Trends in incidence and hormonal management of endometrial cancer during potentially reproductive age in Japan: a population-based study.

BACKGROUND: We aimed to investigate the trends in the incidence and treatment of endometrial cancer (EC) during potentially reproductive age in Japan, with a special focus on the relative oncologic safety of hormonal therapy (HT) over surgery. METHODS: This population-based retrospective cohort study was conducted using data from the Osaka Cancer Registry from 2004 to 2018. Women with EC were first identified and then distributions of age, stage, histology, and initial treatment were examined. Then, the relative oncologic safety of HT over surgery in patients under the age of 50 years was evaluated. RESULTS: Among the 9417 patients with EC, 1937 were diagnosed during their potentially reproductive age (< 50 years). The incidence of EC during potentially reproductive age has increased from 18.5% in 2004-2011 to 21.9% in 2012-2018. ECs during potentially reproductive age more frequently displayed favorable characteristics, such as endometrioid histology, and lower histological grade than those in non-potentially reproductive age. Among the 1223 patients diagnosed with localized endometrioid EC, 74 cases (6.0%) received HT as an initial treatment, while 1100 cases (90.0%) underwent surgery as their initial treatment. When the two treatment groups were compared, there was no significant difference in overall survival (p = 0.3713). The estimated 5-year survival rates were 100 and 98.8% in the HT and surgery groups, respectively. CONCLUSION: EC is increasingly diagnosed during potentially reproductive age in Japan. The use of HT as an initial treatment is increasing, and achieved comparable survival outcomes to urgery against localized endometrioid EC during the potentially reproductive age.

Twenty-five-year mortality trends of four major histological subtypes of cervical cancer: a population-based study using the Osaka cancer registry data.

Objective: To assess the mortality trends of four major histological subtypes of cervical cancer diagnosed between 1994 and 2018. Methods: This population-based retrospective cohort study was conducted using the Osaka Cancer Registry data from 1994 to 2018. A total of 12,003 patients with cervical cancer, squamous cell carcinoma (SCC), adenocarcinoma (A), adenosquamous cell carcinoma (AS), or small cell neuroendocrine carcinoma (SCNEC) were identified. Patients were classified into groups according to the extent of disease (localized, regional, or distant), year of diagnosis (1994-2002, 2003-2010, or 2011-2018), and histological subtype (SCC, A/AS, or SCNEC). Then, their survival rates were assessed using univariate and multivariate analyses. Results: Overall, improved survival rates were observed according to the year of diagnosis in patients with local, regional, and distant cervical cancers. When examined according to the histological subtypes, improved survival rates according to the year of diagnosis were observed in patients with local, regional, and distant SCCs and in those with local and regional A/AS. In patients with distant A/AS, the survival rates did not improve since 2003. In patients with cervical cancer with SCNEC, the survival rates did not improve since 1994 irrespective of the extent of the disease. In the multivariate analysis, non-SCC histology was found to be an independent prognostic factor for OS. Conclusion: In contrast to SCC histology associated with improved survival between 1994 and 2018, SCNEC histology and advanced (stage IVB) A/AS remain to be the unmet medical needs for the management of cervical cancer.

Population-Based Survival Analysis of Stage IVB Small-Cell Neuroendocrine Carcinoma in Comparison to Major Histological Subtypes of Cervical Cancer.

The aim of the current study is to investigate the survival outcome of stage IVB SCNEC of the uterine cervix in comparison to major histological subtypes of cervical cancer. A population-based retrospective cohort study was conducted using the Osaka Cancer Registry data from 1994 to 2018. All FIGO 2009 stage IVB cervical cancer patients who displayed squamous cell carcinoma (SCC), adenocarcinoma (A), adenosquamous cell carcinoma (AS), or small-cell neuroendocrine carcinoma (SCNEC) were first identified. The patients were classified into groups according to the types of primary treatment. Then, their survival rates were examined using the Kaplan-Meier method. Overall, in a total of 1158 patients, clearly differential survival rates were observed according to the histological subtypes, and SCNEC was associated with shortest survival. When examined according to the types of primary treatments, SCNEC was associated with significantly decreased survival when compared to SCC or A/AS, except for those treated with surgery. In patients with FIGO 2009 stage IVB cervical cancer, SCNEC was associated with decreased survival when compared to SCC or A/AS. Although current treatments with either surgery, chemotherapy or radiotherapy have some therapeutic efficacies, to improve the prognosis, novel effective treatments specifically targeting cervical SCNEC need to be developed.

