The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer.

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.

Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer.

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.

Pre-treatment prognostic nutritional index is superior to platelet count in predicting disease-specific survival in patients with epithelial ovarian cancer.

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

A phase II study of irinotecan combined with S-1 in patients with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy.

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

Radiotherapy for isolated recurrent epithelial ovarian cancer: A single institutional experience.

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.

Myeloid-derived suppressor cells and their role in gynecological malignancies.

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.

Comparison of clinical utility between neutrophil count and neutrophil-lymphocyte ratio in patients with ovarian cancer: a single institutional experience and a literature review.

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.

The significance of tumor-associated neutrophil density in uterine cervical cancer treated with definitive radiotherapy.

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.

The Significance of Pretreatment Thrombocytosis and Its Association With Neutrophilia in Patients With Surgically Treated Endometrial Cancer.

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.

The efficacy of surgical treatment of recurrent or persistent cervical cancer that develops in a previously irradiated field: a monoinstitutional experience.

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.

Predictors of distant relapse in patients with FIGO stage IIB-IVA cervical cancer treated with definitive radiotherapy.

AIM: To investigate the predictors of distant relapse in International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IVA cervical cancer patients treated with definitive radiotherapy (RT). METHODS: The clinical data of 219 patients with FIGO stage IIB-IVA cervical cancer treated with definitive RT between January 1997 and December 2011 were retrospectively reviewed. The cumulative distant relapse, progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards regression model was used to investigate the predictors of distant relapse in patients. RESULTS: Following treatment with definitive RT, 61 of the 219 (27.9%) patients developed distant relapse with median PFS and OS rates of 9.9 and 32.8 months, and estimated five-year PFS and OS rates of 4.9% and 21.3%, respectively. Multivariate analysis revealed that pelvic node metastasis, pretreatment leukocytosis and pretreatment neutrophilia were significant predictors of distant relapse. The risk of developing distant relapse was found to be associated with the number of predictors that the patients displayed: the estimated five-year distant relapse rates of the patients with no predictors, one predictor and two predictors were 20.3%, 35.5% and 88.9%, respectively. CONCLUSIONS: Roughly 28% of patients with FIGO stage IIB-IVA cervical cancer developed distant relapse after definitive RT. Pelvic lymph node metastasis and pretreatment leukocytosis/neutrophilia are independent predictors of distant relapse.

Phase I Clinical Study of Irinotecan Plus S-1 in Patients With Advanced or Recurrent Cervical Cancer Previously Treated With Platinum-Based Chemotherapy.

OBJECTIVES: This study aimed to determine the maximum tolerated dose and acute dose-limiting toxicities (DLTs) of intravenous irinotecan plus oral S-1 in patients with advanced or recurrent uterine cervical cancer. METHODS: Irinotecan was administered intravenously over the course of 90 minutes on day 1, and S-1 was given orally in 2 divided doses from days 1 to 14 of a 21-day cycle. The dose of S-1 was escalated in a stepwise fashion from 40 (level 1) to 60 mg/m (level 2) and then 80 mg/m (level 3), whereas the dosage of irinotecan remained the same (150 mg/m). The primary end point for the escalation study was acute DLT that occurred within 2 cycles of chemotherapy. RESULTS: Twelve patients were enrolled and treated over 3 dose levels. Their median age was 47 years (range, 28-48 years). At level 1, one episode of grade 3 anemia and a grade 3 fatigue were observed, but no DLT developed. At level 2, the first patient experienced febrile neutropenia, which was considered to be a DLT. To evaluate the toxicity of this dose level, 5 more patients were evaluated. However, no DLT developed in these patients. At level 3, although grade 1 to 2 hematological and nonhematological toxicities developed, no DLT occurred. CONCLUSIONS: In women with advanced or recurrent cervical cancer previously treated with platinum-based chemotherapy, S-1 plus irinotecan in a triweekly setting is a reasonable treatment regimen with an acceptable toxicity profile. The recommended doses of S-1 and irinotecan for this regimen are 80 and 150 mg/m, respectively.

Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer.

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.

Incorporation of pretreatment leukocytosis and thrombocytosis into the FIGO staging system for prognosis in surgically treated endometrial cancer.

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<0.001; OS, P=0.004). In contrast, pretreatment leukocytosis, pretreatment thrombocytosis, and concurrent pretreatment leukocytosis and thrombocytosis did not provide any prognostic information for women with Stage IV disease. In ROC curve analysis, incorporation of concurrent pretreatment leukocytosis and thrombocytosis into the FIGO staging system resulted in a higher area under the curve for predicting recurrence for women with Stages I-III disease (0.770 vs 0.755; P=0.045). CONCLUSION: Incorporating concurrent pretreatment leukocytosis and thrombocytosis into the FIGO staging system might improve predictive performance and allow additional risk stratification for women with Stage I-III endometrial cancer.

Pretreatment tumor-related leukocytosis misleads positron emission tomography-computed tomography during lymph node staging in gynecological malignancies.

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.

Prognostic significance of the pretreatment prognostic nutritional index in patients with epithelial ovarian cancer.

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

The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: clinical and preclinical investigations.

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.

Estrogen stimulates female cancer progression by inducing myeloid-derived suppressive cells: investigations on pregnant and non-pregnant experimental models.

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.

Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer.

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. .

The Highly Metastatic Nature of Uterine Cervical/Endometrial Cancer Displaying Tumor-Related Leukocytosis: Clinical and Preclinical Investigations.

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.