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1.
Anticancer Res ; 40(3): 1481-1486, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32132047

RESUMEN

BACKGROUND/AIM: Peritoneal carcinomatosis is a sign of advanced ovarian cancer. If cytoreductive surgery results in a tumor-free situation with the remaining tumor being less than 0.25 cm, Hyperthermic intraperitoneal chemotherapy (HIPEC) may further improve prognosis. PATIENTS AND METHODS: Patients with ovarian cancer and peritoneal carcinomatosis underwent cytoreductive surgery. In 43 patients with optimal tumor debulking, HIPEC was performed. The peri- and post-operative course was observed. Adverse events were recorded after the Clavien-Dindo classification. RESULTS: The median age of the patients was 56 years, the median peritoneal cancer index (PCI) was 13, and the median operation time was 356 min. There was no postoperative surgery associated death. No adverse events were recorded in 16 (37.2%) of 43 patients, no grade III or IV adverse events were reported for 33 (76.7%) patients, and no grade IV adverse events were reported for 41 (95.3%) patients. Grade III adverse events occured in 19 (44.2%) of the 43 patients. Grade IV adverse events occured in 3 (7.0%) of the 43 patients. CONCLUSION: In ovarian cancer, multiple surgical procedures may be necessary in order to have macroscopically eradicated tumor tissue. The combination with HIPEC, further improves survival of patients with peritoneal carcinomatosis.


Asunto(s)
Carcinoma Epitelial de Ovario/terapia , Hipertermia Inducida/efectos adversos , Neoplasias Ováricas/terapia , Adulto , Anciano , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/cirugía , Estudios de Cohortes , Femenino , Humanos , Hipertermia Inducida/métodos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/cirugía , Neoplasias Peritoneales/terapia
2.
Anticancer Res ; 40(3): 1543-1550, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32132055

RESUMEN

BACKGROUND/AIM: The aim of the study was to assess the outcome of advanced ovarian cancer patients who i) underwent primary surgery followed by carboplatin/paclitaxel-based chemotherapy with or without bevacizumab, ii) were in complete response after chemotherapy, iii) and subsequently recurred. PATIENTS AND METHODS: The hospital records of 138 complete responders after chemotherapy with (n=58) or without (n=80) bevacizumab were reviewed. RESULTS: Both survival after recurrence and overall survival were related to age (≤61 vs. >61 years, p=0.002 and p=0.0001), performance status (0 vs. ≥1, p=0.002 and p=0.001), histotype (serous vs. non serous, p=0.005 and p=0.01), time to recurrence (≥12 vs. <12 months, p<0.0001 and p<0.0001) and treatment at recurrence (surgery plus chemotherapy vs. chemotherapy, p=0.01 and p=0.004), but not to first-line treatment. CONCLUSION: This investigation failed to detect a more aggressive behavior of recurrent ovarian cancer after bevacizumab-containing primary treatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Bevacizumab/administración & dosificación , Carboplatino , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Italia/epidemiología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Paclitaxel , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento
3.
Bull Cancer ; 107(3): 385-390, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32115180

RESUMEN

The group of rare malignant ovarian tumors includes the group of germ cell tumors, sex cords stromal ovarian tumors, small cell carcinoma, malignant Brenner tumors, rare epithelial tumors such as mucinous carcinoma, clear cell carcinoma, or low-grade serous carcinoma, as well as ovarian carcinosarcoma. Together they comprise about 10% of all ovarian tumors. Due to their low prevalence and their heterogeneity, data and treatment recommendations are limited. Even though all ovarian tumors are staged according to the FIGO staging of epithelial ovarian tumors, treatment differs especially in germ cell tumors and sex cords stromal ovarian tumors. Non-epithelial ovarian tumors can arise from a variety of ovarian precursor cells such as germ cells, granulosa cells, theca cells, or stromal fibroblasts. As can be expected already due to their divergent precursor lesions, these malignancies are substantially different but united by their rarity. This overview article gives a comprehensive summary on the pathology and clinical presentation, as well as therapy recommendations of a selection of those rare ovarian tumors, based on the latest national guidelines and related important publications.