Comparison of the Survival Outcomes of Minimally Invasive Surgery with Open Surgery in Patients with Uterine-Confined and Node-Negative Cervical Cancer: A Population-Based Study.

We aimed to compare the oncological outcomes between Japanese women with uterine-confined and node-negative cervical cancer who underwent open surgery and those who underwent minimally invasive surgery (MIS). A population-based retrospective cohort study was conducted using data from the Osaka Cancer Registry that ranged from 2011 to 2018. A total of 2279 patients who underwent surgical treatment for uterine-confined and node-negative cervical cancer were identified. The patients were classified into groups according to surgery type (open and MIS groups) and year of diagnosis (group one, 2011-2014; group two, 2015-2018). The oncologic outcomes were compared between the MIS and open groups. When the MIS group (n = 225) was compared with open group (n = 2054), overall, there was no significant between-group difference in terms of overall survival. Based on Kaplan-Meier estimates, the probability of overall survival at four years was 99.5% in the MIS group and 97.2% in the open group (p = 0.1110). When examined according to the year of diagnosis, there were no significant between-group differences in the overall survival in both groups one and two. In this population-based cohort study, MIS did not compromise survival outcomes when compared with conventional open surgery in Japanese patients with uterine-confined and node-negative (FIGO 2018 stage I) cervical cancer.

Evaluation of survival outcomes between minimally invasive and open surgery in the treatment of early-stage endometrial cancer: a population-based study in Osaka Japan.

OBJECTIVE: To compare the oncological outcomes between Japanese women who underwent minimally invasive surgery and those who underwent open surgery for early-stage endometrial cancer. METHODS: This population-based retrospective cohort study was conducted using data from the Osaka Cancer Registry from 2011 to 2018. Surgically treated patients for localized (uterine-confined) endometrial cancer were identified. Patients were classified into two groups according to the type of surgery (minimally invasive surgery group and open-surgery group), pathological risk factors (low-risk and high-risk), and year of diagnosis (Group 1, 2011-14; Group 2, 2015-18). Overall survival was compared between the minimally invasive surgery and open-surgery groups. RESULTS: In the analyses including all patients, there was no difference in overall survival between the minimally invasive surgery and open-surgery groups (P = 0.0797). The 4-year overall survival rate was 97.1 and 95.7% in the minimally invasive surgery and open-surgery groups, respectively. When investigated according to pathological risks, there were no differences in overall survival between the minimally invasive surgery and open-surgery groups in both the low- and high-risk groups. In the low-risk group, the 4-year overall survival rates in the minimally invasive surgery and open-surgery groups were 97.7 and 96.5%, respectively. In the high-risk group, the 4-year overall survival rates in the minimally invasive surgery and open-surgery groups were 91.2 and 93.2%, respectively. Similarly, there were no differences in overall survival between the minimally invasive surgery and open-surgery groups in both Group 1 (P = 0.4479 in low-risk and P = 0.1826 in high-risk groups) and Group 2 (P = 0.1750 in low-risk and P = 0.0799 in high-risk groups). CONCLUSION: Our study provides epidemiological evidence that minimally invasive surgery is an effective alternative to open surgery in Japanese patients with early-stage endometrial cancer.

Laboratory Findings of Benign Convulsions With Mild Gastroenteritis: A Meta-Analysis.

