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To investigate the prognostic significance of pretreatment C-reactive protein (CRP), albumin, and the CRP to albumin ratio (CRP/Alb) in epithelial ovarian cancer (EOC) patients. Clinical data from 308 EOC patients between April 2007 and March 2016 were collected and retrospectively reviewed. The cutoff values for CRP, albumin, and CRP/Alb were defined by receiver operating characteristics (ROC) analyses. Univariate or multivariate analysis was conducted to evaluate the prognostic significance of these factors for disease-specific survival. The cutoff values for CRP, albumin, and CRP/Alb were 0.76, 3.8, and 0.048 by ROC analysis, respectively. Cox regression analyses demonstrated that an elevated CRP/Alb is an independent predictor of short disease-specific survival irrespective of clinical stage or optimal surgery rate. When examined according to clinical stage, elevated CRP/Alb was associated with short disease-specific survival in both early-stage and advanced-stage patients. Cox regression analyses demonstrated that an elevated CRP, but not lower albumin, is also an independent predictor of short disease-specific survival. When two prognosticators were compared, CRP/Alb was found to be superior to CRP for predicting disease-specific survival in EOC patients. Pretreatment elevated CRP/Alb is a predictor of shorter survival in EOC patients regardless of clinical stage.

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.

ObjectiveBoth 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.MethodsClinical 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.ResultsA 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 (pConclusionsThe 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.

// Naoko Komura 1 , Seiji Mabuchi 1 , Eriko Yokoi 1 , Kotaro Shimura 1 , Mahiru Kawano 1 , Yuri Matsumoto 1 and Tadashi Kimura 1 1 Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan Correspondence to: Seiji Mabuchi, email: smabuchi@gyne.med.osaka-u.ac.jp Keywords: ovarian cancer; prognostic nutritional index; clinical stage; survival; prognostic factor Received: July 23, 2018 Accepted: April 14, 2019 Published: June 04, 2019 ABSTRACT 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 mm 3 ) 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

ObjectivesWe 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.MethodsPatients 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.ResultsA 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.ConclusionS-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.

OBJECTIVE Turner syndrome (TS) is a congenital disease characterized by delayed puberty, ovarian dysgenesis and short stature. Although most patients are diagnosed with primary amenorrhea, approximately 15-20% of patients with TS are reported to have spontaneous menarche. However, little is known about their menstruation status after spontaneous menarche. In the current study, we investigated the menstrual abnormalities after spontaneous menarche in TS patients. DESIGN Retrospective study. PATIENTS This study included TS patients with spontaneous menarche at Osaka Police Hospital or Komura Women's Clinic between April 2015 and December 2019. MEASUREMENTS Data regarding the age of menarche, menstruation status and chromosomal karyotype were collected and retrospectively analyzed. RESULTS Of 172 TS patients, 32 with spontaneous menarche were identified. The median age of menarche was 12 years old. Premature ovarian insufficiency (POI) after menarche was observed in 12 patients (37.5%) and the median age at menopause was 20 years old. The average period from spontaneous menarche to menopause in these patients was 5.1 years. Five patients (15.6%) had irregular menstruation and 15 (46.9%) had regular menstruation. When examined according to the structural abnormality of the X chromosome, all patients with structural abnormality of the X chromosome were diagnosed with POI after spontaneous menarche, and none with mosaic without structural abnormality were diagnosed with POI. CONCLUSION Approximately one-third of TS patients with spontaneous menarche were diagnosed with POI after menarche for an average of 5.1 years. Counseling is required for TS patients and their parents, including information about menstrual abnormalities or fertility preservation.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that exhibit immunosuppressive activity. They also directly stimulate tumor cell proliferation, metastasis, and angiogenesis. In ovarian cancer, there are increased numbers of circulating or tumor-infiltrating MDSCs, and increased frequencies of MDSCs are associated with a poor prognosis or an advanced clinical stage. Moreover, in murine models of ovarian cancer, MDSC depletion has shown significant growth-inhibitory effects and enhanced the therapeutic efficacy of existing anticancer therapies. In this review, we summarize the current knowledge on MDSC biology, clinical significance of MDSC, and potential MDSC-targeting strategies in ovarian cancer.

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.

OBJECTIVE To investigate the impact of incorporating pretreatment leukocytosis and/or thrombocytosis in the FIGO staging system on prognostic prediction among women with surgically treated endometrial cancer. METHODS Retrospective review of clinical data from 900 women with endometrial cancer treated at Osaka University Hospital, Japan, between 2000 and 2016. The effect of concurrent leukocytosis and thrombocytosis on the prediction of recurrence and survival outcomes was evaluated via receiver operating characteristic (ROC) curve analysis and the Kaplan-Meier method. RESULTS Among 678 women with Stage I-III disease, pretreatment leukocytosis or thrombocytosis alone were not prognostic indicators, but concurrent pretreatment leukocytosis and thrombocytosis was associated with significantly shorter survival (PFS, P

// 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.

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

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.

