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Angiomyofibroblastoma and superficial myofibroblastoma are distinctive benign mesenchymal tumors occurring in the female lower genital tract. Despite their significant overlapping clinicopathologic features, including the presence of bland-looking spindle or oval cells with myofibroblastic or myoid differentiation, the tumors have been regarded as separate entities. Although subepithelial, hormone-sensitive mesenchymal cells of the female lower genital tract are considered as their potential common progenitor cells, their potential kinship or pathogenetic similarities remain elusive. Based on the identification of a novel RNA sequencing-based MTG1-CYP2E1 fusion transcript in an angiomyofibroblastoma index case, we investigated an additional ten samples of the tumor and its site-specific histological mimics, including eight superficial myofibroblastomas, four deep angiomyxomas, four cellular angiofibromas, three fibroepithelial stromal polyps, and eight non-site-specific mesenchymal tumors occurring in the female lower genital tract. Using reverse transcription-polymerase chain reaction, we showed that the MTG1-CYP2E1 fusion transcripts were consistently detectable in angiomyofibroblastomas (5/5, 100%) and often in superficial myofibroblastomas (3/5, 60%) but were not detected in the other examined site-specific or non-site-specific mesenchymal tumors. Our immunohistochemical experiments showed that CYP2E1, an isoenzyme belonging to the cytochrome P450 superfamily, exhibited increased positivity in tumors with MTG1-CYP2E1 than was observed in fusion-negative tumors (RR = 6.56, p = 0.001). The results of our study provide further evidence supporting the assertion that angiomyofibroblastoma and superficial myofibroblastoma represent phenotypic variants of site-specific mesenchymal tumors and share a common oncogenic mechanism.

Giant cell tumor is a highly aggressive tumor characterized by a marked proliferation of pleomorphic, bizarre giant cells usually observed in the lungs. The importance of histopathological imaging and the clinical course of this tumor are unknown. The objective of our report was to investigate whether these components affect treatment outcomes and prognosis compared to conventional cancers. A 40-year-old woman with cervical cancer showed leukocytosis and elevated granulocyte colony simulating factor (G-CSF). The patient underwent a radical abdominal hysterectomy. Pathology revealed a poorly differentiated squamous cell carcinoma of the cervix, similar to giant cell carcinoma. The patient recovered from the disease and is alive 37 months after concurrent chemoradiotherapy (CCRT). Leukocytosis and G-CSF were normalized after treatment. This was our second case of giant cell carcinoma of the cervix. Cumulative data on giant cell carcinoma are limited, thus we considered the prognostic significance of the presence of giant cell carcinoma in uterine carcinoma.

This study aimed to investigate the cytotoxicity of a cluster of differentiation 70 antibody‐drug conjugate (CD70‐ADC) against ovarian cancer in in vitro and in vivo xenograft models. CD70 expression was assessed in clinical samples by immunohistochemical analysis. Western blotting and fluorescence‐activated cell sorting analyses were used to determine CD70 expression in the ovarian cancer cell lines A2780 and SKOV3, and in the cisplatin‐resistant ovarian cancer cell lines A2780cisR and SKOV3cisR. CD70 expression after cisplatin exposure was determined in A2780 cells transfected with mock‐ or nuclear factor (NF)‐κB‐p65‐small interfering RNA. We developed an ADC with an anti‐CD70 monoclonal antibody linked to monomethyl auristatin F and investigated its cytotoxic effect. We examined 63 ovarian cancer clinical samples; 43 (68.3%) of them expressed CD70. Among patients with advanced stage disease (n = 50), those who received neoadjuvant chemotherapy were more likely to exhibit high CD70 expression compared to those who did not (55.6% [15/27] vs 17.4% [4/23], P, The immunohistochemical analysis of ovarian cancer specimens revealed that cluster of differentiation 70 (CD70) is expressed in approximately 70% of patients who received platinum‐based neoadjuvant chemotherapy. CD70 is induced in cisplatin‐treated ovarian cancer cells and is strongly expressed in platinum‐resistant cells. The CD70 antibody‐drug conjugate is effective against CD70‐expressing ovarian cancer both in vitro and in vivo. Our translational research indicates that the effectiveness of CD70 antibody‐drug conjugate merits further investigation as a novel therapeutic strategy for women with ovarian cancer.

Background Although the shock index (SI) (heart rate/systolic blood pressure) and heart rate (HR) are a helpful indicator in the management of postpartum blood loss, there are few reports of SI in pregnant women complicated with hypertensive disorders in pregnancy (HDP). The purpose of this study was to examine whether SI and HR would be a clinically helpful indicator, and to detect the cutoff value for judging abnormal obstetric bleeding. Methods This was a retrospective case-control study in 107 patients with HDP in a singleton tertiary perinatal medical facility. The values of postpartum highest SI (peak SI) and highest HR (peak HR), and the amount of bleeding until peak SI and peak HR were retrospectively examined and analyzed. We used the receiver operating characteristic analysis to assess the diagnostic value of peak SI and peak HR for judging abnormal obstetric bleeding. Results Peak SI and peak HR were significantly related to the amount of bleeding up to peak SI and up to peak HR. The cutoff values of peak SI with blood loss volumes above 500 ml, 1000 ml, and 1500 ml were 0.77, 0.76, and 0.99, respectively. The cutoff values of peak HR with blood loss volumes above 500 ml, 1000 ml, and 1500 ml were 97, 98, and 103, respectively. Conclusion In cases of pregnant women complicated with HDP, both SI and HR were probably useful indicators in the management of postpartum blood loss. Further prospective trials are warranted to confirm these results.

Background Preoperative anemia affects perioperative outcomes and often causes fatigue and psychological disorders. Therefore, anemia should be treated before a patient undergoes surgery. Ninjin’yoeito (NYT), a Japanese Kampo medicine composed of ginseng and Japanese angelica root with the other 10 herbs, is administered for anemia, fatigue and anxiety; however, there are a few reports that have prospectively examined the effects of NYT before surgery for gynecological diseases. Hence, we tended to investigate its efficacy and safety. Methods In this open-label randomized trial, women with gynecological diseases accompanied by preoperative anemia (defined as Results Forty patients were enrolled of whom 30 patients were finally analyzed after allocating 15 to each group. There was no difference in the characteristics between both groups. Hb significantly increased in both groups (iron supplementation group, 9.9 ± 0.8 g/dL vs. 11.9 ± 1.6 g/dL; NYT group, 9.8 ± 1.0 g/dL vs. 12.0 ± 1.0 g/dL); the difference in the elevations in Hb between both groups was statistically insignificant (P = 0.72). Contrarily, CFS (17.9 ± 10.2 vs. 8.1 ± 5.2) and VAS-A (56 mm (50–70) vs. 23 mm (6–48)) scores were significantly decreased only in the NYT group and these changes were greater in the NYT group (∆CFS, P = 0.015; ∆VAS-A, P = 0.014). Liver dysfunction occurred in one patient of the NYT group. Conclusions For treating preoperative anemia in women with gynecological conditions, NYT administration along with iron supplementation safely and efficiently improved the preoperative fatigue and anxiety in addition to the recovery from anemia. Trial registration: jRCT1051190012 (28/April/2019, retrospectively registered).

Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are extremely rare, occurring in less than 1% of uterine stromal tumors, and they are considered to have a low malignant potential. Due to the small number of cases, no standard treatment has been defined. A 77-year-old woman with postmenopausal bleeding was admitted to our department. Imaging studies revealed a substantial mass around 30 mm in size on the anterior uterine wall. A total hysterectomy and bilateral salpingo-oophorectomy were performed for further diagnosis and treatment. The tumor revealed histopathological findings of a sex cord-like growth pattern in the form of fascicles, cords, or small nests. Immunohistochemical findings revealed that the tumor cells were positively reactive to alpha-SMA, calretinin, CD99, estrogen receptor, and progesterone receptor, collectively diagnosed as UTROSCT. No recurrence was observed over 12 months after treatment. We experienced the treatment of UTROSCT, an extremely rare tumor that occurs in elderly women. Although most cases of UTROSCT have a benign clinical course, several cases of recurrence and metastasis have been reported. It should be followed up for a long term after treatment.

INTRODUCTION: In Japan, two groups of women, HPV vaccinated and unvaccinated, are approaching age 20, when they should begin cervical cancer screening. To improve Japan’s current poor cervical cancer screening rate, we need to know how these women are thinking about screening. METHODS: We conducted an internet survey of 20-y-old women, exploring their understanding of HPV and cervical cancer screening. We then gave them leaflets with basic information about HPV and cervical cancer, stressing the importance of early detection by screening. We analyzed the leaflet’s effects on their attitudes based on their vaccination status. RESULTS: Our study of 618 women found a significantly higher intention for engagement for cervical cancer screening in women HPV-vaccinated as teenagers (29% versus 17%). They were also more aware that: (1) HPV is transmitted by sexual intercourse (49.1% versus 39.2%); (2) the HPV vaccine prevents cervical cancer (49.0% to 34.0%); and (3) the appropriate cervical cancer screening interval is every 2 y (63.3% versus 56.2%). Women in both groups responded well to the leaflet, with significant improvements in intention to receive screening. However, 65%-67% were not swayed. DISCUSSION: HPV-vaccinated women were more knowledgeable about cervical cancer and had a greater intention to receive screening. Our educational leaflet was moderately effective in both groups for increasing intentions to screen, but the majority in both groups were still resistant to screening. CONCLUSION: Japan needs to develop more effective educational programs and tools to vigorously impart the importance of cervical cancer screening.

Adventitial cystic disease (ACD) is a rare condition in which a mucinous cyst forms within the adventitia, usually in arteries but rarely in veins. A 79-year-old patient presented with stomachache and nausea. Computerized tomography showed pelvic cysts on either side of the pelvis. The right tumor was 120×100 mm, and the left tumor was 45×35 mm. Our diagnosis was bilateral ovarian tumors and we performed laparoscopic tumor resection. In the abdominal cavity, we saw that the left ovary was swollen by about 3-4 cm and the right ovary was normal size. There was a mucous cyst located in the right retroperitoneal cavity that adhered around and bordered the right external iliac vein and the right obturator nerve. We peeled the adhesion away carefully and resected the tumor but the operation caused temporary obturator nerve paralysis. From pathological examination, we diagnosed the right retroperitoneal cyst to be venous ACD originating from the right external iliac vein. We found that venous ACD can grow as large as a pelvic tumor and is difficult to distinguish from an ovarian tumor, which is why we chose laparoscopic surgery. In this case, we performed the operation laparoscopically and no sequelae or recurrent tumor appeared during a 1-year follow-up. However, graft replacement is sometimes necessary for ACD, thus venous ACD should be considered a differential diagnosis and a surgical strategy should be developed when pelvic tumors are observed.

Objective Chemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients. Materials and methods Eleven female patients with breast cancer or gynecologic cancer (mean age 64.8 [standard deviation 7.8]) who had neuropathic pain and/or peripheral sensory neuropathy, with a minimum two grade severity based on the scale of the National Cancer Institutes’ Common Terminology Criteria for Adverse Events (version 4.0) were enrolled. Patients received rTMS (5-Hz; 500 pulses/session; figure-8 coil) on their primary motor cortex corresponding to the target extremity. The intensity of pain and dysesthesia for all extremities was evaluated using a visual analog scale for pain, dysesthesia, and the Japanese version of the short-form McGill Pain Questionnaire 2 (SFMPQ2). Results rTMS for target extremity significantly decreased the visual analog scale of pain and dysesthesia. The intensity of pain measured by the SFMPQ2 was also decreased in the target extremity. Regarding non-target extremities, only dysesthesia significantly decreased as a result of rTMS. No adverse events were observed. Conclusion This is an initial report demonstrating the potential of rTMS for the treatment of CIPN. We suggest rTMS could be potentially beneficial and effective as a treatment for pain and dysesthesia in patients with CIPN.

OBJECTIVE. To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy. METHODS. This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged

Endometrioid carcinoma is the most common histological type of concurrent synchronous cancers of the uterus and ovary. Here we report a case of synchronous seromucinous carcinoma of the ovary and mucinous carcinoma of the endometrium with a literature review. A 51-year-old multiparous female complained of irregular bleeding and shortness of breath. Computed tomography revealed a large pelvic mass that consisted of cystic and solid components, a tumor of the endometrium, and a large amount of pleural effusion. An endometrial biopsy indicated adenocarcinoma, and adenocarcinoma cells were found in the pleural fluid. The patient with advanced ovarian cancer or endometrial cancer with massive pleural effusion received three courses of neoadjuvant chemotherapy (NAC) with paclitaxel and carboplatin followed by interval debulking surgery (IDS). The NAC was effective, and IDS was performed with no gross residual lesions. The post-operative diagnosis was seromucinous carcinoma of the ovary in FIGO (2014) stage IVA (ypT3cNxM1a) and mucinous carcinoma of the endometrium in FIGO (2008) stage IA (ypT1aNXM0). Three courses of postoperative TC therapy were performed, and maintenance therapy with Bevacizumab is ongoing. The patient is well without evidence of recurrence, sixteen months after surgery.

Intra-tumoral budding (ITB) has been well demonstrated to be an independent risk factor for adverse outcomes in colorectal carcinoma. This study investigated the prognostic significance of ITB in high-grade serous ovarian carcinomas (HGSOCs). The medical records and slides of 84 SOCs, including 13 with neoadjuvant chemotherapy (NAC), were retrospectively reviewed. The histopathologic examination with scoring of p53 expression showed them to be 80 HGSOCs and 4 low-grade serous ovarian carcinomas (LGSOCs). ITB was found in 64 (80.0%) of the 80 HGSOCs and 1 (25.0%) of 4 LGSOCs. The presence of ITB in HGSOC was significantly correlated with a higher level of CA125, an advanced 2014 FIGO stage, the presence of Lymph node metastasis, and the presence of lymphovascular space invasion (LVSI). The median progression-free survival (PFS) was 18 months in patients with HGSOC with ITB and 36 months in patients with HGSOC without ITB (P = 0.006), and their median overall survival (OS) was 50 months and 60 months (P = 0.060). The multivariate analysis revealed that ITB was not an independent prognostic factor. ITB is a cost-effective prognostic indicator for patients with HGSOC and ITB in ovarian tumor tissue is considered a useful histological biomarker of the progression of HGSOCs.

