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Invasive ability of the ME180-GCSF or ME180-control cells in vitro.

Clinicopathological characteristics of cervical cancer and endometrial cancer patients.

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.

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., Modern imaging techniques can detect cancer cells in the lymph nodes of cancer patients. In this study, the authors show that tumour related leukocytosis, a phenomenon where leukocytes are increased in number, can lead to the false positive detection of cancer cells in lymph nodes.

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.

// Hiromasa Kuroda 1, * , Seiji Mabuchi 1, * , Eriko Yokoi 1, * , Naoko Komura 1 , Katsumi Kozasa 1 , Yuri Matsumoto 1 , Mahiru Kawano 1 , Ryoko Takahashi 1 , Tomoyuki Sasano 1 , Kotaro Shimura 1 , Michiko Kodama 1 , Kae Hashimoto 1 , Kenjiro Sawada 1 , Eiichi Morii 2 and Tadashi Kimura 1 1 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan 2 Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan * These authors contributed equally to this work Correspondence to: Seiji Mabuchi, email: smabuchi@gyne.med.osaka-u.ac.jp Keywords: MDSC; CSC; prostaglandin E2; cervical cancer; celecoxib Received: April 13, 2018 Accepted: October 24, 2018 Published: November 20, 2018 ABSTRACT 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.

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.

Aska Toda, Kenjiro Sawada, Akihiko Yoshimura, Erika Nakatsuka, Hiromasa Kuroda, Katsumi Kozasa, Mayuko Miyamoto, Kae Hashimoto, Seiji Mabuchi, Tadashi Kimura Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan 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

We retrospectively investigated the prognostic significance and clinical utility of pretreatment neutrophilia and elevated neutrophil–lymphocyte ratio (NLR) in patients with epithelial ovarian cancer. 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. 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

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.

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 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.

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.

The aim of this study was to identify prognostic factors and establish a model for predicting life expectancy in International Federation of Gynecology and Obstetrics stage IVB cervical cancer patients.The baseline characteristics and outcome data of patients with stage IVB cervical cancer between May 1994 and October 2014 were collected and retrospectively reviewed. A Cox proportional hazards regression model was used to identify independent predictors of survival in stage IVB cervical cancer patients.A total of 107 patients were included in our database. The median overall survival (OS) period was 16 months. Multivariate analysis revealed that the metastatic site (hazards ratio, 3.09; 95% confidence interval, 1.94-4.88; P0.0001) and a white blood cell (WBC) count exceeding 10,000/μL (hazards ratio, 2.02; 95% confidence interval, 1.19-3.30; P = 0.0102) were significant prognostic factors in terms of OS. Patient survival was inversely correlated with the number of these prognostic factors possessed. When the patients were divided into 3 prognostic groups, the median OS of the patients with 0, 1, or 2 poor prognostic factors was 26, 12, and 7 months, respectively. Among the patients with WBC counts of less than 10,000/μL, treatment with radiotherapy resulted in improved survival compared with chemotherapy or palliative care alone. In contrast, radiotherapy had minimal effects on survival in patients with WBC counts of greater than 10,000/μL.The metastatic site and an elevated WBC count are significant prognostic factors in patients with stage IVB cervical cancer. Our prognostic model composed of these 2 clinical variables might enable physicians to predict survival more accurately.

•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.

The aim of this study is to investigate the significance of lymphatic space invasion (LSI) and tumor VEGF-C expression in the lymphatic spread of ovarian cancer. By performing immunostaining using human ovarian cancer specimens, we first investigated the association between the extent of LSI and tumor VEGF-C expression, tumor lymphangiogenesis, or the lymphatic metastasis. Moreover, by performing in vitro and in vivo experiments, we elucidated the role of VEGF-C in tumor lymphangiogenesis and lymph node metastasis as well as its role as a therapeutic target in ovarian cancer. The presence of LSI was associated with lymph node metastasis in patients with ovarian cancer. VEGF-C overexpression was significantly associated with the increased LSI and LVD in ovarian cancer. VEGF-C stimulated the lymphangiogenesis in vitro, induced the new lymph vessel formation, and increased the lymph node metastasis in mice models of ovarian cancer. The attenuation of VEGF-C expression by the treatment with mTORC1 inhibitor significantly inhibited lymphangiogenesis, and decreased lymph node metastasis in mice models of ovarian cancer. The presence of LSI is an indicator of nodal metastasis and is associated with higher tumor VEGF-C expression and worse clinical outcome of ovarian cancer patients. VEGF-C plays a crucial role in tumor lymphangiogenesis and lymph node metastasis of ovarian cancer.

