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1.
Oncoimmunology ; 8(12): e1662708, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31741758

RESUMO

Systemic inflammatory responses including thrombocytosis, leukocytosis, or neutrophilia have gained attention as prognostic indicators in patients with various solid malignancies.current study, we aimed to investigate the clinical implications and underlying biological mechanism of the systemic inflammatory response in endometrial cancer. Clinical data from 900 patients with endometrial cancer were analyzed to investigate the association between pretreatment leukocytosis, thrombocytosis, and treatment outcome. Clinical samples, endometrial cancer cell lines, and a mouse model of endometrial cancer were used to examine the mechanisms responsible for systemic inflammatory response in endometrial cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and MDSCs. Then, we showed that pretreatment concurrent leukocytosis and thrombocytosis is associated with significantly shorter survival and decreased chemosensitivity among patients with endometrial cancer. In vitro and in vivo experiments revealed that tumor-derived G-CSF and G-CSF-mediated IL-6 production from the tumor microenvironment are involved in the development of leukocytosis and thrombocytosis in patients with endometrial cancer. Moreover, increased tumor-infiltrating MDSCs induced by tumor-derived G-CSF, MDSC-mediated T cell suppression, and MDSC-mediated cancer stem cell induction are responsible for progression and chemoresistance in this type of endometrial cancer. MDSC depletion using an anti-Gr-1 neutralizing antibody or inhibition of MDSC activity by celecoxib inhibited tumor growth and enhanced chemosensitivity in endometrial cancer displaying concurrent leukocytosis and thrombocytosis. In conclusion, Pretreatment concurrent leukocytosis and thrombocytosis are associated with significantly shorter survival and decreased chemosensitivity among patients with endometrial cancer. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy for these patients.

2.
Int J Gynaecol Obstet ; 147(2): 252-257, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31420876

RESUMO

OBJECTIVE: To retrospectively review the efficacy and safety of novel direct oral anticoagulants (DOACs) and compare the results with those of vitamin K antagonists (VKA) when used in clinical practice to treat venous thromboembolism (VTE) because there is insufficient evidence regarding its use in patients with gynecological cancers. METHODS: A study was conducted of patients diagnosed with gynecological cancers at Osaka University Hospital between January 2010 and December 2017. The medical records of those who suffered from deep venous thrombosis (DVT) and/or pulmonary embolism (PE) were retrospectively reviewed. RESULTS: Among the 1698 cases of gynecological cancers, 107 (6.3%) cases were diagnosed as having VTE. A total of 34 (31.8%) patients presented DVT plus PE and 73 (68.2%) patients had DVT alone. Fifty-four cases were treated with DOACs and 53 with VKA. Although 3 of the 53 patients (5.7%) in the VKA group developed recurrent VTE, only 1 (1.9%) patient in the DOAC group showed clinically relevant bleeding from a tumor penetrating the rectum. DOACs were non-inferior to VKA with respect to the composite outcome, including recurrent venous thrombosis and relevant bleeding (hazard ratio 0.31, 95% confidence interval 0.03-3.12, P=0.363). CONCLUSION: DOACs can be effectively and safely used in VTE patients with gynecological cancers.


Assuntos
Anticoagulantes/administração & dosagem , Heparina/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Administração Oral , Idoso , Feminino , Neoplasias dos Genitais Femininos/epidemiologia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Tromboembolia Venosa/epidemiologia
3.
Int J Gynecol Cancer ; 29(6): 1057-1063, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31203199