Investigating factors associated with benign convulsions with mild gastroenteritis (CwG) is important for early detection and treatment. In previous studies, uric acid (UA) has been reported to be associated with CwG. However, the association between CwG and abnormal laboratory values remains inconclusive. We performed a meta-analysis of recent reports to determine the association between CwG and laboratory findings, including UA, in patients with acute gastroenteritis without convulsions. We conducted electronic searches of three databases (PubMed, EMBASE, and Cochrane Library) and one scholarly search engine (Google Scholar (Google, Inc., Mountain View, CA, USA)) up to February 2023 for studies on CwG. Eligible studies were observational studies that assessed patients with CwG, reported laboratory data, and stated the presence or absence of convulsions during illness episodes. Patients were children with mild gastroenteritis, with the exposure group developing convulsions and the control group not. The outcome was a comparison of laboratory data between the two groups. The effect size was calculated using the standardized mean difference (SMD), and random-effects models were used for the analysis because of high heterogeneity. In total, 148 articles were included in this study. After the screening, nine studies, including 8,367 patients, were selected for the meta-analysis. The most prevalent laboratory finding was an increased serum UA level, with an SMD of 1.42 (N = 6,411; 95% confidence interval (CI): (1.12, 1.72); Z = 9.242, p< 0.001; I 2 = 81.68%, p= 0.002). The optimal serum UA cutoff value was 7.21 mg/dL, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.827 (95% CI: (0.807, 0.846)). This meta-analysis suggests that CwG is strongly associated with increased serum UA levels. These results demonstrate that more attention should be paid when interpreting laboratory findings in pediatric patients with acute gastroenteritis.

Platelets Increase the Expression of PD-L1 in Ovarian Cancer.

The interactions between platelets and cancer cells activate platelets and enhance tumor growth. Platelets increase proliferation and epithelial-mesenchymal transition in cancer cells, inhibit anoikis, enhance the extravasation of cancer cells, and protect circulating tumor cells against natural killer cells. Here, we have identified another mechanism by which platelets dampen the immune attack on cancer cells. We found that platelets can blunt the antitumor immune response by increasing the expression of inhibitory immune checkpoint (PD-L1) on ovarian cancer cells in vitro and in vivo. Platelets increased PD-L1 in cancer cells via contact-dependent (through NF-κB signaling) and contact-independent (through TFGßR1/Smad signaling) pathways. Inhibition of NF-κB or TGFßR1 signaling in ovarian cancer cells abrogated platelet-induced PD-L1 expression. Reducing platelet counts or inhibiting platelet functions reduced the expression of PD-L1 in ovarian cancer. On the other hand, an increase in platelet counts increased the expression of PD-L1 in tumor-bearing mice.

Hyponatremia and Recurrent Febrile Seizures During Febrile Episodes: A Meta-Analysis.

Several studies have investigated the potential effects of hyponatremia on recurrent febrile seizures (RFS) during febrile illness. Because findings were inconsistent across studies, we aimed to evaluate the serum sodium levels in febrile seizures (FS) of children with or without RFS during the same episode. We conducted electronic searches in three databases (PubMed, EMBASE, Cochrane Library) and one scholarly search engine (Google Scholar) up to June 2021 for studies on FS. Screening was done based on the titles and abstracts of primary studies. Then, eligibility was reviewed based on the abstracts. Finally, in order to match the inclusion and exclusion criteria, full-text articles were evaluated by two authors and inconsistencies were discussed. Data extraction was carried out by two independent authors. The extracted variables were author's name, article title, journal name, year of publication, study location, study design, sample size, and mean and standard deviation of blood Na concentration in FS. We performed a risk of bias assessment of included studies using the Newcastle-Ottawa Scale (NOS). The effect size was calculated using the standardized mean difference (SMD), and random-effects models were used for the analysis. A total of 12 articles were included with a single outlier. This analysis suggested that serum sodium level was lower in patients with RFS during the same febrile episode than in those with single FS, with SMD of -0.70, (n=1784; 95% CI: -1.03, -0.36; Z=-4.10, p<0.01; I 2 86.67%, p<0.01). In the sensitivity analysis, no significant change was observed in pooled SMD. The optimal cutoff value of serum sodium level was 134.72 mmol/L with an area under the receiver operating characteristic curve of 0.81 (95% CI: 0.61, 1.00), with sensitivity of 80.0% and specificity of 70.0%. This result indicated a significant association between hyponatremia and RFS during the same febrile episode. Decreased serum sodium levels may be involved in seizure recurrence and may play a role in FS pathogenesis.

Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer.

