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1.
Sci Rep ; 11(1): 2257, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33500424

RESUMO

We investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(18F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer.


Assuntos
Medula Óssea/metabolismo , Fluordesoxiglucose F18/farmacocinética , Neoplasias dos Genitais Femininos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Aorta/metabolismo , Linhagem Celular Tumoral , Feminino , Neoplasias dos Genitais Femininos/diagnóstico por imagem , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Análise Multivariada , Células Supressoras Mieloides/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Intervalo Livre de Progressão , Ratos
2.
J Surg Case Rep ; 2020(12): rjaa506, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33365120

RESUMO

Peritoneal inclusion cysts (PICs) often develop in post-operative patients. Since the incidence of adhesions is lower with laparoscopic surgery than with open surgery, PICs are less likely to occur in the former. Although post-operative adhesions or PICs rarely develop after laparoscopic surgery (such as total laparoscopic hysterectomy: TLH), we encountered two cases of giant PICs with abdominal pain after TLH. In Case 1, strong adhesion was already present when TLH was performed. Therefore, this case may have been predisposed to the development of adhesions in the abdominal cavity. However, no adhesions were observed during TLH in case 2, and there were no risk factors, such as pre-operative adhesions and endometriosis. Therefore, adhesions and PICs may develop even after TLH, and approaches need to be considered for their prevention.

3.
Gynecol Oncol Rep ; 34: 100642, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33015277

RESUMO

•Malignant peritoneal mesothelioma, particularly the sarcomatoid type, is rare and aggressive.•Accurate diagnosis by ascites cytology is difficult.•Histological examination such as laparoscopy aids in diagnosis.•There is no clear consensus treatment for MPM and an extensive research program is needed.

4.
Cancer Immunol Immunother ; 69(12): 2477-2499, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32561967

RESUMO

The aim of this study was to investigate the role of myeloid-derived suppressor cells (MDSC) in the induction of cancer stem-like cells (CSC) and programmed death ligand 1 (PD-L1) expression in ovarian cancer. CSC were defined as tumor cells expressing high levels of aldehyde dehydrogenase 1 (ALDH 1). We inoculated G-CSF-expressing or Mock-expressing ovarian cancer cells into mice, and the frequencies of MDSC and CSC in tumors of these models were compared by flow cytometry. To directly demonstrate the role of MDSC in the induction of CSC and the increase in PD-L1 expression, we performed in vitro co-culture. MDSC and CSC (ALDH-high cells) were more frequently observed in G-CSF-expressing cell-derived tumors than in Mock-expressing cell-derived tumors. Co-culture experiments revealed that MDSC increased the number of CSC via the production of PGE2. Moreover, PGE2 produced by MDSC increased tumor PD-L1 expression via the mammalian target of rapamycin (mTOR) pathway in ovarian cancer cells. In an in vitro experiment in which ovarian cancer cells were co-cultured with MDSC, higher expression of PD-L1 was observed in CSC than in non-CSC (ALDH-low cells). Furthermore, by immunofluorescence staining, we found that PD-L1 was co-expressed with ALDH1 in in vivo mouse models. In conclusion, PGE2 produced by MDSC increases the stem cell-like properties and tumor PD-L1 expression in epithelial ovarian cancer. Depleting MDSC may be therapeutically effective against ovarian cancer by reducing the number of CSC and tumor PD-L1 expression.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Epitelial do Ovário/imunologia , Células Supressoras Mieloides/imunologia , Células-Tronco Neoplásicas/imunologia , Neoplasias Ovarianas/imunologia , Família Aldeído Desidrogenase 1/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/imunologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Dinoprostona/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Camundongos , Pessoa de Meia-Idade , Células Supressoras Mieloides/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nat Commun ; 11(1): 1364, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170086

RESUMO

The accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) can be influenced by the increased glycolytic activity of inflammatory lesions. Here, using clinical data obtained from gynecological cancer patients, tumor samples and animal models, we investigate the impact of pretreatment tumor-related leukocytosis (TRL) on the diagnostic performance of 18F-FDG-PET/CT in detecting pelvic and paraaortic lymph node metastasis. We demonstrate that pretreatment TRL misleads 18F-FDG-PET/CT during lymph node staging in gynecological malignancies. In the mechanistic investigations, we show that the false-positive 18F-FDG-PET/CT result for detecting nodal metastasis can be reproduced in animal models of TRL-positive cancer bearing G-CSF expressing cervical cancer cells. We also show that increased 18F-FDG uptake in non-metastatic nodes can be explained by the MDSC-mediated premetastatic niche formation in which proinflammatory factors, such as S100A8 or S100A9, are abundantly expressed. Together, our results suggest that the MDSC-mediated premetastatic niche created in the lymph node of TRL-positive patients misleads 18F-FDG-PET/CT for detecting nodal metastasis.