RESUMO

OBJECTIVE: Both pre-treatment prognostic nutritional index and platelet count were reported to be independent prognostic factors in epithelial ovarian cancer patients. However, their relationship has not been investigated. The aim of this study was to investigate the association between the pre-treatment prognostic nutritional index and platelet count, and to compare their utility as prognostic indicators for patients with epithelial ovarian cancer. METHODS: Clinical data from epithelial ovarian cancer patients treated between April 2007 and March 2016 were collected and retrospectively reviewed. The association between the pre-treatment prognostic nutritional index and platelet count was evaluated using Spearman's rank correlation coefficient. After determining the cut-off values for the pre-treatment platelet count and prognostic nutritional index for predicting disease-specific survival by time-dependent receiver operating characteristic (ROC) curve analysis, we compared the clinical utility of platelet counts and the prognostic nutritional index. RESULTS: A total of 308 patients were included in the analysis. Median age was 57 (range 16-81) years. The International Federation of Gynecology and Obstetrics (FIGO) clinical stage at initial diagnosis was stage I in 137 patients (44.5%), stage II in 27 patients (8.8%), stage III in 96 patients (31.2%), and stage IV in 48 patients (15.6%). Most patients (37.7%) had serous adenocarcinoma. Of the 295 patients who underwent primary or interval debulking surgery, optimal debulking was performed in 240 patients (77.9%). Decresed pre-treatment prognostic nutritional index was correlated with increased pre-treatment platelet count (p<0.0001), and when compared, the prognostic nutritional index had a significantly greater area under the ROC curve value than the platelet count for predicting disease-specific survival (0.8348 vs 0.6413, p=0.0007). An elevated platelet count was significantly associated with a shorter disease-specific survival in epithelial ovarian cancer patients (p<0.0001). However, when the prognostic nutritional index was adjusted, an elevated platelet count did not provide any prognostic information (lower prognostic nutritional index, p=0.45; higher prognostic nutritional index, p=0.77). CONCLUSIONS: The pre-treatment prognostic nutritional index was superior to the platelet count for predicting disease-specific survival for epithelial ovarian cancer patients. Although pre-treatment thrombocytosis was reported to be an independent poor prognostic factor in epithelial ovarian cancer patients, it generally reflects a lower prognostic nutritional index, and did not provide any prognostic information when the prognostic nutritional index was adjusted.

4.
Oncotarget ; 10(38): 3605-3613, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31217896

RESUMO

Objective: We retrospectively investigated the prognostic significance of the pretreatment prognostic nutritional index (PNI) in patients with epithelial ovarian cancer (EOC) according to the clinical stage. Methods: The baseline characteristics and clinical outcomes of 308 EOC patients were collected and retrospectively reviewed. PNI was defined as 10 × serum albumin (g/L) + 0.005 × lymphocyte count (per mm3) in the peripheral blood. The cut-off value of PNI was defined by time-dependent receiver operating characteristics (ROC) analysis. Univariate or multivariate analysis was conducted to evaluate the association between pretreatment PNI, progression-free survival (PFS), and disease-specific survival (DSS) according to the clinical stage. Results: The cut-off value of PNI was defined as 44.7 in early-stage patients and 42.9 in advanced-stage patient by ROC analysis, respectively. Although decreased PNI was not associated with short PFS or DSS in early-stage patients, it was significantly correlated with short PFS (p<0.0001) and DSS (p<0.0001) in advanced-stage patients. In multivariate analysis, decreased PNI was an independent prognostic predictor of recurrence and short survival in advanced-stage patients. Conclusion: A decreased pretreatment PNI was an independent poor prognostic factor in patients with advanced EOC.

5.
Oncotarget ; 10(20): 1887-1902, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30956772

RESUMO

Objective: To investigate the clinical implications of 17ß-estradiol (E2) in estrogen receptor α (ERα)-negative female cancer progression as well as the underlying biological mechanisms. Methods: Clinical data from 306 locally-advanced cervical cancer (stage IIB-IVA) patients were analyzed in order to investigate the relationships between age, serum E2 levels, and treatment outcomes. Clinical samples, ERα-negative cervical and breast cancer cell lines, and mouse xenograft models of cervical and breast cancers were employed in order to elucidate the mechanisms responsible for the E2- and pregnancy-mediated progression of cervical and breast cancers, with a focus on the role of myeloid-derived suppressor cells (MDSC). Results: Younger patients with elevated E2 levels showed significantly shorter progression-free survival (P = 0.040) and overall survival (P = 0.039). The exogenous E2 treatment stimulated the mobilization of MDSC from bone marrow and directly augmented their suppressive activities, leading to the progression of ERα-negative cervical and breast cancers. The co-administration of an anti-Gr-1 neutralizing antibody with E2 prevented the E2-mediated induction of MDSC, and attenuated E2-mediated tumor growth in cervical and breast cancer xenografts. Significantly increased MDSC numbers and enhanced tumor growth were observed during pregnancy in mice with cervical or breast cancer. Significantly increased MDSC numbers were also observed during pregnancy in cervical cancer patients. Conclusions: E2 facilitates the progression of ERα-negative cervical or breast cancer under non-pregnant and pregnant conditions by inducing MDSC. MDSC inhibition therapy may have therapeutic efficacy in premenopausal or pregnant female cancer patients.

