwent PDS between January 2013 and December 2020 were included. Patients were divided into two groups according to the radicality of the operation, i.e., extensive or standard surgery, and their outcomes were compared. RESULTS: In total, 172 patients were included; 119 underwent extensive surgery, and 53 had standard surgery. Clavien-Dindo grade 3-5 (CDC 3+) complications were detected in 41.2% of patients after extensive operations and in 17% after standard surgery (p = 0.002). The most common CDC 3+ complication was pleural effusion. Despite the difference in the complication rates, the delay in chemotherapy did not differ between the extensive and standard groups (p = 0.98). CONCLUSIONS: Complications are common after PDS. Extensive surgery increases the complication rate, but most complications can be treated effectively; therefore, a delay in adjuvant treatment is rare.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Complicações Pós-Operatórias , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Idoso , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução/métodos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Adulto , Estudos Retrospectivos , Tempo para o Tratamento/estatística & dados numéricosRESUMO
OBJECTIVE: The aim of this study was to explore the clinical application value of two-dimensional ultrasound (2D-US) combined with contrast-enhanced ultrasonography (CEUS) in the differential diagnosis of benign, borderline ovarian tumors (BOTs), and malignant ovarian epithelial tumors (OETs). METHODS: The clinical data of 108 patients who underwent surgery for pathologically confirmed of OETs at Peking University People's Hospital between December 2018 and November 2023 were retrospectively studied. The diagnostic value of 2D-US combined with CEUS for diagnosing OETs was analyzed using chi-square tests, receiver operating characteristic (ROC) curves, and random forest models. RESULTS: Among the 108 cases of OETs, 23 were benign, 34 were BOTs, and 51 were malignant. Chi-square tests confirmed that the perfusion pattern of the contrast agent plays an important role in the differential diagnosis of OETs. Compared with those in the benign group, the BOTs were not significantly different in terms of perfusion phase and enhancement intensity, but the regression time of the BOTs was earlier (P < 0.05). Compared with the BOTs, the malignant tumors group showed earlier perfusion and higher enhancement intensity, with no significant difference in regression time. The ROC curve results indicated that the combined diagnostic efficiency of 2D-US and CEUS in distinguishing OETs was significantly higher than that of a single diagnostic technique in terms of sensitivity, specificity, accuracy, and AUC. The random forest model results revealed that among the various parameters used in the differential diagnosis of OETs, the perfusion pattern was the most significant factor. CONCLUSION: 2D-US combined with CEUS helps improve the differential diagnostic efficiency for benign, BOTs, and malignant OETs.
Assuntos
Carcinoma Epitelial do Ovário , Meios de Contraste , Neoplasias Ovarianas , Ultrassonografia , Humanos , Feminino , Diagnóstico Diferencial , Ultrassonografia/métodos , Pessoa de Meia-Idade , Adulto , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Curva ROC , Estudos Retrospectivos , Idoso , Adulto JovemRESUMO
Epithelial ovarian cancer is the deadliest gynecologic malignancy, characterized by high metastasis. Transforming growth factor-ß1 (TGF-ß1) drives epithelial- mesenchymal transformation (EMT), a key process in tumor metastasis. Tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TIPE2) acts as a negative regulator of innate and adaptive immunity and involves in various cancers. However, its relationship with TGF-ß1 in ovarian cancer and its role in reversing TGF-ß1-induced EMT remain unclear. This study examined TIPE2 mRNA and protein expression using quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of epithelial ovarian cancer cells were assessed through 5-ethynyl-2-deoxyuridine, colony-forming, transwell migration and invasion assays. The relationship between TIPE2 and TGF-ß1 was investigated using qRT-PCR and enzyme-linked immunosorbent assay, while the interaction between TIPE2 and Smad2 was identified via co-immunoprecipitation. The results revealed that TIPE2 protein was significantly down-regulated in epithelial ovarian cancer tissues and correlated with the pathological type of tumor, patients' age, tumor differentiation degree and FIGO stage. TIPE2 and TGF-ß1 appeared to play an opposite role to each other during the progression of human ovarian cancer cells. Furthermore, TIPE2 inhibited the metastasis and EMT of ovarian cancer cells by combining with Smad2 in vitro or in an intraperitoneal metastasis model. Consequently, these findings suggest that TIPE2 plays a crucial inhibitory role in ovarian cancer metastasis by modulating the TGF-ß1/Smad2/EMT signaling pathway and may serve as a potential target for ovarian cancer, providing important direction for future diagnostic and therapeutic strategies.
Assuntos
Carcinoma Epitelial do Ovário , Movimento Celular , Transição Epitelial-Mesenquimal , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Ovarianas , Proteína Smad2 , Fator de Crescimento Transformador beta1 , Proteína Smad2/metabolismo , Proteína Smad2/genética , Humanos , Feminino , Fator de Crescimento Transformador beta1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Animais , Camundongos , Invasividade Neoplásica , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Camundongos Endogâmicos BALB C , Transdução de SinaisRESUMO
OBJECTIVE: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). RESULTS: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. CONCLUSION: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.