BACKGROUND: Podoplanin (PDPN) is a sialylated membrane glycoprotein that binds to C-type lectin-like receptor 2 on platelets resulting in platelet activation. PDPN is expressed on lymphatic endothelial cells, perivascular fibroblasts/pericytes, cancer cells, cancer-associated fibroblasts, and tumor stromal cells. PDPN's expression on malignant epithelial cells plays a role in metastasis. Furthermore, the expression of PDPN in brain tumors (high-grade gliomas) was found to correlate with an increased risk of venous thrombosis. OBJECTIVE: We examined the expression of PDPN and its role in tumor progression and venous thrombosis in ovarian cancer. METHODS: We used mouse models of ovarian cancer and venous thrombosis. RESULTS: Ovarian cancer cells express PDPN and release PDPN-rich extracellular vesicles (EVs), and cisplatin and topotecan (chemotherapies commonly used in ovarian cancer) increase the expression of podoplanin in cancer cells. The expression of PDPN in ovarian cancer cells promotes tumor growth in a murine model of ovarian cancer and that knockdown of PDPN gene expression results in smaller primary tumors. Both PDPN-expressing ovarian cancer cells and their EVs cause platelet aggregation. In a mouse model of venous thrombosis, PDPN-expressing EVs released from HeyA8 ovarian cancer cells produce more frequent thrombosis than PDPN-negative EVs derived from PDPN-knockdown HeyA8 cells. Blood clots induced by PDPN-positive EVs contain more platelets than those in blood clots induced by PDPN-negative EVs. CONCLUSIONS: In summary, our findings demonstrate that the expression of PDPN by ovarian cancer cells promotes tumor growth and venous thrombosis in mice.

Myeloid-Derived Suppressor Cells as Therapeutic Targets in Uterine Cervical and Endometrial Cancers.

Uterine cervical and endometrial cancers are the two most common gynecological malignancies. As demonstrated in other types of solid malignancies, an increased number of circulating or tumor-infiltrating myeloid-derived suppressor cells (MDSCs) have also been observed in uterine cervical and endometrial cancers, and increased MDSCs are associated with an advanced stage, a short survival, or a poor response to chemotherapy or radiotherapy. In murine models of uterine cervical and endometrial cancers, MDSCs have been shown to play important roles in the progression of cancer. In this review, we have introduced the definition of MDSCs and their functions, discussed the roles of MDSCs in uterine cervical and endometrial cancer progression, and reviewed treatment strategies targeting MDSCs, which may exhibit growth-inhibitory effects and enhance the efficacy of existing anticancer treatments.

The effect of platelet G proteins on platelet extravasation and tumor growth in the murine model of ovarian cancer.

We and other investigators have shown that platelets promote metastasis and the growth of tumors. Our rationale for conducting this study is that platelets' prometastatic and progrowth effects depend on a close encounter between platelets and cancer cells. This interaction occurs inside blood vessels with circulating tumor cells and outside blood vessels with cancer cells residing in the tumor parenchyma. Our hypothesis was that platelet extravasation is required for the effect of platelets on tumor growth. Platelets respond to environmental stimuli by activation of G protein-coupled receptors on their surface. We investigated the impact of various platelet G proteins on the growth of ovarian cancer tumors and platelet extravasation. We used mice with platelet-specific deficiency of Gαi2 (Gi), Gα13 (G13), or Gαq (Gq) in a syngeneic ovarian cancer model. We measured the total weight of tumor nodules resected from tumor-bearing mice. We developed methods for automated whole-slide image acquisition and unbiased computerized image analysis to quantify extravasated platelets. We compared the number of platelets inside tumor nodules of platelet G protein-deficient tumor-bearing mice. We found that deficiency of Gi and G13, but not Gq, in platelets resulted in smaller tumors compared with those in corresponding littermates. Deficiency of Gi and G13 in platelets reduced the number of extravasated platelets by >90%, but deficiency of Gq did not reduce the number of extravasated platelets significantly. The lack of Gi or G13 in platelets reduced platelet extravasation into the tumor and tumor growth.

Targeting Myeloid-Derived Suppressor Cells in Ovarian Cancer.

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.

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.

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.

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.

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.

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.

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. .

Effect of Japanese Kampo Medicine Therapy for Menopausal Symptoms after Treatment of Gynecological Malignancy.

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