6.
Int J Gynecol Cancer ; 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917999

RESUMO

Radical trachelectomy combined with pelvic lymphadenectomy has been used to treat patients with early-stage cervical cancer who wish to preserve their fertility. Vaginal, abdominal, laparoscopic, and robotic approaches have been employed during this procedure, but all cause peritoneal damage, which could result in periadnexal adhesion. As periadnexal adhesion can lead to female infertility due to restricted sweeping of the fimbria over the ovary, it is important to minimize peritoneal damage during the fertility-preserving surgery. Aiming to minimize peritoneal damage, we recently developed a new surgical approach. The techniques used are similar to those used for type III radical hysterectomy; however, all procedures are performed via the extraperitoneal approach.In this video article, we describe a step-by-step technique of this new fertility-preserving surgical procedure. Surgical procedures are as follows: (1) extraperitoneal pelvic lymphadenectomy, (2) excision of the vesicohypogastric fascia and median umbilical ligament, (3) bladder dissection from the peritoneum and identification of uterine cervix, (4) transection of the cardinal ligaments and vesicouterine ligaments, (5) transection of the vagina, (6) excision of the rectovaginal and uterosacral ligaments, (7) transection of the uterine cervix, (8) cervical cerclage and placement of a Foley catheter, (9) anastomosis of the uterine cervix, (10) suture of the median umbilical ligament and vesicohypogastric fascia. During these procedures, the uterine arteries, inferior hypogastric nerve, and pelvic splanchnic nerve were preserved. The advantages of this new surgical approach are first, peritoneal injuries can be completely avoided as the procedure is performed extraperitoneally, and second, it can be carried out using conventional low-cost instruments. In view of these features, we consider that this technique could be an ideal treatment option for selected women with early-stage cervical cancer. The oncological and reproductive outcomes of this new surgical approach need to be evaluated in future clinical studies.

7.
J Obstet Gynaecol Res ; 45(6): 1173-1182, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843318

RESUMO

AIM: To evaluate the efficacy and toxicity of external beam radiotherapy (RT) for isolated recurrent epithelial ovarian cancer (EOC). METHODS: Twenty-four isolated recurrent EOC patients treated with RT at Osaka University Hospital between January 2000 and January 2017 were included in the current study. Data regarding the primary or recurrent diseases, follow-up findings, and efficacy or toxicities of RT were collected and retrospectively analyzed. Survival rates were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Their median age was 59 years. Most patients had International Federation of Gynecology and Obstetrics stage III-IV diseases at the initial diagnosis. Histologically, serous adenocarcinoma was predominant, followed by clear cell adenocarcinoma. All patients had received at least one regimen of platinum-based chemotherapy; 8 were platinum-sensitive relapse and the others were platinum-resistant. Lymph nodes were the most common sites of recurrence, and the median tumor size was 25.5 mm. The median total dose of RT administered was 54 Gy, with a median daily dose of 2 Gy. RT was well-tolerated, and no patients experienced Grade 3/4 toxicities. The in-field overall response rate was 58.3% (14/24), the median regression rate was -40.2% (range: -100 to 0) and the median survival period after RT was 17 months. The 1-year survival and local progression-free survival rates after RT were 66.7% and 45.8%, respectively. CONCLUSION: RT showed significant antitumor effect against isolated recurrent EOC without causing severe toxicities. Prospective studies with sufficient statistical power are warranted to further evaluate the role of RT in this patient population.