Assuntos
Indazóis , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma Epitelial do Ovário/tratamento farmacológico , População do Leste Asiático , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recombinação Homóloga , Indazóis/efeitos adversos , Indazóis/uso terapêutico , Japão , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/tratamento farmacológico , Ftalazinas/efeitos adversos , Ftalazinas/uso terapêutico , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
Human papillomaviruses (HPVs) and herpesviruses are detected in patients with epithelial ovarian cancer (EOC). We sought to analyze the prevalence of HPV's 16 and 18, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) DNA in peripheral blood, ovarian, and fallopian tube (FT) tissue samples collected from 97 EOC patients, including 71 cases of high-grade serous ovarian carcinoma (HGSOC), and from 60 women with other tumors or non-neoplastic gynecological diseases. DNA isolates were analyzed by PCR methods, including droplet digital PCR. The results demonstrate that (1) HPV16 DNA has been detected in one-third of the FT and tumor samples from EOCs; (2) the prevalence and quantity of HPV16 DNA were significantly higher in FT samples from HGSOCs, non-HGSOCs, and ovarian metastases than in those from non-neoplastic diseases; (3) CMV and EBV have been detected in approximately one-seventh of EOC samples. The results suggest that HPV16 might be a potential risk factor for EOC development.
Assuntos
Carcinoma Epitelial do Ovário , Tubas Uterinas , Papillomavirus Humano 16 , Neoplasias Ovarianas , Infecções por Papillomavirus , Humanos , Feminino , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/complicações , Fatores de Risco , Carcinoma Epitelial do Ovário/virologia , Carcinoma Epitelial do Ovário/patologia , Pessoa de Meia-Idade , Tubas Uterinas/virologia , Tubas Uterinas/patologia , Adulto , Idoso , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Neoplasias Ovarianas/virologia , Neoplasias Ovarianas/patologia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/genética , Citomegalovirus/isolamento & purificação , Citomegalovirus/genética , DNA Viral/genéticaRESUMO
BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.
Assuntos
Adipócitos , Exossomos , MicroRNAs , Invasividade Neoplásica , Neoplasias Ovarianas , Paclitaxel , Feminino , Exossomos/metabolismo , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Omento/patologia , Omento/metabolismo , Proliferação de Células/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacosRESUMO
OBJECTIVE: The TGF-ß superfamily member activin, a dimer of the gene products of INHBA and/or INHBB, has been implicated in immune cell maturation and recruitment, but its immune impact within epithelial ovarian cancer (EOC) is not well characterized. We sought to explore differences in activin (INHBA/ Inhibin-ßA and INHBB/ Inhibin-ßB) between malignant and ovarian tissues at the RNA and protein level and assess the relationship between activin and immune cells in EOC. METHODS: Publicly available RNA sequencing data were accessed from GEO (#GSE143897) with normalization and quantification performed via DESeq2. Immune gene expression profile was further explored within the TCGA-OV cohort derived from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to evaluate activin A and T-cell markers CD8 and FoxP3 at the protein level. ELISA to activin-A was used to assess levels in the ascites of advanced EOC patients. Kaplan-Meier curves were generated to visualize survival outcomes. RESULTS: Gene expression levels of components of the activin signaling pathway were elevated within EOC when compared to a benign cohort, with differences in activin type I/II receptor gene profiles identified. Additionally, INHBA gene expression was linked to lymphocytic immune markers in EOC samples. Immunohistochemistry analysis revealed a positive correlation of CD8 and FOXP3 staining with activin A at the protein level in both primary and metastatic epithelial ovarian cancer samples. Furthermore, Activin-A (inhibin-ßA) is significantly elevated in EOC patient ascites. CONCLUSION: INHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin-A may play a role in suppressing anti-tumor immunity in EOC, highlighting its potential as a therapeutic target.
Assuntos
Ativinas , Carcinoma Epitelial do Ovário , Subunidades beta de Inibinas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/genética , Subunidades beta de Inibinas/genética , Subunidades beta de Inibinas/metabolismo , Ativinas/metabolismo , Ativinas/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genéticaRESUMO
BACKGROUND AND AIMS: CircRNAs and autophagy are closely involved in the physiological and pathological processes of ovarian cancer; however, their exact mechanisms are still undetermined. This investigation aimed to elucidate the function and associated pathways of circFAM188A, which modulates proliferation, autophagy, and invasion in ovarian cancer (EOC). METHODS: The expression of circFAM188A in the tissues of EOC patients was assessed via RT-PCR. To elucidate proliferation, invasion, and autophagy in the tumor cells, Transwell, 5-ethynyl-2'-deoxyuridine (EdU), and mRFP-GFP-LC3 reporter assays were conducted. The binding sites between circ-FAM188A and the miR-670-3p, miR-670-3p and YY1 were predicted using bioinformatics and verified by dual-luciferase reporter assays. Pulldown assays demonstrated binding between ULK1 and circ-FAM188A. ULK1 was found to be crucial in the initial stage of autophagy. Moreover, an in vivo xenograft model was established by subcutaneous injection of nude mice with EOC cells. RESULT: Expression of circ-FAM188A was increased in EOC tissues relative to normal ovarian tissues and circ-FAM188A overexpression promoted proliferation, invasion, and autophagy; these effects were reversed by circ-FAM188A silencing. miR-670-3p and circ-FAM188A co-localized in the cytoplasm. circ-FAM188A enhanced YY1 expression by sponging miR-670-3p and was also shown to interact with ULK1. CONCLUSION: It is thus suggested that circ-FAM188A modulates autophagy by sponging miR-670-3p as well as interacting with ULK1.