Asunto(s)
Neoplasias Ováricas , Enfermedades Raras , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/terapia , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/terapia , Tumor de Brenner/patología , Tumor de Brenner/terapia , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/terapia , Carcinosarcoma/patología , Carcinosarcoma/terapia , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/terapia , Femenino , Humanos , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Enfermedades Raras/patología , Enfermedades Raras/terapia , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/terapia
4.
Chirurgia (Bucur) ; 115(1): 50-62, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32155399

RESUMEN

Introduction: Ovarian cancer is one of most fatal gynecological condition. The number of patients diagnosed in advanced stages is very high, hence the recurrence rate is high, and the chance of survival at 5 years is less than 45%. Purpose: To evaluate correspondance between overall survival with clinical, paraclinical, tumor or treatment characteristics and to identify prognostic factors in patients with advanced ovarian cancer - stage III and IV FIGO. Material and Method: We performed a retrospective study in 65 patients with advanced ovarian cancer - stages III and IV FIGO operated during 2010-2018, with a follow-up period of at least one year. There were correlations with clinical and paraclinical charateristics, tumor or treatment characteristics and with overall survival. Results: In the univariate statistical analysis of survival, a significant statistical association is obtained by the presence of pelvic pain at presentation (p_value = 0.033744), with the stage III (p_value = 0.007595, respectively p_value = 0.022090), with the type of citoreduction (p_value = 0.035) , with postoperative complications (p_value = 0.000685) within the pathological subtypes (p_value = 0.046266), with adjuvant treatment (p_value = 0.000083). Cox multivariate regression analysis showed that adjuvant chemotherapy (HR = 0.046, 95% CI = (0.008, 0.261), (p_value = 0.000492), suboptimal cytoreduction (HR = 0.346, 95% CI = (0.140, 0.853), (p_value) = 0.021219) and postoperative complications (HR = 53,751, 95% CI = (4,672, 618,365), (p_value = 0.001389) are independent prognostic factors. Conclusions: Absence of pelvic pain at diagnosis, FIGO IIIC stage, suboptimal cytoreduction, presence of postoperative complications, inadequate adjuvant treatment and pathological type of clear cell cancer have been shown to be prognostic factors for overall survival. In patients with advanced ovarian cancer, the type of optimal citoreduction and adjuvant treatment are independent protective factors for overall survival, and the presence of postoperative complications has been shown to be an independent risk factor.


Asunto(s)
Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Femenino , Humanos , Neoplasias Ováricas/patología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo
5.
Medicine (Baltimore) ; 99(11): e19166, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32176042

RESUMEN

RATIONALE: The malignant potential and the appropriate treatment of uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is controversial. Although these tumors generally have benign outcomes, several reports have described recurrences, metastases, and deaths associated with this disease. PATIENT CONCERNS: A 57-year-old Japanese woman (gravida 2, para 2) was referred to our hospital for the evaluation and treatment of uterine fibroids. Magnetic resonance imaging revealed a right ovarian mass and multiple fibroids in the uterine myometrium. DIAGNOSES: The patient was diagnosed with UTROSCT with sarcomatous features. INTERVENTIONS: She initially underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by second-stage surgery comprising pelvic and para-aortic lymphadenectomy and subtotal omentectomy. OUTCOMES: No postoperative recurrence was observed in the patient in 36 months. LESSONS: In this case, extended radical surgery prevented the development of recurrent disease in a patient with UTROSCT with sarcomatous features. These clinicopathological findings suggest that UTROSCT is associated with several risk factors, including older age, presence of necrosis, lymphovascular invasion, significant nuclear atypia, and significant mitotic activity. This lesion type should be considered malignant and treated with curative intent.


Asunto(s)
Neoplasias Ováricas/diagnóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Neoplasias Uterinas/cirugía , Diagnóstico Diferencial , Femenino , Humanos , Histerectomía , Imagen por Resonancia Magnética , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Salpingooforectomía , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico por imagen , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/cirugía , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/diagnóstico por imagen , Neoplasias Uterinas/patología , Útero/patología
6.
Anticancer Res ; 40(2): 759-766, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014918

RESUMEN

BACKGROUND/AIM: Yolk sac tumour (YST) is a rare malignant ovarian germ cell tumour that often occurs in young women or adolescents and exhibits an unfavourable outcome. To evaluate the biological behavior of carcinomas in vitro, permanent tumour cell lines are required. However, previously, only a few human YST cell lines have been established. Therefore, we aimed to establish a novel YST cell line. MATERIALS AND METHODS: We established a novel YST cell line, TC587, from an adolescent patient with ovarian YST. RESULTS: The cell line expressed AFP and SALL4, the characteristics of YST. In addition, we evaluated somatic mutations using next-generation sequencing and revealed some pathogenic variants, including mutations in the NRAS, KIT, KMT2C, RSF1, and TP53 genes. CONCLUSION: The newly established TC587 cell line may represent an effective tool for developing treatments and conducting molecular analyses for YST.