Assuntos
Carcinoma Epitelial do Ovário/radioterapia , Recidiva Local de Neoplasia/radioterapia , Neoplasias Ovarianas/radioterapia , Radioterapia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Protocolos Antineoplásicos , Carcinoma Epitelial do Ovário/mortalidade , Resistência a Medicamentos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/mortalidade , Platina/farmacologia , Radioterapia/efeitos adversos , Estudos Retrospectivos , Análise de Sobrevida
8.
Int J Gynecol Cancer ; 29(3): 474-479, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30833436

RESUMO

OBJECTIVES: We conducted a phase II study to investigate the efficacy and toxicities of irinotecan plus oral S-1 in patients with advanced or recurrent uterine cervical cancer. METHODS: Patients with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy were enrolled. Irinotecan (150 mg/m2) was administered intravenously over the course of 90 min on day 1, and S-1 (80 mg/m2) was given orally in two divided doses from days 1 to 14 of a 21 day cycle. The primary endpoint of this phase II study was response rate. Secondary endpoints included safety, progression free survival, and overall survival. RESULTS: A total of 19 patients were enrolled and treated. The response rate was 29.4%. Grade 3-4 hematologic toxicities were observed in three patients (15.7%). The only grade 3-4 non-hematologic toxicity observed was grade 3 diarrhea. The median progression free survival and overall survival were 3 months and 9 months, respectively. CONCLUSION: S-1 plus irinotecan in a 3 weekly setting is safe and active in women with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy. Future corroborative clinical studies are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Análise de Sobrevida , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia
9.
Oncotarget ; 10(6): 673-683, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30774764

RESUMO

Paclitaxel is a first-line drug for treating epithelial ovarian cancer (EOC). However, prognosis for patients with advanced stage cancer remains poor due to primary or acquired drug resistance. Therefore, overcoming chemoresistance is one of the greatest challenges in treating EOC. In this study, we identified microRNAs (miRNA) that regulate paclitaxel resistance and tested their potential utility as therapeutic targets. Paclitaxel-resistant cell lines were established using two EOC cell lines: SKVO3ip1 and HeyA8. miRNA PCR arrays showed that miR-194-5p was downregulated in paclitaxel-resistant cells. Forced expression of miR-194-5p resensitized resistant cells to paclitaxel. Conversely, miR-194-5p inhibition induced paclitaxel resistance in parental cells. In silico analysis and luciferase reporter assay revealed that MDM2 is a direct target of miR-194-5p. MDM2 was upregulated in paclitaxel resistant cells compared with parental cells. MDM2 inhibition also resensitized resistant cells to paclitaxel and forced MDM2 induced paclitaxel resistance in parental cells. miR-194-5p induced p21 upregulation and G1 phase arrest in resistant cells by downregulating MDM2. Furthermore, a public database showed that high MDM2 expression was associated with a shorter progression-free survival in EOC patients treated with paclitaxel. Collectively, our results show that restoring miR-194-5p expression resensitizes EOCs to paclitaxel, and this may be exploited as a therapeutic option.