Oxytocin (OXT) is produced in the hypothalamic nuclei and secreted into systemic circulation from the posterior pituitary gland. In the central nervous system, OXT regulates behaviours including maternal and feeding behaviours. Our aim is to evaluate whether oestrogen regulates hypothalamic OXT dynamics. Herein, we provide the first evidence that OXT dynamics in the hypothalamus vary with sex and that oestrogen may modulate dynamic changes in OXT levels, using OXT-mRFP1 transgenic rats. The fluorescence intensity of OXT-mRFP1 and expression of the OXT and mRFP1 genes in the hypothalamic nuclei is highest during the oestrus stage in female rats and decreased significantly in ovariectomised rats. Oestrogen replacement caused significant increases in fluorescence intensity and gene expression in a dose-related manner. This is also demonstrated in the rats’ feeding behaviour and hypothalamic Fos neurons using cholecystokinin-8 and immunohistochemistry. Hypothalamic OXT expression is oestrogen-dependent and can be enhanced centrally by the administration of oestrogen.

A combination chemotherapy of paclitaxel plus carboplatin (TC) is the most frequently used regimen for gynecological malignancies. As long as it is effective, a carboplatin-containing combination chemotherapy is used for every relapse. This implies that the number of platinum administrations and the frequency of hypersensitivity reaction (HSR) increase as the prognosis improves. When a patient develops HSR to carboplatin, we have three options: 1) desensitizing and continuing to use carboplatin, 2) switching to other platinum drugs, or 3) changing to a non-platinum drug. Here we report an experience of an HSR to carboplatin in a patient with recurrent uterine carcinosarcoma. The patient was treated by surgery and TC therapy initially, resulting in no residual disease. The patient relapsed 18 months after the completion of the first-line chemotherapy and was treated with TC therapy again as second-line. An HSR to carboplatin occurred at the 10th cycle of TC in total. We replaced the carboplatin with cisplatin. A chemotherapy including cisplatin and adriamycin was repeated without further HSR. We reviewed the literature regarding HSR to carboplatin and in this paper we summarize the management for dealing with it.

The purpose of our study was to conduct a detailed survey of radical hysterectomy in Japanese patients with early-stage cervical cancer, and to compare oncologic outcomes between open and minimally invasive radical hysterectomy. In Japan during 2015, the medical records of 929 patients with FIGO stage IB1 and IIA disease treated with radical hysterectomy were retrospectively reviewed. We assessed patients’ characteristics, disease-free survival (DFS), overall survival (OS) and prognostic factors for survival. The median patient age was 44 (20–80) years. Most patients (94.4%) had stage IB1 disease. Of the patients who underwent radical hysterectomy, 91.2% underwent open surgery and 8.8% underwent minimally invasive surgery (MIS). The median follow-up period was 40.8 months (range, 0.49–51.1 months). The rate of DFS and OS at 4 years in all patients was 88.3% and 96.4%, respectively. Multivariate analysis identified age (≥ 47), adenocarcinoma histology, tumor size (≥ 2 cm), parametrial invasion, positive lymph node metastasis and institutional accreditation as independent predictors of recurrence, and adenocarcinoma, other cell types, and positive lymph node metastasis as independent predictors of death. Oncologic outcomes in all patients were similar between open and MIS, including DFS and OS. The survival rate of the Japanese patients underwent radical hysterectomy for early-stage cervical cancer was favorable. No significant differences were observed for DFS and OS between open and MIS performed by a limited number of surgeons at a limited number of facilities in Japan. Further investigations are required to identify the appropriate patients might benefit from MIS.

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare disease with a poor prognosis. The lack of established disease models has hampered therapy development. We generated a panel of cancer tissue-originated spheroid (CTOS) lines derived from SCNEC of the uterine cervix using a method based upon cell-cell contact throughout the preparation and culturing processes. Using 11 CTOS lines, we assessed the sensitivity of various drugs used in clinical practice. Drug sensitivity assays revealed significant heterogeneous inter-CTOS chemosensitivity. Microarray analyses were then performed to identify sensitivity-related gene signatures. Specific gene sets were identified which likely contribute to the sensitivity to the tested drugs. We identified a line (Cerv54) that was exceptionally sensitive to irinotecan. Cerv54 had increased levels of CES1, which catalyzes the conversion of irinotecan to the active form, SN38, although in Cerv54 cells, SN38 was undetectable, CES1 expression and activity were markedly low compared to the liver, and a CES1 inhibitor had no effect on irinotecan sensitivity. These results suggested a novel irinotecan mode of action in Cerv54. Our CTOS lines may be useful for understanding the variation and mechanism of drug sensitivity, contributing to the understanding and development of chemotherapeutic drugs.

Objective To evaluate timing and a prediction model for pregnancy in early-stage cervical cancer patients who underwent fertility-sparing trachelectomy. Design Retrospective cohort. Setting Academic multicenter. Patient(s) Women ages Intervention(s) Planned fertility-sparing trachelectomy. Main Outcome Measure(s) Cumulative incidences and clinicopathological characteristics of those who developed subsequent pregnancy were examined. Result(s) There were 77 (21.6%) women who had subsequent pregnancies after fertility-sparing trachelectomy with 1-, 2-, and 5-year cumulative pregnancy rates of 2.8%, 6.2%, and 17.4%, respectively. The median time to develop subsequent pregnancy was 3.2 years. In a competing risk analysis, women had a higher risk of recurrent cancer than conception during the first 11 months postsurgery. On multivariable analysis, younger age, being married, and postoperative reproductive treatment were independently associated with an increased chance of developing a subsequent pregnancy. The subsequent pregnancy index (SPI) score to predict the likelihood of having pregnancy was proposed, and it was calculated based on age, marital status, and reproductive treatment (2, 2, and 4 points, respectively). Women with a higher SPI score had significantly higher subsequent pregnancy rates (5-year pregnancy rate; the score was 3 in 4.7% of cases; 4 to 5 in 11.3%; 6 to 7 in 27.4%; and 8 in 50.8%), but they had similar recurrence rates (5.0%). Conclusion(s) The SPI score proposed in our study is useful in predicting subsequent pregnancy in women with early-stage cervical cancer undergoing fertility-sparing trachelectomy.

Background Uterine leiomyosarcoma is a rare and aggressive gynecologic malignancy originating in the myometrium of the uterine corpus that tends to recur even after complete surgical excision. Current therapeutic agents have only modest effects on uterine leiomyosarcoma. Although antibodies and antibody-drug conjugates have been recognized as useful targeted therapies for other cancers, no study has yet evaluated the effects of this approach on uterine leiomyosarcoma. Objective This study aimed to examine the activity of tumoral CD70 in uterine leiomyosarcoma and assess the antitumor activity of CD70–antibody-drug conjugate treatment in uterine leiomyosarcoma. Study Design Target membrane proteins were screened by profiling and comparing membrane protein expression in 3 uterine leiomyosarcoma cell lines (SK-UT-1, SK-LMS-1, and SKN) and normal uterine myometrium cells using the isobaric tags for relative and absolute quantitation labeling method. Western blotting, fluorescence-activated cell sorting analyses, and immunohistochemistry were used to examine CD70 expression in the membrane proteins in uterine leiomyosarcoma cell lines and clinical samples. We developed an antibody-drug conjugate with a monoclonal antibody of the target membrane protein linked to monomethyl auristatin F and investigated its antitumor effects against uterine leiomyosarcoma (in vitro, in vivo, and in patient-derived xenograft models). Results CD70 was identified as a specific antigen highly expressed in uterine leiomyosarcoma cell lines. Of the 3 uterine leiomyosarcoma cell lines, CD70 expression was confirmed in SK-LMS-1 cells by western blotting and fluorescence-activated cell sorting analysis. CD70 overexpression was observed in 19 of 21 (90.5%) tumor specimens from women with uterine leiomyosarcoma. To generate CD70–antibody-drug conjugate, anti-CD70 monoclonal antibody was conjugated with a novel derivative of monomethyl auristatin F. CD70–antibody-drug conjugate showed significant antitumor effects on SK-LMS-1 cells (half maximal inhibitory concentration, 0.120 nM) and no antitumor effects on CD70-negative uterine leiomyosarcoma cells. CD70–antibody-drug conjugate significantly inhibited tumor growth in the SK-LMS-1 xenograft mouse model (tumor volume, 129.8 vs 285.5 mm3; relative reduction, 54.5%; P Conclusion Uterine leiomyosarcoma tumors highly express CD70 and targeted therapy with CD70–antibody-drug conjugate may have a potential therapeutic implication in the treatment of uterine leiomyosarcoma.