Assuntos
Leucocitose/patologia , Linfonodos/patologia , Neoplasias/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Fluordesoxiglucose F18 , Humanos , Leucocitose/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/patologia
6.
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.

7.
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.

8.
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.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias do Colo do Útero/prevenção & controle , Animais , Apoptose , Proliferação de Células , Cisplatino/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
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. .

10.
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.

11.
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
12.
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
13.
Int J Womens Health ; 9: 821-825, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29180905

RESUMO

BACKGROUND: In clinical practice, patients with postmenopausal osteoporosis have often shown a poor response to treatment with an antiresorptive agent for several years. The purpose of this study was to investigate the efficacy of switching raloxifene with minodronate in patients who responded poorly to the treatment of postmenopausal osteoporosis with raloxifene. PATIENTS AND METHODS: This observational study was conducted based on a single-arm, non-randomized, open-label design and was approved by the institute's institutional review board. Postmenopausal women with osteoporosis who became unresponsive in terms of bone mineral density (BMD) after being administered raloxifene for two or more years were enrolled. Patients were treated with 1 mg minodronate daily or 50 mg minodronate monthly. Changes in BMD and serum bone turnover markers were monitored at baseline, 6, 12, and 24 months after switching treatment. RESULTS: Twenty-seven patients were enrolled. Two discontinued treatment because of adverse events related to the study drug. Among the remaining 25 patients, lumbar BMD significantly increased by 3.67%, 5.08%, and 6.97% at 6, 12, and 24 months, respectively, and femoral neck BMD increased by 1.63%, 2.18%, and 3.85% at 6, 12, and 24 months, respectively. Serum bone-specific alkaline phosphatase showed a significant reduction of 30.35% from the baseline (p<0.0001) within the first 6 months, suggesting a stronger antiresorptive effect of minodronate. Serum N-terminal telopeptide of type I collagen showed a tendency to decrease. CONCLUSION: Switching raloxifene with minodronate is effective in poor responders of osteoporosis treatment and should be considered as one of the treatment options for osteoporosis.

14.
Oncotarget ; 8(33): 55394-55404, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903428

RESUMO

OBJECTIVE: To compare the clinical utilities of the platelet count and platelet-lymphocyte ratio (PLR) for predicting survival in patients with cervical cancer. RESULTS: Multivariate analyses demonstrated that thrombocytosis and elevated PLR were found to be independent prognostic factors for progression-free survival (PFS, P = 0.0077, P = 0.044) and overall survival (OS, P = 0.025, P = 0.019) in separate Multivariate analyses. In the ROC analysis, the platelet count showed a significantly greater area under the ROC curve (AUC) value than that of PLR for predicting patient recurrence (0.5941 versus 0.5331, p = 0.018) and survival (0.6139 versus 0.5468, p = 0.029). In patients without thrombocytosis, elevated PLR correlated with shorter survival (PFS, P = 0.041; OS, P = 0.017). In contrast, PLR in patients with thrombocytosis did not provide prognostic information. We divided patients into 3 prognostic groups using platelet counts and PLR: high-risk (thrombocytosis with any PLR); intermediate-risk (elevated PLR without thrombocytosis); low-risk (none of the above), which allowed for individualized and accurate survival estimates. MATERIALS AND METHODS: The baseline characteristics and clinical outcomes of cervical cancer patients were identified. Patients were grouped according to their pretreatment platelet counts or PLR, and clinicopathological characteristics and patient survival were then compared between these groups. The clinical utilities of the platelet count and PLR were compared using a time-dependent receiver operating characteristic (ROC) analysis. CONCLUSIONS: Pretreatment thrombocytosis and elevated PLR were identified as independent predictors in cervical cancer patients. Platelet counts were superior to PLR for predicting the prognosis of uterine cervical cancer patients. Our prognostic model consisting of platelet counts and PLR offers individualized survival estimates.

15.
Immunotherapy ; 9(10): 805-817, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28877631

RESUMO

AIM: To evaluate the ability of PM01183 to eliminate myeloid-derived suppressor cells (MDSCs). MATERIALS & METHODS: The effect of PM01183 on MDSCs, NK cells and CD8+ T cells was examined in vitro and in vivo. The mechanism by which PM01183 depletes MDSCs was also investigated. RESULTS: PM01183 reduced the number of MDSCs by inducing apoptosis and attenuated the MDSC-mediated suppression of CD8+ T cells by inhibiting arginase-1 production, whereas no significant effect on CD8+ T or NK cells was noted. The inhibitory effect of PM01183 on MDSC was mediated by the attenuation of STAT3 phosphorylation. The inhibitory effect of PM01183 on MDSCs was greater than those of existing anticancer agents. CONCLUSION: PM01183 exhibits strong inhibitory effects on MDSCs.