10.
J Radiat Res ; 60(2): 264-269, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649485

RESUMO

Outcomes for patients with Stage IB1-IVA cervical cancer treated with computed tomography (CT)-based image-guided brachytherapy (IGBT) were examined in this study. A total of 84 patients were analyzed between March 2012 and June 2015. Whole-pelvic radiotherapy with a central shield was performed for each patient, and the total pelvic sidewall dose was 50 Gy. IGBT was delivered in 2-4 fractions. The initial prescription dose (6.8 Gy) was delivered at Point A, and the dose distribution was modified manually by graphical optimization. The total dose was calculated as the biologically equivalent dose in 2 Gy fractions (EQD2). Concurrent chemotherapy was administered to 64 patients (76%). The median follow-up period was 36 months (range 2-62 months). The 3-year overall survival, local control, and progression-free survival rates were 94%, 89% and 81%, respectively. The mean EQD2 for HR-CTV D90 was 73.4 Gy, and the EQD2 for HR-CTV D90 was not significantly associated with the local control rate. In multivariate analysis, adenocarcinoma (P = 0.03) and tumor size ≥45 mm (P = 0.06) were risk factors for local control. The patients were divided into four groups based on histology (squamous cell carcinoma vs adenocarcinoma) and tumor size (<45 vs ≥45 mm). Those with large adenocarcinomas had significantly worse outcomes. In conclusion, CT-based IGBT achieved favorable local control, but different treatment strategies may be necessary for large adenocarcinomas.


Assuntos
Braquiterapia , Radioterapia Guiada por Imagem , Tomografia Computadorizada por Raios X , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Carga Tumoral
11.
Invest New Drugs ; 37(5): 818-827, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30374654

RESUMO

Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin on cervical cancer with a special focus on its effects on cancer stem cells (CSCs). Methods Using two cervical cell lines (ME180 and CaSki cells), the antitumor effects of lurbinectedin were assessed in vitro using the MTS assay and colony formation assay. The growth inhibitory effects of paclitaxel and cisplatin were also evaluated as controls. By employing ALDH1 activity as a marker of CSCs, the antitumor effects of lurbinectedin on cervical CSCs and non-CSCs were individually evaluated. Finally, we investigated the mechanisms by which lurbinectedin eliminated cervical CSCs. Results Lurbinectedin had significant antitumor activity toward cervical cancer cells at low nanomolar concentrations in vitro. Mouse xenografts of cervical cancer revealed that lurbinectedin significantly inhibits tumor growth. The growth-inhibitory effect of lurbinectedin was greater than that of cisplatin and paclitaxel. ALDH-high CSCs were observed in both cervical cancer cell lines (4.4% and 2.4% in ME180 and CaSki cells, respectively). Lurbinectedin downregulated stem cell-related gene expression (Oct4, Nanog, and SOX2), inhibited HDAC1 activity, and effectively eliminated ALDH-high CSCs. Conclusions Lurbinectedin is highly effective on uterine cervical cancer because it eliminates CSCs, and lurbinectedin is a promising agent to overcome platinum resistance in cervical cancer.

12.
Oncotarget ; 9(91): 36317-36330, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30555631

RESUMO

Myeloid-derived suppressor cells (MDSCs) enhance tumor progression by suppressing tumor-specific T cell responses, stimulating tumor angiogenesis, or promoting tumor cell metastasis. However, the biology of MDSCs have not been fully investigated. In the current study, we investigated the role of MDSCs in inducing cancer stem-like cells and explored a clinically feasible approach for targeting MDSCs-mediated cancer stem-like cells induction. In vitro and in vivo experiments revealed that MDSCs induced by tumor-derived G-CSF enhanced the stemness of cervical cancer cells by producing Prostaglandin E2 (PGE2). We also demonstrated that anti-Gr-1 neutralizing antibody or celecoxib inhibited the induction of cancer stem-like cells and enhanced the efficacy of cisplatin in cervical cancer. In clinical samples, MDSCs, PGE2, and CSCs had positive correlations. In conclusion, G-CSF-induced MDSCs enhance the stemness of uterine cervical cancer cells by producing PGE2. Targeting MDSCs or PGE2 might be a reasonable strategy for enhancing the efficacies of treatments. .

13.
BMC Cancer ; 18(1): 1065, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30396333

RESUMO

BACKGROUND: microRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles such as exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced from epithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminate patients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs in ovarian cancer progression. METHODS: Exosomes were collected from the culture media of serous ovarian cancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that several miRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels of serum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthy volunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. To investigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritoneal mesothelial cells (HPMCs) were treated with EOC-derived exosomes and then expression levels of miR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and the effect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis with the tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potential target genes of miR-99a-5p were examined. RESULTS: The serum miR-99a-5p levels were significantly increased in patients with EOC, compared with those in benign tumor patients and healthy volunteers (1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with a cut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (area under the curve = 0.88). Serum miR-99a-5p expression levels were significantly decreased after EOC surgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment with EOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected with miR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectin and vitronectin. CONCLUSIONS: Serum miR-99a-5p is significantly elevated in ovarian cancer patients. Exosomal miR-99a-5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin and vitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression.


