Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to ...preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent "cancer stem cell theory" postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches.
Tumor‐associated macrophages (TAM) are known to possess the immunosuppressive M2 macrophage phenotype. They contribute to tumor growth, invasion, and metastasis by producing various mediators. ...Macrophages, especially M2 polarized macrophages, preferentially express CD163 and CD204, but few studies have investigated macrophage phenotypes in human ovarian tumors. The purpose of the present study was therefore to present results on macrophage differentiation in human ovarian serous and mucinous epithelial tumors. The method focused on immunostaining of paraffin‐embedded tumor samples. Almost all macrophages infiltrating tumor tissues expressed CD163 and CD204, indicating the phenotypic shift toward M2 macrophage. The numbers of CD68‐positive macrophages as well as of CD163‐ and CD204‐positive macrophages in borderline and malignant tumors were significantly higher than in benign tumors. They correlated well with histological gradient of malignancy. Macrophage colony‐stimulating factor (also known as colony‐stimulating factor; CSF‐1), which is one of the cytokines considered to induce TAM to polarize toward an M2 phenotype, was then evaluated. CSF‐1 expression in malignant tumor cells was significantly higher than that in benign tumor cells and correlated with histological malignancy. These results suggest that CSF‐1 derived from tumor tissues induces macrophages to shift toward the M2 phenotype, which is considered to promote tumor growth.
Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the ...different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.
The Japan Society of Obstetrics and Gynecology collects and analyzes annual data on gynecologic cancers from member institutions. We present the Patient Annual Report for 2013 and the Treatment ...Annual Report for 2008. Data on 7280 patients with cervical cancer, 8952 with endometrial cancer, 5792 with ovarian cancer and 1903 with ovarian borderline tumor for whom treatment was initiated in 2013 were summarized in the Patient Annual Report. Stage I accounted for 56.7%, stage II for 23.4%, stage III for 9.8% and stage IV for 10.2% of all patients with cervical cancer. Stage I accounted for 71.7%, stage II for 6.5%, stage III for 14.5% and stage IV for 7.3% of all patients with endometrial cancer. Stage I accounted for 42.2%, stage II for 9.8%, stage III for 28.2% and stage IV for 8.3% of all patients with ovarian cancer. Data on the prognosis of 3658 patients with cervical cancer, 4159 with endometrial cancer and 2866 with ovarian cancer for whom treatment was initiated in 2008 were analyzed in the Treatment Annual Report. Survival was analyzed by using the Kaplan-Meier method, the log-rank test and the Wilcoxon test. The 5-year overall survival rates for patients with cervical cancer were 93.0% for stage I, 73.1% for stage II, 55.2% for stage III and 24.2% for stage IV. The equivalent rates for patients with endometrial cancer were 94.5%, 90.3%, 74.2% and 24.0%, respectively; and those for patients with ovarian cancer (surface epithelial-stromal tumors) were 90.5%, 73.5%, 48.1% and 29.4%, respectively.
The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2017 for the Treatment of Uterine Cervical Cancer are for the purpose of providing standard treatment strategies for cervical cancer, ...indicating treatment methods currently considered appropriate for cervical cancer, minimizing variances in treatment methods among institutions, improving the safety of treatment and prognosis of diseases, reducing the economic and psychosomatic burden of patients by promoting performance of appropriate treatment, and enhancing mutual understanding between patients and healthcare professionals. The guidelines were prepared through consensus of the JSGO Guideline Committee, based on careful review of evidence gathered through the literature searches and in view of the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise eight chapters and five algorithms. The main features of the 2017 revision are as follows: (1) evidence was collected using a search formula and with cooperation of the Japan Library Association. The bibliographical search formula was placed at the end of the book; (2) regarding clinical questions (CQs) where evidence or clinical inspection in Japan was lacking, opinions of the Guidelines Committee were described as “proposals for future directions”; (3) cervical intraepithelial neoplasia (CIN) 3 and adenocarcinoma in situ (AIS) were treated as a cervical precancerous lesion; (4) the CQs of endoscopic surgery, radical trachelectomy, and sentinel node biopsy were newly added in Chapter 3, “primary treatment for stage IB–II cervical cancer”; and (5) the CQ about hormone replacement therapy after cancer treatment was newly established. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2017 for the Treatment of Uterine Cervical Cancer.