ObjectiveThe phenotypic and pathological features of small cell cervical carcinoma (SMCC) and small small cell lung cancer (SCLC) are very similar; thus, the chemotherapy regimens used for the rare SMCC have been routinely based on regimens used for common SCLC. We set out to explore the protein expression profile similarities between these 2 cancers to prove that linking their therapeutic regimens is justified, with a secondary aim of finding tumor-specific proteins to use as additional biomarkers for more accurate diagnosis of SMCC, and potentially to use as therapeutic targets.MethodsProtein expression analysis was performed for 3 cases of SMCC and 1 example each of SCLC, mucinous adenocarcinoma of the cervix (MACC), lung mucinous adenocarcinoma (MACL), and squamous cell carcinoma of the cervix (SCC). We used cancer tissue–originated spheroids (CTOS) and isobaric tags for relative and absolute quantitation (iTRAQ)–based comprehensive and quantitative protein expression profile analysis. Expression in corresponding clinical samples was verified by immunohistochemistry.ResultsRather than organ of origin–specific patterns, the SMCC and SCLC samples revealed remarkably similar protein expression profiles—in agreement with their matching tumor pathology phenotypes. Sixteen proteins were expressed at least 2-fold higher in both small cell carcinomas (SMCC and SCLC) than in MACC or SCC. Immunohistochemical analysis confirmed higher expression of creatine kinase B-type in SMCC, compared with MACC and SCC.ConclusionsWe demonstrate a significant overlapping similarity of protein expression profiles of lung and cervical small cell carcinomas despite the significant differences in their organs of origin.

Neuroendocrine carcinoma of small cell type (SCNEC) is a rare pathological subtype in cervical cancer, which has a worse prognosis than other histological cell types. Due to its low incidence and the lack of experimental platforms, the molecular characteristics of SCNEC in the cervix remain largely unknown. Using the cancer tissue-originated spheroid (CTOS) method—an ex vivo 3D culture system that preserves the differentiation status of the original tumors—we established a panel of CTOS lines of SCNEC. We demonstrated that xenograft tumors and CTOSs, respectively, exhibited substantial intra-tumor and intra-CTOS variation in the expression levels of chromogranin A (CHGA), a neuroendocrine tumor marker. Since hypoxia affects differentiation in various tumors and in stem cells, we also investigated how hypoxia affected neuroendocrine differentiation of SCNEC of the uterine cervix. In the CTOS line cerv21, hypoxia suppressed expression of the neuroendocrine markers CHGA and synaptophysin (SYP). Flow cytometry analysis using CD99 (a membrane protein marker of SCNEC) revealed decreased CD99 expression in a subset of cells under hypoxic conditions. These expression changes were attenuated by HIF-1α knockdown, and by a Notch inhibitor, suggesting that these molecules played a role in the regulation of neuroendocrine differentiation. The examined SCNEC markers were suppressed under hypoxia in multiple CTOS lines. Overall, our present results indicated that neuroendocrine differentiation in SCNEC of the uterus is a variable phenotype, and that hypoxia may be one of the factors regulating the differentiation status.

Purpose Development of new treatment strategies for endometrial cancer that has become refractory or resistant to taxane/platinum is a critical need. The present study was a phase I/II study of gemcitabine, levofolinate, irinotecan, and 5-fluorouracil (5-FU) (GLIF) combination chemotherapy to determine optimal dosages, safety, and efficacy. Methods Taxane/platinum-resistant or -refractory endometrial disease was defined as tumor progression within 6 months after a taxane/platinum-based regimen. Maximum tolerated dose was investigated by a 3 + 3-designed phase I study. The phase II study was conducted using the recommended doses determined in the phase I study. Results The dosages recommended for the phase II trial were determined, in the phase I trial, to be: gemcitabine 800 mg/m2, levofolinate 100 mg/m2, irinotecan 80 mg/m2, and 5-FU 1000 mg/m2. Thirty patients were enrolled, including the three patients who received GLIF therapy at the same dose as the recommended phase II dose in the phase I study. Two patients were excluded at this point due to study protocol violations, and the remaining 28 patients were included for analysis. Phase II revealed that the response and disease control rates were 7.1% (2/28) and 39.3% (11/28), respectively, and that the median PFS and OS were 3 months [95% confidence interval (CI) 3–7] and 12 months (95% CI 9–17), respectively. Febrile or grade 4 neutropenia was observed in 14% (4/28) of the cases. Grade 3 or 4 thrombocytopenia was not observed. Conclusion We found that GLIF combination chemotherapy is potentially a useful treatment option for endometrial cancers refractory or resistant to taxane/platinum-based chemotherapy.

OBJECTIVE. The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS. This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I–IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS. Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36–2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39–2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION. In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.

Background In Japan, the rate of cervical cancer screening is remarkably low, especially among women in their twenties and thirties, when cervical cancer is now increasing dramatically. The aim of this study was to test whether a modified government reminder for 20-year-old women to engage in cervical cancer screening, acting through maternal education and by asking for a maternal recommendation to the daughter to receive the screening, could increase their participation rate. Methods In two Japanese cities, 20-year-old girls who had not received their first cervical cancer screening before October of fiscal year 2014 were randomized into two study arms. One group of 1,274 received only a personalized daughter-directed reminder leaflet for cervical cancer screening. In the second group of 1,274, the daughters and their mothers received a combination package containing the same reminder leaflet as did the first group, plus an additional informational leaflet for the mother, which requested that the mother recommend that her daughter undergo cervical cancer screening. The subsequent post-reminder screening rates of these two study arms were compared. Results The cervical cancer screening rate of 20-year-old women whose mothers received the information leaflet was significantly higher than that for women who received only a leaflet for themselves (11% vs 9%, P = 0.0049). Conclusions An intervention with mothers, by sending them a cervical cancer information leaflet with a request that they recommend that their daughter receive cervical cancer screening, significantly improved their daughters' screening rate.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR+ EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very-low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro, and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment. Significance: These findings offer preclinical evidence of the therapeutic efficacy of a novel targeted antibody therapy against deadly epithelial ovarian cancers. Cancer Res; 78(2); 516–27. ©2017 AACR.