Assuntos
Fibronectinas/genética , MicroRNAs/genética , Neoplasias/genética , Neoplasias Ovarianas/genética , Vitronectina/genética , Adulto , Idoso , Linhagem Celular Tumoral , Epitélio/metabolismo , Epitélio/patologia , Exossomos/genética , Exossomos/metabolismo , Feminino , Fibronectinas/sangue , Regulação Neoplásica da Expressão Gênica/genética , Voluntários Saudáveis , Humanos , MicroRNAs/sangue , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias/sangue , Neoplasias/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Peritônio/metabolismo , Peritônio/patologia , Vitronectina/sangue
14.
J Ovarian Res ; 11(1): 81, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30219071

RESUMO

BACKGROUND: microRNAs (miRNAs) stably exist in circulating blood encapsulated in extracellular vesicles such as exosomes; therefore, serum miRNAs have the potential to serve as novel cancer biomarkers. New diagnostic markers to detect high grade serous ovarian cancer (HGSOC) are urgently needed. The aim of this study was to identify miRNAs specific to HGSOC and analyze whether serum miRNA can discriminate HGSOC patients from healthy controls or patients with ovarian malignancies of other histological types. METHODS: Exosomes from ovarian cancer cell lines were collected and exosomal miRNAs extracted. miRNA microarray analysis revealed several elevated miRNAs specific to HGSOC. Among these, we focused on miR-1290. Sera from 70 ovarian cancer patients and 13 healthy controls were gathered and its expression levels detected by quantitative real-time polymerase chain reaction. RESULTS: In HGSOC patients, serum miR-1290 was significantly overexpressed compared to in healthy controls (3.52 fold; P = 0.03), unlike in patients with ovarian cancers of other histological types. The relative expression of miR-1290 was higher in advanced stages of HGSOC than in early stages (4.23 vs. 1.58; P = 0.23). Its expression significantly decreased after operation (5.87 to 1.17; P < 0.01), indicating that this miRNA reflects tumor burden. A receiver operating characteristic curve analysis showed that at the cut-off of 1.20, the sensitivity and specificity were 63% and 85% respectively for discriminating patients with HGSOC (area under the curve [AUC] = 0.71) from healthy controls, and at the cut-off of 1.55, the sensitivity and specificity were 47% and 85% respectively for discriminating patients with HGSOC (AUC = 0.76) from those with malignancies of other histological types. CONCLUSIONS: Serum miR-1290 is significantly elevated in patients with HGSOC and can be used to discriminate these patients from those with malignancies of other histological types; it is a new potential diagnostic biomarker for HGSOC.


Assuntos
Biomarcadores Tumorais/sangue , MicroRNAs/genética , Neoplasias Ovarianas/genética , Estudos de Coortes , Feminino , Humanos , MicroRNAs/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos
15.
Tumour Biol ; 40(7): 1010428318776485, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30074452

RESUMO

Myeloid-derived suppressor cells are a heterogeneous population of immature myeloid cells that exhibit immunosuppressive activity (they block the proliferation and activity of both T cells and natural killer cells). In addition to their role in suppressing immune responses, myeloid-derived suppressor cells directly stimulate tumor cell proliferation, metastasis, and angiogenesis. In the area of gynecological cancer, increased numbers of circulating myeloid-derived suppressor cells or tumor-infiltrating myeloid-derived suppressor cells have been detected, and the increased frequencies of myeloid-derived suppressor cells are associated with a poor prognosis. Thus, the successful myeloid-derived suppressor cells depletion may hold the key to maximizing existing anti-cancer therapies and improving the prognosis of gynecological cancer. In this review, we summarize current knowledge regarding myeloid-derived suppressor cells biology, clinical significance of myeloid-derived suppressor cells, and the potential myeloid-derived suppressor cells-targeting strategies in gynecological cancer.