Asunto(s)
Tumor del Seno Endodérmico/diagnóstico , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias Ováricas/diagnóstico , Línea Celular Tumoral , Niño , Tumor del Seno Endodérmico/patología , Tumor del Seno Endodérmico/terapia , Femenino , Humanos , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia
7.
Crit Rev Oncol Hematol ; 147: 102888, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32018126

RESUMEN

BACKGROUND: The purpose of this study was to analyze the efficacy of PARP inhibitor on solid tumors. METHODS: For this study, the following databases were searched for articles published from its inception until July 2019: PubMed, Web of Science, EBSCO, and Cochrane library, of which the main conclusion was the overall survival (OS) and progression-free survival (PFS). RESULTS: We conducted a meta-analysis and the results showed that PARP inhibitor increased the patients' PFS (HR: 0.51, p < 0.001), PFS with BRCA1/2 mutations (HR: 0.32, p < 0.001), OS (HR: 0.74, p < 0.001), OS with BRCA1/2 mutations (HR: 0.78, p = 0.03), complete response (CR) (RR: 1.89, p = 0.10), partial response (PR) (RR: 1.34, p = 0.01), overall response rate (ORR) (RR: 1.42, p = 0.001) respectively. The main adverse events (AEs) observed were decreased appetite. CONCLUSIONS: PARP inhibitors may prolong survival. PARP inhibitors were more favorable for BRCA1/2 mutations in ovarian cancer patients. Additionally, the overall safety factor was controllable.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adenosina Difosfato Ribosa , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Poli(ADP-Ribosa) Polimerasas , Pronóstico , Sobrevida , Resultado del Tratamiento
8.
Isr Med Assoc J ; 22(2): 75-78, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32043322

RESUMEN

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.


Asunto(s)
Carcinoma Epitelial de Ovario , Quimioterapia Adyuvante/métodos , Procedimientos Quirúrgicos de Citorreducción/estadística & datos numéricos , Neoplasias Ováricas , Factores de Edad , Anciano , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Israel/epidemiología , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Supervivencia sin Progresión , Estudios Retrospectivos , Resultado del Tratamiento
9.
Medicine (Baltimore) ; 99(8): e19228, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32080121

RESUMEN

We investigated the effect of the maximum standardized uptake value (SUVmax) and peritoneal dissemination derived from F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) imaging on prognosis in patients with recurrent ovarian cancer.We retrospectively analyzed 145 patients with suspected recurrent ovarian cancer who had undergone F-FDG PET/CT scans after cytoreductive surgery and chemotherapy. The degree of peritoneal spread was classified as localized (1-3 FDG foci) or diffuse (>3 FDG foci). Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for predicting recurrence.A total of 145 patients were retrospectively reviewed in this study. 29 patients were excluded as their follow-up results were not available. One hundred sixteen patients were included in the final analysis. The median duration of progression-free survival was 14 months. F-FDG PET/CT detected peritoneal carcinomatosis in 82 patients. With a cut-off SUVmax of 2.0 obtained from the ROC curve analysis, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SUVmax of peritoneal carcinomatosis for predicting recurrence were 77.6%, 87.5%, 65.1%, 97.4%, and 38.9%, respectively. The area under the curve was 0.85. In a multivariate analysis, significant independent prognostic variables were SUVmax of peritoneal disease, peritoneal dissemination, and CA125 levels. In patients with peritoneal involvement, the Kaplan-Meier survival curves showed significantly longer PFS in those with localized disease.SUVmax of peritoneal disease is valuable in predicting the recurrence of ovarian cancer. SUVmax of peritoneal disease, peritoneal dissemination and CA125 level could be used as independent prognostic factors for ovarian cancer patients.


Asunto(s)
Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Adulto , Anciano , Anciano de 80 o más Años , Antígeno Ca-125/sangre , Femenino , Fluorodesoxiglucosa F18 , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Supervivencia sin Progresión , Curva ROC , Radiofármacos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X
10.
Life Sci ; 243: 117296, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31935390

