RESUMO
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative real-time polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. RESULTS: Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1, CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo. CONCLUSION: Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína Forkhead Box M1/antagonistas & inibidores , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ascite/tratamento farmacológico , Ascite/metabolismo , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box M1/biossíntese , Proteína Forkhead Box M1/genética , Humanos , Terapia de Alvo Molecular , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Platina/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tioestreptona/administração & dosagemRESUMO
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. RESULTS: Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1 and CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo. CONCLUSION: Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Proteína Forkhead Box M1/antagonistas & inibidores , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Tioestreptona/farmacologia , Ascite/tratamento farmacológico , Ascite/patologia , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box M1/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Tioestreptona/administração & dosagemRESUMO
Mature cystic teratomas are the most common type of ovarian germ cell tumors. In about 1% of cases, usually among postmenopausal women, a mature cystic teratoma can undergo malignant transformation. Among malignant transformations, squamous cell carcinoma is the most common histology, comprising approximately 80% of cases. In this report, we present the unique case of a 55-yr-old woman with a pelvic mass found to be a mature cystic teratoma with malignant transformation to adenocarcinoma with breast/adnexal, upper gastrointestinal, and neuroendocrine differentiation. The predominant malignant component was the adenocarcinoma exhibiting breast/skin adnexal differentiation, which was found to involve the omentum and a right para-aortic node. We provide an in-depth review of the pathologic findings, as well as a review of the current literature on malignant transformation to adenocarcinoma. This report aims to open a conversation regarding the management of these patients, with a specific focus on the role of molecular analysis and targeted therapies.
Assuntos
Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/patologia , Teratoma/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Transformação Celular Neoplásica , Cisplatino/uso terapêutico , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Humanos , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Paclitaxel/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Teratoma/tratamento farmacológico , Teratoma/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: Given the relative chemo-resistant nature of clear-cell gynecologic cancers, we investigated the utility of radiation therapy (RT) to treat recurrent clear-cell carcinoma (CCC) of the ovary. METHODS: A retrospective chart review of patients with recurrent CCC managed from 1994-2012 was conducted at 2 academic medical centers. Demographic and clinicopathologic factors were abstracted and evaluated using Pearson χ or t tests, Kaplan-Meier and Cox regression analyses. RESULTS: Fifty-three patients had recurrent CCC, and 24 (45.3%) of these patients received RT. There were no significant differences in age, stage, optimal cytoreduction, platinum response, or the percentage of patients that received more than 3 regimens of chemotherapy between the 2 groups. Patients who received RT for recurrent CCC were more likely to have had a focal recurrence (62.5% vs 10.3%, P ≤ 0.001) and to have undergone secondary cytoreduction (70.8% vs 10.3%, P ≤ 0.001). Of patients who received RT, 73.9% underwent surgery with or before their treatment. Five-year survival after recurrence was significantly higher in the group that received RT, 62.9% versus 18.8% (P = 0.002). In a multivariate analysis, platinum-sensitive disease and RT were associated with improved survival from recurrence, (hazard ratio, 0.26; 95% confidence interval, 0.08-0.81; P = 0.02 and hazard ratio, 0.28; 95% confidence interval, 0.09-0.90, P = 0.03, respectively). CONCLUSIONS: In this cohort of patients with recurrent CCC, platinum-sensitive disease and RT are associated with improved survival. However, it is important to note that the majority of these patients underwent surgery along with RT, and it may be that the benefit of RT is limited to those who undergo secondary cytoreduction.
Assuntos
Adenocarcinoma de Células Claras/radioterapia , Recidiva Local de Neoplasia/radioterapia , Neoplasias Ovarianas/radioterapia , Adenocarcinoma de Células Claras/mortalidade , Adulto , Idoso , California/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/mortalidade , Estudos RetrospectivosRESUMO
Genital herpes is one of the most common sexually transmitted infections, affecting 1 in 6 people in the United States. Women are twice as likely to be infected as men and infections in women of reproductive age carry the additional risk of vertical transmission to the neonate at the time of delivery. Neonatal herpes infections can be devastating with up to 50% mortality for disseminated herpes simplex virus (HSV) infections in the newborn. Rates of transmission are affected by the viral type of HSV infection and whether the infection around delivery is primary or recurrent. Current management approaches decrease rates of active lesions at the time of delivery and thereby cesarean deliveries, but have not been shown to decrease the incidence of neonatal herpes infections. More research is needed to better elucidate the risk factors for transmission to the neonate and to improve our current management methodology to further decrease vertical transmission. In this review, we will discuss management of antenatal and peripartum herpes infections, considerations for mode of delivery, and the course of neonatal HSV infections.