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.

// Katsumi Kozasa 1 , Seiji Mabuchi 1 , Naoko Komura 1 , Eriko Yokoi 1 , Kuroda Hiromasa 1 , Tomoyuki Sasano 1 , Mahiru Kawano 1 , Yuri Matsumoto 1 , Eiji Kobayashi 1 and Tadashi Kimura 1 1 Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Correspondence to: Seiji Mabuchi, email: smabuchi@gyne.med.osaka-u.ac.jp Keywords: cervical cancer, thrombocytosis, survival, platelet count, platelet-lymphocyte ratio Received: April 11, 2017 Accepted: July 12, 2017 Published: July 25, 2017 ABSTRACT 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.

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.

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.

There are no guidelines about the selection of recurrent cervical cancer patients for salvage surgery. 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. 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. 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.

ObjectiveThe aim of this study was to investigate the prevalence and prognostic significance of an elevated platelet count at the time of the initial diagnosis in patients with cervical cancer who are treated with definitive radiotherapy.MethodsThe baseline characteristics and outcome data of cervical cancer patients who were treated with definitive radiotherapy between November 1993 and December 2011 were collected and retrospectively reviewed. The patients were separated into 2 groups according to their platelet counts. The clinicopathological characteristics and overall survival rates of the 2 groups were compared. A Cox proportional hazards regression model was used to investigate the prognostic significance of an elevated platelet count.ResultsAn elevated platelet count was found to be associated with younger age (P = 0.0003), an advanced clinical stage (P < 0.0001), larger tumors (P = 0.0025), lower hemoglobin levels (P < 0.0001), and more frequent treatment failure (P = 0.0015). Multivariate analysis demonstrated that an advanced clinical stage (hazards ratio [HR], 2.93; 95% confidence interval [CI], 1.47–6.70; P = 0.0015), nonsquamous cell carcinoma histology (HR, 2.67; 95% CI, 1.52–4.42; P = 0.0011), larger tumors (HR, 3.86; 95% CI, 2.18–7.03; P < 0.0001), lower hemoglobin levels (HR, 1.99; 95% CI, 1.34–2.93; P = 0.0008), and an elevated platelet count (HR, 1.65; 95% CI, 1.03–2.56; P = 0.0395) were significant predictors of survival.ConclusionsAn elevated platelet count at the time of the initial diagnosis is an independent prognostic factor in cervical cancer patients who are treated with definitive radiotherapy.

Granulocyte-colony stimulating factor (G-CSF) producing malignant tumor has been reported to occur in various organs and has been associated with poor clinical outcome. The aim of this study is to investigate the significance of tumor G-CSF expression in the chemosensitivity of uterine cervical cancer. The clinical data of recurrent or advanced cervical cancer patients who were treated with platinum-based chemotherapy were analyzed. Clinical samples, cervical cancer cell lines and a mouse model of cervical cancer were employed to examine the mechanisms responsible for the development of chemoresistance in G-CSF-producing cervical cancer, focusing on myeloid-derived suppressor cells (MDSC). As a result, the tumor G-CSF expression was significantly associated with increased MDSC frequencies and compromised survival. In vitro and in vivo experiments demonstrated that the increased MDSC induced by tumor-derived G-CSF is involved in the development of chemoresistance. The depletion of MDSC via splenectomy or the administration of anti-Gr-1 antibody sensitized G-CSF-producing cervical cancer to cisplatin. In conclusion, tumor G-CSF expression is an indicator of an extremely poor prognosis in cervical cancer patients that are treated with chemotherapy. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy as a treatment for G-CSF-producing cervical cancer.

The aim of this study was to investigate the prognostic significance of an elevated neutrophil count at the time of the initial diagnosis in patients with surgically treated endometrial cancer.The baseline characteristics and outcome data of patients who were diagnosed with endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into two groups according to their neutrophil counts. The clinicopathological characteristics and overall survival rates of the two groups were compared. A Cox proportional hazard regression model was used to investigate the prognostic significance of an elevated neutrophil count among patients with surgically treated endometrial cancer.An elevated neutrophil count was found to be associated with an advanced clinical stage (P0.0001), lymphovascular space involvement (P=0.0003), cervical involvement (P=0.0049), the proportion of patients that received adjuvant therapy (P=0.0020), elevated NLR (P0.0001), and treatment failure (P0.0001). Multivariate analyses demonstrated that age (hazard ratio (HR)=2.23, 95% confidence interval (95% CI)=1.30 to 3.91; P=0.0035), clinical stage (HR=4.72, 95% CI=2.61 to 8.90; P0.0001), lymphovascular space involvement (HR=3.15, 95% CI=1.60 to 6.68; P=0.0007), an elevated neutrophil count (HR=2.76, 95% CI=1.43 to 5.03; P=0.0033), and an elevated white blood cell count (HR=2.79, 95% CI=1.50 to 4.96; P=0.0017) were significant predictors of survival.The elevated neutrophil or leukocyte counts at the time of the initial diagnosis are independent prognostic factors in patients with surgically treated endometrial cancer.

Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype. Methods Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy. Results Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies. Conclusions Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment.

Objectives:Lurbinectedin is a marine-derived covalent DNA minor groove binder and is structurally similar to trabectedin except for the C subunit. Lurbinectedin (PM01183) is a newly developed antitumor agent that is currently being investigated in phase I/II clinical trials in patients with solid tumors including ovarian cancer. The objective of this study is to investigate the effectiveness of lurbinectedin as a single agent or as combination with existing antitumor agent against ovarian clear cell carcinoma which is regarded as an aggressive chemoresistant histological subtype. Methods:Using human ovarian clear cell carcinoma cell lines, the anti-tumor effects of lurbinectedin, SN38, topotecan, doxorubicin, cisplatin and paclitaxel as single agent were assessed by MTS assay. Then the cytotoxicities of combination treatments involving lurbinectedin and 1 of the 4 agents were evaluated by isobologram analysis to examine which of these combinations displayed synergistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant ovarian clear cell carcinoma sublines, which were derived from the parental clear cell carcinoma cells by continuously exposing them to cisplatin or paclitaxel. Finally, using nude mice inoculated with clear cell carcinoma cells, we examined the growth-inhibitory effect of lurbinectedin in vivo. Results:Lurbinectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that lurbinectedin significantly inhibits tumor growth. Concurrent exposure to lurbinectedin and SN-38 resulted in synergistic interactions in CCC cell lines. The combination of lurbinectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of single agent lurbinectedin and combination of lurbinectedin plus SN-38. Conclusions:Lurbinectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, lurbinectedin combined with irinotecan may be more efficacious for the management of CCC. Citation Format: Ryoko Takahashi, Seiji Mabuchi, Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Hiromasa Kuroda, Katsumi Kozasa, Kenjirou Sawada, Tadashi Kimura. Antitumor activity of lurbinectedin toward ovarian clear cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1642. doi:10.1158/1538-7445.AM2015-1642

// Katsumi Kozasa 1 , Seiji Mabuchi 1 , Yuri Matsumoto 1 , Hiromasa Kuroda 1 , Eriko Yokoi 1 , Naoko Komura 1 , Mahiru Kawano 1 , Ryoko Takahashi 1 , Tomoyuki Sasano 1 , Kotaro Shimura 1 , Michiko Kodama 1 , Kae Hashimoto 1 , Kenjiro Sawada 1 , Kazunori Nagasaka 2 and Tadashi Kimura 1 1 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan 2 Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo, Japan Correspondence to: Seiji Mabuchi, email: smabuchi@gyne.med.osaka-u.ac.jp Keywords: MDSC; estrogen; cervical cancer; brest cancer; pregnancy Received: January 07, 2019 Accepted: February 09, 2019 Published: March 08, 2019 ABSTRACT Objective: To investigate the clinical implications of 17β-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.

Background The purpose of this study is to report our clinical outcomes using intensity-modulated radiation therapy (IMRT) for adjuvant treatment of cervical cancer, compared with three-dimensional conformal radiation therapy (3DCRT), in terms of tumor control, complications and dose-volume histogram (DVH) parameters. Methods Between March 2008 and February 2014, 62 patients were treated with concurrent nedaplatin-based chemotherapy and whole-pelvic external beam radiation therapy (RT). Of these patients, 32 (52 %) received 3DCRT and 30 (48 %) received IMRT. Results The median follow-up periods were 40 months (range 2–74 months). The 3-year overall survival rate (OS), locoregional control rate (LRC) and progression-free survival rate (PFS) were 92, 95 and 92 % in the IMRT group, and 85, 82 and 70 % in the 3DCRT group, respectively. A comparison of OS, LRC and PFS showed no significant differences between IMRT and 3DCRT. The 3-year cumulative incidences of grade 2 or higher chronic gastrointestinal (GI) complications were significantly lower with IMRT compared to 3DCRT (3 % vs. 45 %, p 340 mL (3 % vs. 45 %, p