Assuntos
Neoplasias dos Genitais Femininos/imunologia , Neoplasias dos Genitais Femininos/patologia , Células Supressoras Mieloides/patologia , Feminino , Humanos , Prognóstico
16.
Clin Cancer Res ; 24(16): 4018-4029, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29752277

RESUMO

Purpose: The aim of this study was to investigate the metastatic potential of uterine cervical and endometrial cancer displaying tumor-related leukocytosis (TRL).Experimental Design: Clinical data on uterine cervical (N = 732) and endometrial cancer (N = 900) were collected, and the metastatic potential of TRL-positive cancer was evaluated in univariate and multivariate analyses. Tumor and blood samples obtained from patients with cervical cancer, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms underlying the highly metastatic nature of TRL-positive cancer, focusing on tumor-derived G-CSF and the myeloid-derived suppressor cell (MDSC)-mediated premetastatic niche.Results: Pretreatment TRL was significantly associated with visceral organ metastasis in patients with uterine cervical or endometrial cancer. The patients with TRL-positive cervical cancer displayed upregulated tumor G-CSF expression, elevated G-CSF levels, and increased MDSC frequencies in the peripheral blood compared with the TRL-negative patients. In vitro and in vivo investigations revealed that MDSCs produced in response to tumor-derived G-CSF are involved in premetastatic niche formation, which promotes visceral organ metastasis of TRL-positive cancer. The depletion of MDSCs attenuated this premetastatic niche formation and effectively inhibited the visceral organ metastasis of TRL-positive cancer.Conclusions: Uterine cervical/endometrial cancer displaying TRL is a distinct clinical entity with high metastatic potential. Tumor-derived G-CSF and the MDSC-mediated premetastatic niche are responsible for the highly metastatic nature of this type of cancer. MDSC-targeting therapy might represent a potential strategy for combating metastasis derived from TRL-positive uterine cancer. Clin Cancer Res; 24(16); 4018-29. ©2018 AACR.


Assuntos
Neoplasias do Endométrio/terapia , Leucocitose/terapia , Células Supressoras Mieloides/transplante , Neoplasias do Colo do Útero/terapia , Animais , Modelos Animais de Doenças , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/genética , Humanos , Leucocitose/genética , Leucocitose/patologia , Camundongos , Metástase Neoplásica , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
17.
Obstet Gynecol Int ; 2018: 9475919, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29805451

RESUMO

Loss of ovarian function by the treatment for gynecological malignancy results in a drastic decrease of estrogen causing physical and mental symptoms. The purpose of this study is to evaluate the effect of Japanese Kampo Kamikihito (KKT) and Kamishoyosan (KSS) on menopausal symptoms in gynecological cancer patients. Patients who had menopausal symptoms after gynecologic malignancy treatment were enrolled and randomly divided into a KKT or a KSS group. Kupperman Menopausal Index (KI) questionnaires were obtained before tumor treatment, at baseline, and at 4 and 8 weeks. Changes in KI scores and severity of each symptom were evaluated. A total of 33 patients were enrolled: 18 in the KKT group and 15 in the KSS group. The KI scores significantly decreased at 4 and 8 weeks compared with baseline in both groups. Although no significant difference was found in change in KI scores between the KKT and KSS groups, efficacy showed some differences. Both KKT and KSS were effective for insomnia, vertigo, and palpitation. KSS was also effective for vasomotor symptoms and arthralgia/myalgia. In conclusion, both KKT and KSS were effective for menopausal symptoms in patients after gynecological tumor treatment. Tailor-made Kampo therapy may contribute to improve patients' physical and mental symptoms.