Assuntos
Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Carbolinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Células Matadoras Naturais/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Arginase/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Terapia de Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Supressoras Mieloides/fisiologia , Fosforilação , Fator de Transcrição STAT3/metabolismo
16.
Int J Gynaecol Obstet ; 139(2): 185-191, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28755426

RESUMO

OBJECTIVE: To evaluate the safety and efficacy of radical hysterectomy after radiotherapy (RH-AR) for recurrent or persistent cervical cancer. METHODS: The present retrospective study included patients who underwent RH-AR for recurrent or persistent cervical cancer at Osaka University Hospital, Japan, between May 1, 2010 and September 30, 2016. Patient characteristics, intraoperative and postoperative adverse events, and surgical outcomes were investigated to identify patients at increased risk of recurrence or severe surgical adverse events. RESULTS: There were 31 patients scheduled for treatment with RH-AR; one hysterectomy procedure was aborted. No intraoperative adverse events or treatment-related deaths occurred, and 8 (27%) patients experienced severe postoperative adverse events. After a median 34 months of follow-up, 13 (43%) patients had developed recurrent disease, predominantly at distant sites. The estimated 3-year overall survival rate was 53.8%. Positive surgical margins, nodal metastasis, parametrial invasion, and no adjuvant treatment after RH-AR were found to be predictors of increased risk of recurrence. No predictors of severe surgical adverse events were identified. CONCLUSION: RH-AR was a safe, curative treatment for patients with recurrent or persistent cervical cancer. However, considering the significant risk of surgical adverse events, RH-AR should only be performed for a select group of patients.


Assuntos
Histerectomia , Recidiva Local de Neoplasia/cirurgia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Terapia Combinada , Feminino , Humanos , Japão/epidemiologia , Excisão de Linfonodo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Complicações Pós-Operatórias , Radioterapia Adjuvante , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
17.
Int J Gynecol Cancer ; 27(7): 1399-1407, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28604454

RESUMO

OBJECTIVE: The aim of this study was to investigate the prognostic significance of a pretreatment thrombocytosis and its association with neutrophilia in patients with surgically treated endometrial cancer. METHODS: The baseline characteristics and outcome data of 508 patients with surgically treated endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into 4 groups according to their platelet counts and the neutrophil counts, and the progression-free and overall survival rates of the 4 groups were compared. A Cox proportional hazards regression model was used to explore the independent prognostic factors. RESULTS: Pretreatment thrombocytosis was found to be associated with advanced stage (P = 0.0186), nonendometrioid histology (P = 0.0139), a deeper myometrial invasion (P = 0.0103), lymphovascular space involvement (P = 0.0404), cervical involvement (P = 0.004), positive peritoneal cytology (P = 0.0198), lymph node metastasis (P = 0.0301), and more frequent treatment failure (P = 0.0006). Multivariate analysis demonstrated that an older age (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.46-4.51; P = 0.0009), advanced clinical stage (HR, 5.27; 95% CI, 2.94-9.86; P < 0.0001), lymphovascular space involvement (HR, 3.37; 95% CI, 1.74-7.07; P = 0.0002), and pretreatment thrombocytosis (HR, 4.99; 95% CI, 2.47-9.39; P < 0.0001) were significant predictors of survival. When examined according to clinical stage, pretreatment thrombocytosis was prognostically significant only in patients with stage III-IV disease. The neutrophil count in patients who display thrombocytosis was significantly greater than that observed in patients without thrombocytosis (median, 6702 vs 4406/µL; P < 0.0001). Moreover, patients who displayed both thrombocytosis and neutrophilia had significantly shorter survival than that in those with either thrombocytosis or neutrophilia alone. CONCLUSIONS: Presence of thrombocytosis at the time of the initial diagnosis is an independent predictor of shorter survival in patients with advanced-stage (stages III-IV) endometrial cancer. Moreover, pretreatment thrombocytosis and concurrent neutrophilia are an independent predictor of shorter survival regardless of clinical stage.


Assuntos
Carcinoma Endometrioide/sangue , Carcinoma Endometrioide/cirurgia , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/cirurgia , Transtornos Leucocíticos/fisiopatologia , Neutrófilos/patologia , Trombocitose/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Histerectomia , Transtornos Leucocíticos/sangue , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Cuidados Pré-Operatórios , Prognóstico , Estudos Retrospectivos , Salpingo-Ooforectomia , Trombocitose/sangue , Adulto Jovem
18.
Int J Clin Oncol ; 22(5): 927-936, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28551815