RESUMEN

AIMS: Ovarian cancer (OC) is the most lethal gynecologic malignant tumors all over the world. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) has been reported as an important regulator in multiple tumors. However, the functions of HOTAIRM1 in OC and its possible molecular mechanisms remain unclear. MAIN METHODS: qRT-PCR analysis was performed to detect the expression levels of HOTAIRM1, miR-106a-5p and ARHGAP24 mRNA in OC tissues and cells. The functional effects of HOTAIRM1, miR-106a-5p and ARHGAP24 on OC cells were determined by MTT, colony formation, flow cytometry and Transwell assays. Luciferase reporter, RIP and RNA pull-down assays were used to examine the interaction between miR-106a-5p and HOTAIRM1 or ARHGAP24. Tumor xenografts were constructed in nude mice to confirm the roles of HOTAIRM1 in OC in vivo. KEY FINDINGS: HOTAIRM1 expression was lowered in OC tumor tissues and cells. Decreased HOTAIRM1 expression was associated with advanced FIGO stages and lymphatic metastasis. Up-regulation of HOTAIRM1 suppressed OC cell proliferation and invasion, and promoted apoptosis. Also, HOTAIRM1 slowed OC tumor growth in vivo. Moreover, HOTAIRM1 could serve as a competing endogenous RNA (ceRNA) of miR-106a-5p to derepress ARHGAP24 expression. HOTAIRM1-mediated inhibitory effect on OC progression was partly reversed following the restoration of miR-106a-5p expression. Furthermore, ARHGAP24 overexpression repressed OC progression in vitro. SIGNIFICANCE: In conclusion, our study showed that HOTAIRM1 suppressed OC progression through derepression of ARHGAP24 by sponging miR-106a-5p. This finding provides novel insights into the mechanisms of HOTAIRM1 in OC and highlights a potential therapeutic strategy for the treatment of OC.


Asunto(s)
Proliferación Celular/fisiología , Proteínas Activadoras de GTPasa/genética , MicroARNs/genética , MicroARNs/fisiología , Invasividad Neoplásica/genética , Neoplasias Ováricas/patología , Animales , Apoptosis/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Humanos , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Ováricas/genética
11.
Chem Commun (Camb) ; 56(15): 2320-2323, 2020 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-31990000

RESUMEN

Novel biotinylated diazido-Pt(iv) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-[Pt(py)2(N3)2(biotin)(OH)] (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Biotinilación , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Estructura Molecular , Imagen Óptica , Compuestos Organoplatinos/síntesis química , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/patología , Procesos Fotoquímicos , Relación Estructura-Actividad
13.
BMC Infect Dis ; 20(1): 21, 2020 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-31910823

RESUMEN

BACKGROUND: Meningitis is a very rare atypical presenting feature of anti-NMDA receptor encephalitis. In our case report, we describe an unusual clinical presentation of anti-NMDA receptor encephalitis with a biphasic pattern of meningitis followed by encephalitis and discuss potential mechanisms underlying this presentation. We aim to widen the differential diagnosis to be considered in a patient presenting with clinical meningitis and pyrexia. CASE PRESENTATION: This is a case of a 33-year old Caucasian woman who initially presented with a lymphocytic meningitis attributed to a viral infection. She subsequently developed fluctuating consciousness, agitation, visual hallucinations, dyskinetic movements, a generalized tonic-clonic seizure, and autonomic instability. Investigations revealed a diagnosis of anti-NMDA receptor encephalitis secondary to a previously unidentified ovarian teratoma. She made an excellent recovery with immunotherapy and removal of the teratoma. CONCLUSION: Clinicians should consider autoimmune encephalitides in individuals with meningitis, particularly where extensive investigations fail to identify a causative pathogen and there is rapid development of an encephalitic phenotype.


Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Meningitis Viral/diagnóstico , Neoplasias Ováricas/patología , Teratoma/patología , Administración Intravenosa , Adulto , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Anticuerpos/sangre , Diagnóstico Diferencial , Encefalitis/diagnóstico , Femenino , Fiebre/diagnóstico , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Enfermedad de Hashimoto/diagnóstico , Humanos , Inmunoterapia , Metilprednisolona/administración & dosificación , Metilprednisolona/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/etiología , Neoplasias Ováricas/cirugía , Intercambio Plasmático , Receptores de N-Metil-D-Aspartato/inmunología , Convulsiones/diagnóstico , Teratoma/tratamiento farmacológico , Teratoma/etiología , Teratoma/cirugía , Resultado del Tratamiento
15.
Gynecol Oncol ; 156(1): 13-22, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31708167

RESUMEN

BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles. FINDINGS: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. INTERPRETATION: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). FUNDING: National Cancer Institute.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma Epitelial de Ovario/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Neoplasias de las Trompas Uterinas/patología , Femenino , Humanos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Persona de Mediana Edad , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Neoplasias Peritoneales/patología , Supervivencia sin Progresión
16.
Gynecol Oncol ; 156(1): 6-12, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31711656