Glypican-1 (GPC1) is highly expressed in solid tumors, especially squamous cell carcinomas (SCCs), and is thought to be associated with disease progression. We explored the use of a GPC1-targeted antibody-drug conjugate (ADC) as a novel treatment for uterine cervical cancer. On immunohistochemical staining, high expression levels of GPC1 were detected in about 50% of uterine cervical cancer tissues and also in a tumor that had relapsed after chemoradiotherapy. Novel anti-GPC1 monoclonal antibodies were developed, and clone 01a033 was selected as the best antibody for targeted delivery of the cytotoxic agent monomethyl auristatin F (MMAF) into GPC1-positive cells. The anti-GPC1 antibody was conjugated with MMAF. On flow cytometry, HeLa and ME180 cervical cancer cells highly expressed GPC1, however, RMG-I ovarian clear cell cancer cell line showed weak expression. The GPC1-ADC was rapidly internalized into GPC1-expressing cells in vitro and was potently cytotoxic to cancer cells highly expressing GPC1. There were no inhibitory effects on cancer cells with low expression of GPC1. In a murine xenograft model, GPC1-ADC also had significant and potent tumor growth inhibition. GPC1-ADC-mediated G2/M phase cell cycle arrest was detected, indicating that the dominant antitumor effect in vivo was MMAF-mediated. The toxicity of GPC-ADC was tolerable within the therapeutic dose range in mice. Our data showed that GPC1-ADC has potential as a promising therapy for uterine cervical cancer.

To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/mA total of 35 patients were enrolled. The recommended dose was defined as 100 mg/mCombination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.

Background In Japan, the cervical cancer preventative HPV vaccination rate has dramatically declined, directly as a result of repeated broadcasts of so-called adverse events and the resulting suspension of the government’s recommendation. Our previous survey of obstetricians and gynecologists in Japan regarding their opinions toward HPV vaccination revealed that these key specialists were as negatively influenced by the reports of purported negative events as were the general population. Here, we report a 3-year follow-up survey of these clinicians. Methods We reused the same questionnaire format as used in our 2014 survey, but added new questions concerning opinions regarding a WHO statement and reports of a Japanese nation-wide epidemiological study related to the adverse events, released in 2015 and 2016, respectively. Results The response rate was 46% (259/567): 5 (16.1%) of 31 doctors had inoculated their own teenaged daughters during the time period since the previous survey, despite the continued suspension of the governmental recommendation, whereas in the previous survey none of the doctors had done so. Among the respondents, the majority claimed awareness of the recent pro-vaccine WHO statement (66.5%), and of the report of a Japanese epidemiological study (71.5%), and a majority affirmed they currently held positive opinions of the safety (72.7%) and effectiveness (84.3%) of the HPV vaccine. Conclusions Our re-survey of Japan’s obstetricians and gynecologists regarding their opinions about the HPV vaccine found that their opinions have changed, potentially leading to a more positive future re-engagement for HPV vaccination in Japan.

Background Sheehan’s syndrome occurs because of severe postpartum hemorrhage causing ischemic pituitary necrosis. Sheehan’s syndrome is a well-known condition that is generally diagnosed several years postpartum. However, acute Sheehan’s syndrome is rare, and clinicians have little exposure to it. It can be life-threatening. There have been no reviews of acute Sheehan’s syndrome and no reports of successful pregnancies after acute Sheehan’s syndrome. We present such a case, and to understand this rare condition, we have reviewed and discussed the literature pertaining to it. An electronic search for acute Sheehan’s syndrome in the literature from January 1990 and May 2014 was performed. Case presentation A 27-year-old woman had massive postpartum hemorrhage (approximately 5000 mL) at her first delivery due to atonic bleeding. She was transfused and treated with uterine embolization, which successfully stopped the bleeding. The postpartum period was uncomplicated through day 7 following the hemorrhage. However, on day 8, the patient had sudden onset of seizures and subsequently became comatose. Laboratory results revealed hypothyroidism, hypoglycemia, hypoprolactinemia, and adrenal insufficiency. Thus, the patient was diagnosed with acute Sheehan’s syndrome. Following treatment with thyroxine and hydrocortisone, her condition improved, and she was discharged on day 24. Her next pregnancy was established 2 years after her first delivery. She required induction of ovulation for the next conception. The pregnancy, delivery, and postpartum period were uneventful. An electronic search of the literature yielded 21 cases of acute Sheehan’s syndrome. Presenting signs varied, including adrenal insufficiency (12 cases), diabetes insipidus (4 cases), hypothyroidism (2 cases), and panhypopituitarism (3 cases), with a median time of presentation after delivery for each of those conditions being 7.9, 4, 18, and 9 days, respectively. Serial changes in magnetic resonance imaging were reported in some cases of acute Sheehan’s syndrome. Conclusion Clinicians should be aware of the risk of acute Sheehan’s syndrome after a massive postpartum hemorrhage in order to diagnose it accurately and treat it promptly.

Objective: In Japan, the possible adverse events upon HPV vaccination was widely reported in the media. MHLW announced the suspension of aggressively encouraging HPV vaccination in 2013, and inoculation rate has sharply declined. The aim of the present study was estimation of future cervical cancer risk. Methods: The latest data on vaccination rate at each age in Sakai City were first investigated. The rate of experiencing sexual intercourse at the age of 12, 13, 14, 15, 16, 17 and throughout lifetime is assumed to be 0%, 1%, 2%, 5%, 15%, 25%, and 85% respectively. The cervical cancer risk was regarded to be proportional to the relative risk of HPV infection over the lifetime. The risk in those born in 1993 whom HPV vaccination was not available yet for was defined to be 1.0000. Results: The cumulative vaccination rates were 65.8% in those born in 1994, 72.7% in 1995, 72.8% in 1996, 75.7% in 1997, 75.0% in 1998, 66.8% in 1999, 4.1% in 2000, 1.5% in 2001, 0.1% in 2002, and 0.1% in 2003. The relative cervical cancer risk in those born in 1994–1999 was reduced to 0.56–0.70, however, the rate in those born in 2000–2003 was 0.98–1.0, almost the same risk as before introduction of the vaccine. Discussion: The cumulative initial vaccination rates were different by the year of birth. It is confirmed that the risk of future cervical cancer differs in accordance with the year of birth. For these females, cervical cancer screening should be recommended more strongly.

Microscopic examination of urine sediment is a basic, common method of detecting diseases of the urinary tract. We experienced a case involving a patient who had developed a fever after undergoing a urinary-diversion operation. Results of the microscopic examination of the urine collected from the urostomy pouch of the patient showed a food debris-like component. Based on this finding, we suspected a fistula between the urinary and intestinal tracts. However, after performing an experiment to verify the results, we determined that no fistula was present. Instead, we discovered that the food debris-like component originated from the urostomy skin barrier. To our knowledge, ours is the first report in the literature to demonstrate that the urostomy skin barrier can dissolve and mimic food debris in urine sediment, leading to incorrect assumptions regarding the presence of fistulas. We believe that it is important to derive a correct diagnosis when an unfamiliar component is observed in urinary sediment. We further believe that the findings from this case are valuable to professionals who administer clinical treatment and perform laboratory testing.

The purpose of this study is to evaluate dose–volume histogram (DVH) predictors for the development of chronic gastrointestinal (GI) complications in patients with cervical cancer who have undergone postoperative concurrent chemotherapy and whole-pelvic radiation therapy (WPRT). The subjects were 135 patients who had undergone postoperative WPRT with concurrent nedaplatin-based chemotherapy between 2000 and 2014. Associations between selected DVH parameters and the incidence of chronic GI complications of G3 or higher were evaluated. Chronic GI complications of severity G3 occurred in 18 (13%) patients. Patients with GI complications had significantly greater V5–V45, mean dose and the generalized equivalent uniform dose (gEUD) of the small bowel loops, compared with those without GI complications. V30–V45, mean dose and gEUD of the bowel bag also showed significant differences between patients with and without GI complications. In contrast, no parameter for the large bowel loop was correlated with GI complications. Receiver operating characteristics curve analysis indicated that V30–V45 of the small bowel loops were better predictors than these respective parameters for the bowel bag. Next, patients were divided into four groups based on the median V15 and V40 of the small bowel loops. The group with both a high V15 and a high V40 showed a significantly higher probability of chronic GI complications. In conclusion, the small bowel loops are better predictors of chronic GI complications compared with the bowel bag, and a relatively high-dose volume (e.g. V40) of the small bowel loops is a useful predictor of chronic GI complications.