18.
Int J Cancer ; 142(5): 1056-1066, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29055044

RESUMO

Glypican-1 (GPC1) is highly expressed in solid tumors, especially squamous cell carcinomas (SCCs), and is thought to be associated with disease progression. We explored the use of a GPC1-targeted antibody-drug conjugate (ADC) as a novel treatment for uterine cervical cancer. On immunohistochemical staining, high expression levels of GPC1 were detected in about 50% of uterine cervical cancer tissues and also in a tumor that had relapsed after chemoradiotherapy. Novel anti-GPC1 monoclonal antibodies were developed, and clone 01a033 was selected as the best antibody for targeted delivery of the cytotoxic agent monomethyl auristatin F (MMAF) into GPC1-positive cells. The anti-GPC1 antibody was conjugated with MMAF. On flow cytometry, HeLa and ME180 cervical cancer cells highly expressed GPC1, however, RMG-I ovarian clear cell cancer cell line showed weak expression. The GPC1-ADC was rapidly internalized into GPC1-expressing cells in vitro and was potently cytotoxic to cancer cells highly expressing GPC1. There were no inhibitory effects on cancer cells with low expression of GPC1. In a murine xenograft model, GPC1-ADC also had significant and potent tumor growth inhibition. GPC1-ADC-mediated G2/M phase cell cycle arrest was detected, indicating that the dominant antitumor effect in vivo was MMAF-mediated. The toxicity of GPC-ADC was tolerable within the therapeutic dose range in mice. Our data showed that GPC1-ADC has potential as a promising therapy for uterine cervical cancer.


Assuntos
Anticorpos Monoclonais/química , Carcinoma de Células Escamosas/tratamento farmacológico , Glipicanas/imunologia , Imunoconjugados/uso terapêutico , Terapia de Alvo Molecular , Oligopeptídeos/química , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Feminino , Glipicanas/antagonistas & inibidores , Humanos , Imunoconjugados/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Prognóstico , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
19.
Int J Clin Oncol ; 23(1): 104-113, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28951992

RESUMO

OBJECTIVE: We retrospectively investigated the prognostic significance and clinical utility of pretreatment neutrophilia and elevated neutrophil-lymphocyte ratio (NLR) in patients with epithelial ovarian cancer. METHODS: Clinical data were collected from 344 surgically staged ovarian cancer patients between April 2007 and March 2016 and retrospectively reviewed. Neutrophilia and elevated NLR were defined as a neutrophil count ≥ 8,000/µl and an NLR ≥ 4.0, respectively. Univariate or multivariate analysis was conducted to evaluate the association between pretreatment neutrophilia or elevated NLR and clinicopathological characteristics, optimal surgery rate, progression-free survival (PFS) and disease-specific survival (DSS). Finally, we compared the clinical utility between neutrophil count and NLR by receiver operating characteristic (ROC) analysis. RESULTS: Pretreatment neutrophilia and elevated NLR were observed in 24 (7.0%) and 142 (41.3%) patients, respectively. In univariate analysis, both neutrophilia and elevated NLR were found to be associated with short PFS and DSS (p < 0.005). Multivariate analysis showed that neutrophilia and elevated NLR were predictors for shorter survival. In ROC analysis, the NLR tended to have a greater area under the ROC curve (AUC) value than the neutrophil count in predicting recurrence (0.7011 vs 0.6516, p = 0.0546) and had a significantly greater AUC value in predicting DSS (0.7249 vs 0.6379, p = 0.0182). Finally, based on the neutrophil count and NLR, we divided the patients into 3 prognostic groups-high-risk group (elevated NLR with neutrophilia), intermediate-risk group (elevated NLR without neutrophilia), and low-risk group (normal NLR), which allows for individualized and accurate survival estimates. CONCLUSIONS: Pretreatment neutrophilia and elevated NLR are independent poor prognostic factors in epithelial ovarian cancer patients. The NLR was superior to neutrophil count in predicting the survival of epithelial ovarian cancer patients.


Assuntos
Contagem de Leucócitos , Transtornos Leucocíticos/etiologia , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/mortalidade , Neutrófilos/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Transtornos Leucocíticos/mortalidade , Contagem de Linfócitos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco
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