RESUMEN

OBJECTIVES: Peritoneal implants of ovarian borderline serous tumors are diagnostically challenging. Distinguishing invasive from non-invasive cases is crucial for patient management. This study aims to develop a molecular signature to distinguish invasive implants with malignant potential from those with benign. METHODS: Archival formalin-fixed paraffin embedded tissues were retrieved from 3 institutions, with consensus histologic review. Lesions were classified as a non-invasive implant (n = 10), invasive implant (n = 9) or high grade (HG) peritoneal metastasis from HG serous ovarian carcinoma (n = 4). The nCounter® GX Human Cancer Gene Reference Assay was used to profile expression of 230 cancer genes and 6 control genes. The DEGs in HG peritoneal metastases compared to non-invasive implants were identified using T-tests performed in the NanoString Diff package, then used to cluster cases using the Eisen cluster 3.0 package. Lasso in glmnet package was used to select the subset of genes that most strongly correlate with a malignant potential. RESULTS: 37 genes were downregulated and 16 genes were upregulated in HG peritoneal metastases. Using this 53-gene signature, one of nine of the invasive implants clustered with the HG peritoneal metastasis. Expression of ABCB1, CDC2, CDKN1A, FAT1, MMP9, MSH2, NQO1 and TOP2A were sufficient to indicate malignant potential of implants. The HG peritoneal metastasis and one invasive implant exhibited a high malignant likelihood (>92%) whereas the non-invasive implants and eight invasive implants displayed a low malignant likelihood (≤0.1%). CONCLUSIONS: Invasive implants are heterogenous and often morphologically indistinguishable lesions with transcriptomes that may be classified as malignant or not. Additional research is needed to determine the importance of these genes as drivers and/or surrogates of malignant potential, and their utility for triaging invasive implants.


Asunto(s)
Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Adulto , Cistadenocarcinoma Seroso/genética , Femenino , Expresión Génica , Heterogeneidad Genética , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Peritoneales/patología , Estándares de Referencia , Adulto Joven
17.
Cancer Immunol Immunother ; 69(1): 115-126, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31802182

RESUMEN

Pro-inflammatory cytokines are crucial mediators of cancer development, representing potential targets for cancer therapy. The molecular mechanism of a vital pro-inflammatory cytokine, IL-17A, in cancer progression and its potential use in therapy through influencing fatty acid (FA) metabolism, especially FA uptake of cancer cells, remains unknown. In the present study, we used IL-17A and ovarian cancer (OvCa), a representative of both obesity-related and inflammation-related cancers, to explore the interactions among IL-17A, cancer cells and adipocytes (which can provide FAs). We found that in the presence of palmitic acid (PA), IL-17A could directly increase the cellular uptake of PA, leading to the proliferation of OvCa cells via the IL-17A/IL-17RA/p-STAT3/FABP4 axis rather than via CD36. Moreover, in vivo experiments using an orthotopic implantation model in IL-17A-deficient mice demonstrated that endogenous IL-17A could fuel OvCa growth and metastasis with increased expression of FABP4 and p-STAT3. Furthermore, analysis of clinical specimens supported the above findings. Our data not only provide useful insights into the clinical intervention of the growth and metastasis of the tumors (such as OvCa) that are prone to growth and metastasis in an adipocyte-rich microenvironment (ARM) but also provides new insights into the roles of IL-17A in tumor progression and immunomodulatory therapy of OvCa.


Asunto(s)
Adipocitos/inmunología , Interleucina-17/metabolismo , Neoplasias Ováricas/inmunología , Ácido Palmítico/metabolismo , Adipocitos/metabolismo , Animales , Antígenos CD36/metabolismo , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Proteínas de Unión a Ácidos Grasos/metabolismo , Femenino , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Ratones , Ratones Noqueados , Persona de Mediana Edad , Neoplasias Ováricas/patología , Ovario/patología , Fosforilación , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Microambiente Tumoral/inmunología
18.
Gynecol Oncol ; 156(1): 211-221, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31776040

RESUMEN

OBJECTIVE: Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC). METHODS: CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed in vitro and in vivo experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells. RESULTS: The patient incidence of high CDK7 expression (CDK7High) gradually increased from normal ovarian epithelium to EOC (P < 0.001). Moreover, CDK7High was associated with an advanced stage and high-grade histology (P = 0.035 and P = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (P = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by G0/G1 cell cycle arrest. In in vivo therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis. CONCLUSION: Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.