Multidrug resistance is a major concern in uterine leiomyosarcoma treatment. Development of effective chemotherapies and management of drug resistance in patients is necessary. The copper efflux transporter adenosine triphosphatase copper transporting beta is a member of the P-type adenosine triphosphatase family and is also known as a strong platinum efflux transporter. Various reports have shown the association between adenosine triphosphatase copper transporting beta and platinum resistance; however, suitable inhibitors or methods for inhibiting platinum efflux via adenosine triphosphatase copper transporting beta are not developed.Our study focused on platinum resistance in uterine leiomyosarcoma. The role of adenosine triphosphatase copper transporting beta in uterine leiomyosarcoma resistance to platinum drugs was investigated both in vitro and in vivo.Adenosine triphosphatase copper transporting beta expression was investigated by Western blotting and the efficacy of copper sulfate pretreatment and cisplatin administration in adenosine triphosphatase copper transporting beta-expressing cells was investigated both in vitro and in vivo.Western blot analysis of SK-LMS-1 cells (uterine leiomyosarcoma cell line) revealed strong adenosine triphosphatase copper transporting beta expression. A permanent SK-LMS-ATPase copper transporting beta-suppressed cell line (SK-LMS-7B cells) was generated, and cisplatin exhibited a significant antitumor effect in SK-LMS-7B cells, both in vitro (SK-LMS-1 cells, half-maximal inhibitory concentration, 17.2 μM; SK-LMS-7B cells, half-maximal inhibitory concentration, 4.2 μM, P.01) and in xenografts compared with that in SK-LMS-1 cells (5.8% vs 62.8%, P.01). Copper sulfate was identified as a preferential inhibitor of platinum efflux via adenosine triphosphatase copper transporting beta. In SK-LMS-1 cells pretreated with 15 μM copper sulfate for 3 hours, the cisplatin half-maximal inhibitory concentration decreased significantly compared with that in untreated cells and resulted in significantly increased intracellular platinum accumulation (1.9 pg/cell vs 8.6 pg/cell, P.01). The combination of copper sulfate pretreatment with cisplatin administration was also effective in vivo and caused cisplatin to exhibit significantly increased antitumor effects in mice with SK-LMS-1 xenografts (3.1% vs 62.7%, P.01).Our study demonstrates that adenosine triphosphatase copper transporting beta is overexpressed in uterine leiomyosarcoma cells and that copper sulfate, which acts as an inhibitor of platinum efflux via adenosine triphosphatase copper transporting beta, may be a therapeutic agent in the treatment of uterine leiomyosarcoma.

To compare the efficacy, safety, and tolerability profiles of pegylated liposomal doxorubicin and carboplatin (PLDC) with those of gemcitabine and carboplatin (GC) for the treatment of patients with platinum-sensitive recurrent ovarian cancer. Ovarian cancer patients with recurrence > 6 months after first-line platinum and taxane-based therapies were randomly assigned to PLDC [pegylated liposomal doxorubicin 30 mg/m2 plus carboplatin area under the curve (AUC) 5 mg/mL/min on day 1] every 4 weeks or GC (gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin AUC 4 mg/mL/min on day 1) every 3 weeks for at least 6 cycles. The primary endpoint was progression-free survival, and overall response rate, overall survival, toxicity, and dose administration were secondary endpoints. One-hundred patients (49 PLDC; 51 GC) were randomly assigned. Over a median follow-up of 24 months, the median progression-free survival was 12.0 months (95% CI 9.2–15.0) for PLDC and 9.8 months (8.9–12.3) for GC [HR 0.69 (0.455–1.047)] with a difference of 2.2 months. The response rate was 57.1% (41.0–72.3) for PLDC and 56.4% (39.6–72.2) for GC. No obvious differences in toxicity (G3/4) were noted between arms. The median relative dose intensity of planned dose per week was 88.9% for pegylated liposomal doxorubicin and 53.1% for gemcitabine (p

The median eminence (ME) anatomically consists of external (eME) and internal (iME) layers. The hypothalamic neurosecretory cells terminate their axons in the eME and secrete their neurohormones regulating anterior pituitary hormone secretion involved in stress responses into the portal vein located in the eME. Magnocellular neurosecretory cells (MNCs) which produce arginine vasopressin (AVP) and oxytocin in the paraventricular (PVN) and supraoptic nuclei (SON) terminate their axons in the posterior pituitary gland (PP) through the iME. Here, we provide the first evidence that oestrogen modulates the dynamic changes in AVP levels in the eME axon terminals in female rats, using AVP-eGFP and AVP-DREADDs transgenic rats. Strong AVP-eGFP fluorescence in the eME was observed at all oestrus cycle stages in adult female rats but not in male transgenic rats. AVP-eGFP fluorescence in the eME was depleted after bilateral ovariectomy but re-appeared with high-dose 17β-oestradiol. AVP-eGFP fluorescence in the MNCs and PP did not change significantly in most treatments. Peripheral clozapine-N-oxide administration induced AVP-DREADDs neurone activation, causing a significant increase in plasma corticosterone levels in the transgenic rats. These results suggest that stress-induced activation of the hypothalamic-pituitary-adrenal axis may be caused by oestrogen-dependent upregulation of AVP in the eME of female rats.

The incidence and long-term survival analysis for vulvar cancer, due to its rarity, has not been fully described in Asian population. The objective of the study is to determine the trends in incidence and long-term survival for vulvar cancer in a Japanese population, using a population-based cancer registry data in Osaka, Japan. The age-standardized incidence rate of 389 cases of vulvar squamous cell carcinoma (SCC) diagnosed between 1976 and 2010 was calculated, using the 1985 model population of Japan. The annual percentage change (APC) of the age-standardized incidence was estimated by the joinpoint regression models. The 5- and 10-year relative survival of 290 cases with vulvar SCC diagnosed between 1976 and 2008 were analyzed, using a cohort or period approach. Using the 10-year relative survival, the conditional 5-year survival for patients who lived for some years after diagnosis was also calculated. We have found that the age-standardized incidence rate for vulvar cancer trended downward during the period of 1979–1992 (APC − 6.3%; 95% confidence interval (CI) [− 11.3% to − 1.0%]), whereas it trended upward from 1993 to 2010 (APC 1.9%; 95% CI [− 0.7% to 4.6%]). There was no statistically significant difference for the 5- and 10-year relative survival between the two periods of 1976–2000 and 2001–2008. A statistically significant increase in the conditional 5-year survival at 2 years after diagnosis was observed (48.4%; 95% CI [41.1–55.3] versus 75.6%; 95% CI [64.0–83.9]). Despite an increasing trend in vulvar cancer incidence among Japanese population, the relative survival rate for vulvar cancer did not change over the 35 years of this study. We found that the conditional 5-year survival for vulvar cancer, as patients survived additional years, approached within reach of 100%. These data can provide valuable information for both patients and clinicians.