The Japan Society of Obstetrics and Gynecology collects and analyzes annual data on gynecologic cancers from member institutions. We present the Patient Annual Report for 2014 and the Treatment ...Annual Report for 2009. Data on 7436 patients with cervical cancer, 9673 with endometrial cancer, 5924 with ovarian cancer, and 1909 with ovarian borderline tumor for whom treatment was initiated in 2014 were summarized in the Patient Annual Report. Stage I accounted for 55.6%, stage II for 22.9%, stage III for 10.2%, and stage IV for 11.2% of all patients with cervical cancer. Stage I accounted for 72.3%, stage II for 6.0%, stage III for 14.1%, and stage IV for 7.7% of all patients with endometrial cancer. Stage I accounted for 43.3%, stage II for 9.1%, stage III for 27.6%, and stage IV for 7.2% of all patients with ovarian cancer. Data on the prognosis of 4126 patients with cervical cancer, 4613 with endometrial cancer, and 3205 with ovarian cancer for whom treatment was initiated in 2009 were analyzed in the Treatment Annual Report. Survival was analyzed by using the Kaplan-Meier method, the log-rank test and the Wilcoxon test. The 5-year overall survival rates for patients with cervical cancer were 92.4% for stage I, 76.7% for stage II, 54.3% for stage III, and 25.2% for stage IV. The equivalent rates for patients with endometrial cancer were 94.6%, 89.4%, 78.3%, and 25.0%, respectively; and those for patients with ovarian cancer (surface epithelial-stromal tumors) were 90.5%, 78.8%, 46.0%, and 25.1%, respectively.
Cervical, endometrial, and ovarian cancers, have both high morbidity and mortality among the gynecologic malignant tumors in Japan. The present study was conducted using both the population-based ...cancer registry and the gynecologic cancer registry to elucidate the characteristics of gynecologic malignant tumors in Japan. Based on nationwide estimates from the population-based cancer registry in Japan, the morbidities and mortality of cervical, endometrial, and ovarian cancers were obtained and used for analysis. Clinicopathologic factors for cervical cancer, endometrial cancer, ovarian cancer, including age, clinical stage, postsurgical stage, histological type, therapeutic strategy, and prognosis were retrieved from the gynecologic cancer registry published by the Japan Society of Obstetrics and Gynecology and used for analysis. The morbidities of cervical, endometrial, and ovarian cancers were 10,908, 13,606, and 9,384 women in 2012, respectively. The prevalence of endometrial cancer has significantly and consistently been increasing and represents the most common gynecologic malignant tumor in Japan. The mortalities of cervical, endometrial, and ovarian cancers were 2.1, 1.3, and 3.2 per 100,000 in 2012, respectively. In 2014, 52.2% of cervical cancer patients were classified as stage I, 22.5% as stage II, 10.2% as stage III, and 11.2% as stage IV. In addition, 71.9% of endometrial cancer patients were classified as stage I, 6.0% as stage II, 13.3% as stage III, and 7.5% as stage IV. Finally, 43.2% of ovarian cancer patients were classified as stage I, 9.1% as stage II, 27.6% as stage III, and 7.2% as stage IV. Twelve-point six percent of ovarian cancer patients received neoadjuvant chemotherapy.
To investigate the safety and efficacy of a single local methotrexate (MTX) injection for the treatment of cesarean scar pregnancy (CSP), assess reproductive outcomes after treatment, and confirm ...clinical outcomes after the treatment of CSP patients according to the presence of fetal cardiac activity or serum human chorionic gonadotropin (hCG) levels.
A retrospective cohort study.