Asunto(s)
Carcinoma Epitelial de Ovario/enzimología , Quinasas Ciclina-Dependientes/biosíntesis , Neoplasias Ováricas/enzimología , Animales , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/biosíntesis , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Femenino , Xenoinjertos , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Recurrencia Local de Neoplasia/enzimología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Fenilendiaminas/farmacología , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología
19.
Cell Prolif ; 53(1): e12719, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31778258

RESUMEN

OBJECTIVES: Stat3 is persistently activated in ovarian cancer cells, with a crucial role in tumour onset and progression. In this study, we examined the anti-tumour effect of a small-molecule inhibitor napabucasin (BBI608) on epithelial ovarian cancer (EOC) in vitro and in vivo, and investigated the underlying molecular mechanism of this drug in combination with paclitaxel. MATERIALS AND METHODS: A total of 156 ovarian cancer patient samples were analysed to determine the correlation between pStat3 expression in tumour cells and the prognosis of EOC patients. The anti-tumour effect of BBI608 and/or paclitaxel on ovarian cancer in vitro was evaluated by CCK-8, flow cytometry, Western blot and transwell assays. An in vivo intraperitoneal model was performed to confirm the effect of BBI608 on pStat3-mediated peritoneal metastasis when combined with paclitaxel. RESULTS: Patients with high expression of pStat3 had poorer overall survival and progression-free survival than those with low pStat3 expression. The synergy of BBI608 in combination with paclitaxel exerted dramatic growth inhibition and induced apoptosis in EOC cell lines. In vivo, the combination of two drugs significantly decreased intraperitoneal tumour burden and ascites volume, prolonged survival of tumour-bearing mice compared with each monotherapy; these results were associated with downregulation of phospho-Stat3 and activation of apoptosis pathway. CONCLUSIONS: Targeting the activation of Stat3 may be a potential therapeutic approach for EOC by acting synergistically with paclitaxel.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Neoplasias/biosíntesis , Neoplasias Ováricas , Paclitaxel/farmacología , Factor de Transcripción STAT3/biosíntesis , Adulto , Anciano , Animales , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Int J Cancer ; 146(6): 1553-1567, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31503345

RESUMEN

Detachment of cancer cells from the primary tumor and formation of spheroids in ascites is required for implantation metastasis in epithelial ovarian cancer (EOC), but the underlying mechanism of this process has not been thoroughly elucidated. To mimic this process, ovarian cancer cells were grown in 3D and 2D culture. Hey and OVCA433 spheroids exhibited decreased cell proliferation and enhanced adhesion and invasion. SMYD3 expression was elevated in ovarian carcinoma spheroids in association with increased H3K4 methylation. Depletion of SMYD3 by transient siRNA, stable shRNA knockdown and the SMYD3 inhibitor BCI-121 all decreased spheroid invasion and adhesion. Gene expression arrays revealed downregulation of integrin family members. Inhibition assays confirmed that invasion and adhesion of spheroids are mediated by ITGB6 and ITGAM. SMYD3-deficient cells regained the ability to invade and adhere after forced overexpression of SMYD3, ITGB6 and ITGAM. However, this biological ability was not restored by forced overexpression of SMYD3 in ITGB6- and/or ITGAM-deficient cancer cells. SMYD3 and H3K4me3 binding at the ITGB6 and ITGAM promoters was increased in spheroids compared to that in monolayer cells, and the binding was decreased when SMYD3 expression was inhibited, consistent with the expression changes in integrins. SMYD3 expression and integrin-mediated adhesion were also activated in an intraperitoneal xenograft model and in EOC patient spheroids. In vivo, SMYD3 knockdown inhibited tumor metastasis and reduced ascites volume in both the intraperitoneal xenograft model and a PDX model. Overall, our results suggest that the SMYD3-H3K4me3-integrin pathway plays a crucial role in ovarian cancer metastasis to the peritoneal surface.


Asunto(s)
Ascitis/patología , Carcinoma Epitelial de Ovario/secundario , N-Metiltransferasa de Histona-Lisina/metabolismo , Integrinas/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Adulto , Anciano , Ascitis/etiología , Carcinoma Epitelial de Ovario/genética , Adhesión Celular/genética , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Metilación de ADN , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , N-Metiltransferasa de Histona-Lisina/genética , Histonas/metabolismo , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genética , Regiones Promotoras Genéticas/genética , Esferoides Celulares , Ensayos Antitumor por Modelo de Xenoinjerto
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