To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma.A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes.Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P0.001).Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Several molecular targeting drugs are being evaluated for endometrial cancer; selecting patients whose cancers are sensitive to these agents is of paramount importance. Previously, we developed the cancer tissue-originated spheroid method for primary cancer cells taken from patients' tumors as well as patient-derived xenografts. In this study, we successfully prepared and cultured cancer tissue-originated spheroids from endometrial cancers. Characteristics of the original tumors were well retained in cancer tissue-originated spheroids including morphology and expression of p53 or neuroendocrine markers. We screened 79 molecular targeting drugs using two cancer tissue-originated spheroid lines derived from endometrioid adenocarcinoma grade 3 and serous adenocarcinoma. Among several hits, we focused on everolimus, a mammalian target of rapamycin complex 1 inhibitor, and YM155, a survivin inhibitor. When sensitivity to everolimus or YM155 was assessed in 12 or 11 cancer tissue-originated spheroids, respectively, from different endometrial cancer patients, the sensitivity varied substantially. The cancer tissue-originated spheroids sensitive to everolimus showed remarkable suppression of proliferation. The phosphorylation status of the mammalian target of rapamycin complex 1 downstream molecules before and after everolimus treatment did not predict the effect of the drug. In contrast, the cancer tissue-originated spheroids sensitive to YM155 showed remarkable cell death. The effect of YM155 was also confirmed in vivo. The histological type correlated with YM155 sensitivity; non-endometrioid adenocarcinomas were sensitive and endometrioid adenocarcinomas were resistant. Non-canonical autophagic cell death was the most likely cause of cell death in a sensitive cancer tissue-originated spheroid. Thus, sensitivity assays using cancer tissue-originated spheroids from endometrial cancers may be useful for screening drugs and finding biomarkers.

Background/Aims: The study aims to prevent serious urologic injury during a radical hysterectomy; we propose that one of the most important procedural steps is the careful management of the vesicouterine ligament (VUL). Patients and Methods: Between January 2013 and October 2014, we used a novel internal retractor in 17 patients undergoing a laparoscopic radical hysterectomy (LRH) for early-stage cervical cancer to obtain and secure a better surgical view. For management of the VUL during the laparoscopic procedure, we routinely used an internal retractor (EndoGrab; Virtual Ports, Misgav, Israel) and vessel tape to reposition the ureter in a safe lateral-caudal direction. Results: Using an EndoGrab, we were easily able to reproduce a suitable surgical view that simulated the one obtained by an abdominal route for radical hysterectomy. Using this improved laparoscopic procedure, we completed radical hysterectomies in all 17 cases without a ureteral injury complication. Conclusion: Our modified method using an EndoGrab is effective for the prevention of ureteral injury during a LRH, and its ease of use makes it suitable even for those surgeons early in their laparoscopic learning curve.

The objective of this study is to analyze the clinical outcomes of abnormal cervical cytology and newly diagnosed human papillomavirus (HPV)-related disease after organ transplantation. Medical records from July 2004 to August 2015 were reviewed, and thirteen patients were identified who had been newly diagnosed with HPV-related disease (cervical intraepithelial neoplasia [CIN] and cervical cancer) after organ transplantation. The median transition time to the aggravation of cervical cytology and the spontaneous regression rate of CIN were evaluated. Clinical outcomes of CIN1 and CIN2 were compared between the general population and patients with organ transplantation. We also reviewed the current literature regarding the incidence of HPV infection, Pap smear abnormality and/or CIN after organ transplantation. The cervical cytology aggravated in nine of the 13 patients (69 %). In seven of the 13 cases (54 %), treatments such as cervical conization, laser vaporization, or radiation therapy, were conducted. HPV-related disease disappeared after treatment in only three of the seven actively treated cases (43 %). In contrast, the lesions persisted in three (43 %) cases after treatment. One patient died from cervical cancer. The spontaneous regression rate of the HPV-related diseases, if left untreated, was 0 %. There was a statistically significant difference in the clinical outcomes of CIN1 and CIN2 between the general population and patients with organ transplantation (p = 0.0026 and 0.0315, respectively; chi-squared test). HPV-related lesions that are newly diagnosed after organ transplantation do not seem to regress as spontaneously as in the general population. Physicians should recognize the importance of close monitoring and long-term follow-up.

The objective of this study was to investigate the predictive value of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for early assessment of tumor response to chemotherapy and for patient survival in gynecologic malignancies. We performed CT and FDG-PET scans before initiation of chemotherapy to determine baseline conditions. PET scan was repeated after the first cycle of chemotherapy. The tumor response was later evaluated by CT scans after three cycles of chemotherapy, using RECIST. The PET response was analyzed in terms of the difference in SUVmax for FDG of the patient’s largest lesion between the baseline scan and after the first cycle of chemotherapy. The metabolic response for the tumor was defined as a 30 % reduction in its SUVmax. Eleven patients received platinum-based regimens, and 20 patients received non-platinum-based regimens. The mean progression-free survival (PFS) for the patients with a metabolic response was 13 months (range 5–29). In contrast, the mean PFS of the patients with no metabolic response was only 4.3 months (range 1–18). There was a statistically significant difference between the metabolic response and PFS (p = 0.002, Mann–Whitney U test). There was a strong correlation between the metabolic response and RECIST, regardless of the chemotherapy regimens used (platinum-based group, p = 0.006; non-platinum group, p = 0.046, Fisher’s exact test). The metabolic change in SUVmax was clearly predictive of tumor response in 93.5 % of patients. Early FDG-PET assessment by measuring the single largest lesion is a very promising tool for rapidly predicting tumor responses and patient survival, regardless of the chemotherapy regimen.

This study aimed to determine the association between umbilical cord leucine-rich alpha-2 glycoprotein (LRG) and fetal infection and investigate the underlying mechanism of LRG elevation in fetuses. We retrospectively reviewed the medical records of patients who delivered at Osaka University Hospital between 2012 and 2017 and selected those with histologically confirmed chorioamnionitis (CAM), which is a common pregnancy complication that may cause neonatal infection. The participants were divided into two groups: CAM with fetal infection (CAM-f[+] group,n =14) and CAM without fetal infection (CAM-f[−] group,n =31). Fetal infection was defined by the histological evidence of funisitis. We also selected 50 cases without clinical signs of CAM to serve as the control. LRG concentrations in sera obtained from the umbilical cord were unaffected by gestational age at delivery, neonatal birth weight, nor the presence of noninfectious obstetric complications (all,p> 0.05). Meanwhile, the LRG levels (median, Interquartile range [IQR]) were significantly higher in the CAM-f(+) group (10.37 [5.21–13.7] μg/ml) than in the CAM-f(−) (3.61 [2.71–4.65] μg/ml) or control group (3.39 [2.81–3.93] μg/ml;p< 0.01). The area under the receiver operating characteristic (ROC) curve of LRG for recognizing fetal infection was 0.92 (optimal cutoff, 5.08 μg/ml; sensitivity, 86%; specificity, 88%). In a mouse CAM model established by lipopolysaccharide administration, the fetal LRG protein in sera andLRGmRNA in the liver were significantly higher than those in phosphate-buffered saline (PBS)-administered control mice (p< 0.01).In vitroexperiments using a fetal liver-derived cell line (WRL68) showed that the expression ofLRGmRNA was significantly increased after interleukin (IL)-6, IL-1β, and tumor necrosis factor- alpha (TNF-α) stimulation (p< 0.01); the induction was considerably stronger following IL-6 and TNF-α stimulation (p< 0.01). In conclusion, LRG is an effective biomarker of fetal infection, and fetal hepatocytes stimulated with inflammatory cytokines may be the primary source of LRG productionin utero.