RESUMO

BACKGROUND: There are no guidelines about the selection of recurrent cervical cancer patients for salvage surgery. METHODS: Patients who developed recurrent or persistent cervical cancer in a previously irradiated field and were subsequently treated with salvage surgery (the surgery group) or palliative care alone (the palliative group) were identified. Patient characteristics, treatment-related complications, and survival were retrospectively compared between the two groups. RESULTS: A total of 79 patients (surgery group, n = 51; palliative group, n = 28) were identified. In the surgery group, no intraoperative complications or treatment-related deaths occurred. Eleven patients (21.6%) experienced severe postoperative complications. After a median follow-up period of 41.5 months, 23 patients (45.1%) had developed recurrent disease, predominantly at distant sites, and 19 patients (37.3%) had died of disease progression. The estimated 3-year progression-free survival (PFS) and overall survival rates of the surgery group were 50.4 and 56.5%, respectively. In the palliative group, all of the patients died of disease progression. Positive surgical margins and lymph node metastasis were found to be independent prognostic factors for PFS in the surgery group. Among the patients with no or one poor prognostic factor, the patients in the surgery group survived significantly longer than those in the palliative group. However, among the patients with 2 poor prognostic factors, the surgery group and palliative group displayed similar survival periods. CONCLUSIONS: Salvage surgery is a curative treatment in recurrent or persistent cervical cancer patients. However, considering its high surgical complication rate, salvage surgery should only be offered to carefully selected patients.


Assuntos
Complicações Pós-Operatórias/etiologia , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Histerectomia/efeitos adversos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Cuidados Paliativos/métodos , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
19.
Gynecol Oncol ; 145(3): 469-475, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28552395

RESUMO

OBJECTIVE: The aim of this study was to investigate the prognostic significance of tumor-associated neutrophil (TAN) density in cervical cancer patients that were treated with definitive radiotherapy. METHODS: The baseline characteristics and outcome data of FIGO stages IB-IVA cervical cancer patients who were treated with definitive radiotherapy between January 1996 and December 2011 were collected. Using biopsy samples obtained at the time of the initial diagnosis, the expression levels of CD66b in the patients' cervical tumors were evaluated by immunohistochemistry. Univariate and multivariate analyses were performed to evaluate the relationships between intratumoral TAN density and various clinicopathological features as well as progression-free survival (PFS) in these patients. RESULTS: The CD66b-positive cells (TAN) were observed in 209 (83.6%) of 250 cervical cancer specimens. The TAN density was significantly associated with shorter PFS. Multivariate analysis identified an increased number of TAN (hazard ratio [HR]: 4.95; 95% confidence interval [CI]: 2.51-10.7; p<0.0001), FIGO stage IVB disease (HR: 2.64; 95% CI: 1.38-5.01; p=0.01), non-squamous cell carcinoma (SCC) histology (HR: 2.50; 95% CI: 1.23-4.64; p=0.01), larger tumors (HR: 1.58; 95% CI: 1.03-2.40; p=0.04), and pelvic lymph node metastasis (HR: 2.24; 95% CI: 1.48-3.38; p=0.0001) as independent prognostic factors for short PFS. CONCLUSION: Intratumoral TAN density is an independent prognostic factor for short PFS in cervical cancer patients treated with definitive radiotherapy.


Assuntos
Neutrófilos/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Braquiterapia , Moléculas de Adesão Celular/imunologia , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutrófilos/patologia , Neutrófilos/efeitos da radiação , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia
20.
J Gynecol Oncol ; 28(2): e19, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28028992

RESUMO

OBJECTIVE: To compare the survival outcomes of patients with cervical squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) among patients with locally advanced cervical cancer that were treated with definitive radiotherapy. METHODS: The baseline characteristics and outcome data of patients with locally advanced cervical cancer who were treated with definitive radiotherapy between November 1993 and February 2014 were collected and retrospectively reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of AC/ASC histology. RESULTS: The patients with AC/ASC of the cervix exhibited significantly shorter overall survival (OS) (p=0.004) and progression-free survival (PFS) (p=0.002) than the patients with SCC of the cervix. Multivariate analysis showed that AC/ASC histology was an independent negative prognostic factor for PFS. Among the patients who displayed AC/ASC histology, larger tumor size, older age, and incomplete response to radiotherapy were found to be independent prognostic factors. PFS was inversely associated with the number of poor prognostic factors the patients exhibited (the estimated 1-year PFS rates; 100.0%, 77.8%, 42.8%, 0.0% for 0, 1, 2, 3 factors, respectively). CONCLUSION: Locally advanced cervical cancer patients with AC/ASC histology experience significantly worse survival outcomes than those with SCC. Further clinical studies are warranted to develop a concurrent chemoradiotherapy (CCRT) protocol that is specifically tailored to locally advanced cervical AC/ASC.


Assuntos
Adenocarcinoma/mortalidade , Carcinoma Adenoescamoso/mortalidade , Carcinoma de Células Escamosas/mortalidade , Neoplasias do Colo do Útero/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Adenoescamoso/patologia , Carcinoma Adenoescamoso/radioterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Quimiorradioterapia , Cisplatino/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia
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