A university hospital.
Women with CSP.
Single local MTX injection under transvaginal ultrasound guidance.
A total of 45 CSP cases were identified; the mean (standard deviation, range) estimated gestational age was 7.7 (1.7, 5.4-12.5) weeks and the mean serum hCG level was 51 801 (40 761, 2307-187 898) mIU/mL. Three cases required additional treatment with MTX, and none of the cases needed uterine artery embolization or hysterectomy. The success rate for a single dose was 93.3%, and it was 100% if additional treatments with MTX were included. The mean time required for hCG normalization in those with fetal cardiac activity or with an initial level of hCG greater than 100 000 mIU/mL was not significantly longer than that in the controls (93.4 vs 77.1 days, p = .12; 113.7 days vs 83.6 days, p = .10). Of the 23 women who desired a subsequent pregnancy, 13 delivered 14 healthy newborns after treatment, 3 had an ongoing pregnancy, and 3 experienced recurrent CSP.
A single local MTX injection is safe and effective for the treatment of CSP despite the presence of fetal cardiac activity or any initial level of hCG and may allow the possibility of a subsequent uneventful pregnancy.
Background
Despite being widely used, to date (June 2021), the regimen of bevacizumab 10 mg/kg every 2 weeks (Q2W) combined with chemotherapy is not approved in Japan for patients with ...platinum-resistant recurrent ovarian cancer. In this retrospective analysis, we evaluated the usage patterns of bevacizumab administered for platinum-resistant recurrent ovarian cancer.
Methods
We obtained clinical data from 155 Japanese medical facilities between November 2013 and December 2018 via a survey. Items included the number of cases of platinum-resistant recurrent ovarian cancer treated with bevacizumab according to dosage. For regimens including bevacizumab 10 mg/kg Q2W, additional information was requested relating to concomitantly administered agents, and the efficacy and safety of the regimen.
Results
Of 1739 bevacizumab-containing regimens reported in 1633 patients with recurrent ovarian cancer, 264 used 10 mg/kg Q2W. The overall response rate (ORR) with this regimen was 26.1%. Response rates varied according to regimen and were particularly favorable when bevacizumab 10 mg/kg Q2W was administered with paclitaxel (ORR, 53.0%) versus liposomal doxorubicin (15.0%;
P
< 0.0001) and irinotecan (7.7%;
P
< 0.028). The most frequent Grade ≥ 3 adverse events associated with bevacizumab 10 mg/kg Q2W were neutropenia (11.7%) and hypertension (11.7%). The most frequent bevacizumab-associated Grade ≥ 3 adverse events with bevacizumab plus paclitaxel versus bevacizumab plus liposomal doxorubicin were hypertension (9.0% versus 13.9%) and proteinuria (3.0% versus 8.4%).
Conclusions
Bevacizumab 10 mg/kg Q2W appears efficacious for patients with recurrent ovarian cancer, with a manageable toxicity profile. Approval of this regimen is clinically desirable for Japanese patients with ovarian cancer.
During spermatogenesis, meiosis is accompanied by a robust alteration in gene expression and chromatin status. However, it remains elusive how the meiotic transcriptional program is established to ...ensure completion of meiotic prophase. Here, we identify a protein complex that consists of germ-cell-specific zinc-finger protein ZFP541 and its interactor KCTD19 as the key transcriptional regulators in mouse meiotic prophase progression. Our genetic study shows that ZFP541 and KCTD19 are co-expressed from pachytene onward and play an essential role in the completion of the meiotic prophase program in the testis. Furthermore, our ChIP-seq and transcriptome analyses identify that ZFP541 binds to and suppresses a broad range of genes whose function is associated with biological processes of transcriptional regulation and covalent chromatin modification. The present study demonstrates that a germ-cell specific complex that contains ZFP541 and KCTD19 promotes the progression of meiotic prophase towards completion in male mice, and triggers the reconstruction of the transcriptional network and chromatin organization leading to post-meiotic development.
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