Background Ultrasound-guided nerve blocks are effective; however, their use in the abdominal wall is reportedly associated with a risk of abdominal organ injury. Laparoscopic-guided nerve blocks are thought to be safer than ultrasound-guided nerve blocks. We evaluated the safety and effectiveness of the laparoscopic-guided rectus sheath block (LGRSB) for umbilical incisions after gynecologic laparoscopy. Materials and methods A single-center, prospective, randomized controlled trial of 210 women who underwent gynecologic laparoscopy was performed at a university teaching hospital in Japan. The intervention group underwent the LGRSB with ropivacaine hydrochloride at the end of laparoscopy under general anesthesia and received regular care. The control group received only regular care without a field block. The postoperative pain score (PPS) was recorded at 6 and 12 h and 1, 2, and 3 days postoperatively. The PPS and use of postoperative analgesics (loxoprofen, diclofenac, and pentazocine) were recorded by the floor nurses, who were blinded to the patients’ data. Results In total, 107 women in the intervention group and 101 women in the control group were analyzed. No adverse events were encountered throughout this study. There was no evidence of differences in the PPS or use of perioperative opioids and postoperative analgesics. Conclusion The LGRSB for umbilical incisions after laparoscopic gynecology was easy and safe. However, this method did not significantly reduce the PPS at rest or during coughing in all postoperative conditions after gynecologic laparoscopy compared with the control.

The use of less radical surgery for early stage cervical cancer has often been discussed. To better determine eligible candidates for less radical surgery, we investigated the risk factors for parametrial involvement (PI).The study included 193 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical cancer who were treated with radical hysterectomy and pelvic lymphadenectomy between 2008 and 2014. The patients were divided into two groups according to whether or not the parametrium was involved pathologically. The two groups were compared with regards to clinical and histopathological variables.Univariate analysis showed that International Federation of Gynecology and Obstetrics stage, clinical tumor size, depth of stromal invasion, lymphovascular space invasion and pelvic lymph node metastasis were significantly associated with PI (P0.05 each). Multivariate analysis showed pelvic lymph node metastasis was an independent risk factor for PI (odds ratio, 10.70; [95% confidence interval, 3.02-48.08]; P = 0.0006). All patients with clinical tumor size less than or equal to 2 cm and negative for pelvic lymph node metastasis had no PI.Cervical cancer with the tumor less than or equal to 2 cm and negative for pelvic lymph node metastasis seldom has PI. These patients are good candidates for less radical surgery.

In Japan, the trend for cervical cancer at younger ages has been increasing. As a countermeasure, the HPV vaccine was introduced as a routine vaccination in April 2013. However, the Ministry of Health, Labour and Welfare (MHLW) announced a “Suspension of its active inoculation recommendation for HPV vaccine” in June 2013. In 2016, 32 months after that suspension, we conducted survey via Internet and compared the results with our previous ones conducted at 9 and 23 months after suspension (in 2014 and 2015, respectively). We examined the ‘time-dependent change’ of the ‘intention of mothers to inoculate their daughters with the HPV vaccine’ in terms of efficacy of external decision-making support. 17.5% of mothers in the first survey replied that they would inoculate their daughters under the current circumstances, 12.1% in the second survey, and 6.7% in the third, showing a consistent decrease in willingness over time (p = 0.03, p < 0.01). If the government recommendation were to be reintroduced, 22.5% of mothers in the first survey replied they would inoculate their daughters, 21.0% in the second survey, which indicated no significant difference (p = 0.65) over the first interval; however, this was significantly decreased to 12.2% in the third survey (p < 0.01). Our study revealed that the intention to inoculate their daughters has been declining among Japanese mothers over time triggered by the suspension.

PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.

OBJECTIVE: To examine significance of sarcoma dominance (SD) patterns In uterine carcinosarcoma (UCS). METHODS: This is a secondary analysis of multicenter retrospective study examining women with stages I-IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. RESULTS: SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P < 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35–1.69, and hetero/dominance 1.47–1.64) and CSS (adjusted-HR ranges: 1.52–1.84 and 1.66–1.81, respectively) compared to homo/non-dominance (all, P < 0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P > 0.05). CONCLUSION: In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy.

Background Placenta percreta is a rare obstetric condition associated with the risk of massive intraoperative hemorrhage. Recently, conservative management of placenta percreta has been performed to reduce maternal morbidity. However, various complications have been reported during such management. Only a few cases of asymptomatic disseminated intravascular coagulation (DIC) or fever without infection have been reported. Here, we discuss such a case and review the related literature to understand this rare condition better. For this, we performed an electronic literature review. Case presentation We present the clinical course, results of blood tests, and serial magnetic resonance images of a 35-year-old female (gravida 5, para 2) with placenta percreta complicated by placenta previa that was managed conservatively. The patient successfully delivered a healthy baby by a cesarean delivery via a transverse uterine fundal incision at 36 weeks of gestation. We did not observe intraoperative complications during cesarean delivery, and the postoperative course remained uncomplicated until 47 days after the delivery. However, asymptomatic DIC developed after 47 days, and her serum fibrinogen level declined to 42 mg/dL, which was successfully treated with anticoagulant therapy by a therapeutic dose of intravenous heparin for 22 days (postoperative days 48–69). Although DIC resolved, subsequent fever persisted for approximately 1 month (postoperative days 67–103). Infection was ruled out, and conservative management was successfully continued. Literature review revealed that successful conservative management of a patient with asymptomatic DIC and subsequent fever without infection is extremely rare. Conclusions Some patients with DIC and fever can continue conservative management of placenta percreta, although careful examination and monitoring are needed.

Mature cystic teratoma is a germ cell tumor of the ovaries and is often observed in clinical practice. However, extragonadal teratomas are rare tumors and have been reported outside the ovaries, (e.g., in the greater omentum). The mechanism underlying the development of extragonadal teratomas remains unknown. We encountered a case of extragonadal teratoma in the pouch of Douglas that appeared to be a parasitic dermoid cyst. From our experience and the literature review, we discuss the potential mechanism leading to the development of extragonadal teratomas. A 41-year-old nonpregnant woman was referred to our department due to myoma and anemia. A 4-cm asymptomatic mass in the pouch of Douglas was observed, and the patient was diagnosed with ovarian mature cystic teratoma. She underwent laparoscopic surgery, and intraoperative findings revealed that the fallopian tube was injured and torn, and a residual small ovary was observed in the left side of the ovary. A tumor measuring approximately 4 cm observed in the pouch of Douglas was extracted without rupturing. The tumor was diagnosed as a parasitic dermoid cyst by macroscopic and histopathological findings. Auto-amputation could be the underlying mechanism that leads to an isolated parasitic dermoid cyst in the pouch of Douglas.

Numerous monoclonal antibodies (mAb) targeting tumor antigens have recently been developed. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) via effector cells such as tumor-infiltrating natural killer (NK) cells and macrophages are often involved in mediating the antitumor activity of mAb. CpG oligodeoxynucleotides (ODN) have a potent antitumor activity and are considered to increase tumor infiltration of NK cells and macrophages. Our group previously reported significant antitumor activity of anti-bone marrow stromal antigen 2 (BST2) mAb against BST2-positive endometrial cancer cells through ADCC. In this study, we evaluated the synergistic antitumor activity of combination therapy with anti-BST-2 mAb and CpG ODN using SCID mice and elucidated the mechanisms underlying this activity. Anti-BST2 mAb and CpG ODN monotherapy had a significant dose-dependent antitumor activity (P = 0.0135 and P = 0.0196, respectively). Combination therapy with anti-BST2 mAb and CpG ODN had a significant antitumor activity in SCID mice (P