The appropriate interval of post-treatment follow-up appointments for uterine cervical cancer is unclear. The aim of this study was to investigate the impact of reducing the frequency of post-treatment follow-up examinations on life expectancy and medical expenses in cervical cancer patients. Cervical cancer patients who were treated with radiotherapy between 2008 and 2017, underwent a less frequent follow-up program, and subsequently developed recurrent disease were included in consecutive group (CG). Non-randomized groups of cervical cancer patients who underwent a frequent follow-up program after radiotherapy between 1997 and 2007, and subsequently developed recurrent disease were also identified through a chart review and served as a comparison group (primary group [PG]). Clinical data regarding the primary disease, follow-up, recurrence, and survival were collected. Univariate and multivariate analyses of predictors of survival were performed. A total of 263 recurrent cervical cancer patients (PG: 154, CG: 109) were included in the current study. A reduction in follow-up frequency of up to 40% did not increase the frequency of symptomatic recurrence (PG: vs. CG: 31.2% vs. 35.8%, p = 0.43) or reduce the median overall survival periods of recurrent cervical cancer patients (PG vs. CG: 32 months vs. 36 months, p = 0.15). However, the reduction in the follow-up frequency significantly reduced follow-up costs. Reducing the frequency of follow-up by up to 40% did not result in shorter overall survival compared with a conventional follow-up program. The results of this study provide a rationale for future studies investigating the optimal follow-up schedule for patients with cervical cancer.

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.

Background Denosumab is a major treatment option for patients with postmenopausal osteoporosis; however, the evidence for its use is lacking. Therefore, in this 24-month retrospective study, we aimed to evaluate the effects of switching from minodronate (MIN) to denosumab in these patients. Methods Patients with postmenopausal osteoporosis either switched from MIN to denosumab (Group 1; n = 32) or continued MIN treatment (Group 2; n = 24). Bone mineral density (BMD) of the lumbar spine (L2–L4) and femoral neck was assessed at baseline and every 6 months for 24 months. Serum bone-specific alkaline phosphatase (BAP) and N-terminal telopeptide were measured at baseline, 12 months, and 24 months. Results Twenty-nine of the 32 patients (90.6%) in group 1 and all patients (24/24) in group 2 completed the 24-month follow-up. Switching from MIN to denosumab (Group 1) significantly increased lumbar BMD at 12, 18, and 24 months (6.1, 7.4, and 9.6%, respectively) and femoral neck BMD at 12, 18, and 24 months (2.8, 3.2, and 3.4%, respectively), whereas MIN continuous treatment (Group 2) showed no significant difference from baseline. Switching therapy also showed a significant decrease in serum BAP from baseline to 12 and 24 months (− 19.3 and − 26.5%, respectively) and serum NTX from baseline to 12 months (− 13.1%), whereas continuous MIN treatment failed to show any significant differences from baseline. Conclusion Switching from MIN to denosumab in patients with postmenopausal osteoporosis showed clinical benefits with regard to BMD and bone turnover markers in comparison with continuous MIN treatment. It may therefore be a valid treatment option in the clinical setting.

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.

Malignant primary tumors arising in the uterine broad ligament are extremely rare, and only 26 cases have been reported to date. We describe 2 new cases of primary adenocarcinoma of the broad ligament, and we review the previous literature on such rare tumors. In Case 1, a 71-year-old woman presented with a 2-month history of increased yellow vaginal discharge and lower abdominal pain during bowel movement. Transvaginal sonography revealed a 6.5 cm mass located on the dorsum of the uterus and a 7.0 cm mass (with cystic and solid parts) near the right adnexa. We postoperatively diagnosed the mass as a high-grade serous carcinoma of the broad ligament (pT3cNXM0). The patient is currently receiving adjuvant chemotherapy with paclitaxel and carboplatin. In Case 2, during a complete medical checkup a 43-year-old woman was found to have a pelvic mass indicative of leiomyoma. Transvaginal sonography revealed a 3.8 cm mass located on the dorsum of the uterus. Following surgery, we diagnosed the mass as a clear cell adenocarcinoma of the broad ligament (pT2bN1M0). This patient is also now receiving adjuvant chemotherapy with paclitaxel and carboplatin.

Borderline ovarian tumors are benign but relatively large tumors that are often initially mistaken as ovarian cancers. We report three cases of stage I borderline ovarian tumors having massive ascites that we (preoperatively) suspected of being advanced ovarian cancer. The three patients (35, 47, and 73 years old) reported feeling fullness of the abdomen before consulting their gynecologist. By CT scan, they were diagnosed with a pelvic tumor accompanied by massive ascites, the diameters of which were 11, 20, and 11 cm, respectively. Postsurgical pathology showed all were stage I borderline ovarian tumors without dissemination; two were mucinous and one was serous. The amount of ascites was 6,300, 2,600, and 3,600 mL, respectively, and was serous in all. Cytodiagnosis of the ascites found that one was positive for tumor cells and two were negative. After resection of the mass, the ascites disappeared in all three cases. No pleural effusion was present at any time. The literature is reviewed concerning ascites and pleural effusions linked to ovarian tumors, and a supposition is forwarded of why pleural effusion presents sporadically in these cases.

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.

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.

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.

Wikipedia is one of the largest online collaborative projects. At present the multi-lingual encyclopedia is the fifth most popular website and contains more than 13 million articles in 271 languages. The technical barriers to contribution, however, remain quite high. This paper describes the qualitative research and design methods used in our efforts to identify and reduce those barriers to participation for non-editors and measurably increase their ability to contribute to the project

// 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.