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Previous studies have largely failed to clarify the relationship between p16INK4A status and cervical adenocarcinoma prognosis. The current study aimed to examine the clinical and pathological significance of p16INK4A expression in several cervical adenocarcinoma subtypes. Eighty-two samples collected from patients with cervical adenocarcinoma were formalin fixed and paraffin embedded. Next, p16INK4A levels were analyzed with immunohistochemistry. Additionally, the relationship between p16INK4A expression and clinicopathological factors as well as prognosis was evaluated. The expression of p16INK4A was mostly detected in all usual cervical adenocarcinoma subtypes. In the gastric type, only a few cases were positive for p16INK4A expression. Results of the Kaplan–Meier analysis indicated that the positive p16INK4A expression in tumor cells was significantly associated with favorable progression-free survival and overall survival in patients with cervical adenocarcinoma (p = 0.018 and p = 0.047, respectively, log-rank test). Our findings suggest that the status of p16INK4A expression may influence prognosis. Thus, p16INK4A expression could be used as a biomarker for improving the prognosis of patients with cervical adenocarcinoma.

Type II endometrial cancer (EC) is responsible for most endometrial cancer-related deaths due to its aggressive nature, late-stage detection, and high tolerance to standard therapies. Thus, novel treatment strategies for type II EC are imperative. For patients with mismatch repair-deficient (dMMR) tumors, immunotherapy with immune checkpoint inhibitors represents a promising therapeutic strategy. However, the prevalence of dMMR tumors in type II EC patients remains unclear. In this study, using immunohistochemistry, we evaluated the expression of mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1) in 60 patients with type II EC (16, 5, 17, and 22 were endometrioid G3, serous, de-differentiated, and carcinosarcoma cases, respectively) to investigate the therapeutic effect of immune checkpoint inhibitors. Approximately 24 cases (40%) had a loss of MMR protein expression. The positivity rate of CD8+ (p = 0.0072) and PD-L1 (p = 0.0061) expression was significantly associated with the dMMR group. These results suggest immune checkpoint inhibitors (anti-PD-L1/PD-1 antibodies) could effectively treat type II EC with dMMR. The presence of dMMR might be a biomarker for a positive response to PD-1/PD-L1 immunotherapy in type II EC.

Although the negative effect of muscle loss during invasive treatment has been widely reported in patients with cancer, its value in patients with ovarian cancer is not clear. Therefore, this study was conducted to clarify whether muscle loss during cytoreductive surgery and chemotherapy affects prognosis in patients with ovarian cancer. We retrospectively recruited 58 patients with ovarian cancer who underwent site reductive surgery and chemotherapy at Shimane University Hospital from March 2006 to November 2013 and for whom pre- and postoperative computed tomography were available. Skeletal muscle changes and fat mass volume during primary debulking surgery and chemotherapy were subsequently investigated at the level of the third lumbar vertebra. Muscle and fat mass loss occurred independently in half of the patients. Muscle loss, but not fat loss, was associated with disease-free survival (p = 0.041 and p = 0.794, respectively) and poor overall survival (p = 0.033 and p = 0.61, respectively). Cancer therapy is invasive and causes compositional changes in the body, such as muscle and fat loss. During cancer therapy, muscle loss, but not fat loss, may be associated with worse prognosis in ovarian cancer.

Ovarian cancer has the highest mortality rate among all gynecological malignancies; therefore, a novel treatment strategy is needed urgently. Utilizing immune checkpoint inhibitors has been considered for microsatellite instability (MSI)-high (MSI-H) tumors. However, the prevalence of MSI-H tumors in ovarian endometrioid and clear cell carcinomas remains unclear. Here, polymerase chain reaction was used to analyze 91 cases of ovarian endometrioid and clear cell carcinomas for the MSI status and the relationship between MSI-H, immune checkpoint molecules, and clinicopathological factors (including patient survival). Only 5 of 91 (5%) cases were MSI-H endometrioid carcinomas. In these cases, CD-8 expression was significantly higher (p = 0.026), confirming an enhanced immune response. From the survival curve, no statistical correlations were found between the MSI-H group and the microsatellite stable (MSS) group; however, the MSS group trended towards better progression-free survival than the MSI-H group (p = 0.056). Patients with PD-L1 expression had shorter overall survival than those without (p = 0.022). Thus, MSI-H is a rare event and not a favorable prognostic factor in ovarian endometrioid and clear cell carcinomas. Thus, to improve the prognosis of ovarian endometrioid carcinoma and clear cell carcinomas, a combination therapy of immune checkpoint inhibitors and other molecular targeted therapies may be required.

Although vascular injury during laparoscopic surgery is rare, it is occasionally reported. Previously, several physicians have reported cases of compartment syndrome resulting from a thrombus during gynecologic surgery. However, few reports describe thrombosis occurring in artery vessels as a result of applying angiopressure. Herein, we report the case of a 53-year-old woman with endometrioid carcinoma and a vascular injury that resulted in thrombus formation; this is the first such case to be reported. The complication was successfully treated by means of direct anastomosis following partial resection of the injured iliac artery. This is the first report of a case in which applying angiopressure for a vascular injury during laparoscopic pelvic lymphadenectomy led to an intra-arterial thrombus which was found and treated without sequelae.

Background Laparoscopic myomectomy (LM) is one of the techniques feasible for the treatment of intramural myoma. This technique is reported to be difficult when large fibroids are involved because of excessive blood loss during surgery. Skillful and fast suturing appears to be associated with reduced blood loss during LM. In this study we compared the surgical outcomes of using bidirectional Stratafix® barbed suture versus conventional suture during LM. Methods This retrospective study included all patients who underwent LM for the treatment of intramural myoma in our institution between 2015 and 2020. The patients were divided into 2 groups according to the technique of suturing during LM: Group 1 comprised patients in whom Stratafix® barbed suture was used (n = 29), and group 2 comprised those in whom conventional suture was used (n = 15). Data of patient age, myoma size, the number of myoma nodes, hemoglobin levels, total operation time, total suturing time, and blood loss during surgery were compared between the 2 groups. Results No significant differences in age (p = 0.463) or myoma size (P = 0.373) were observed between the 2 groups. Operation time (P = 0.0104), suturing time (P = 0.007), and blood loss (P = 0.0375) during surgery were significantly less with Stratafix® barbed suture than with conventional suture. No patient required intraoperative transfusion or conversion to laparotomy. Conclusion The use of bidirectional barbed suture reduces operation time, suturing time, and blood loss. As these new sutures have barbs, no knot-tying is required; thus, continuous suturing becomes very simple and maintaining hemostasis is easy. Unskilled gynecological surgeons who apply this suture technique can also perform LM easily. As the bidirectional barbed suture has multiple points of fixation, this suture technique can reapproximate tissue securely, which reduces the chances of reoperation because of proper suture knotting. Therefore, bidirectional Stratafix® barbed sutures could be an optimal and efficient alternative to conventional sutures for use by gynecological surgeons in Japan.

Purpose Mucinous ovarian carcinomas (MOCs) are relatively rare. It has been proposed that a subset of mucinous cystadenomas (MCAs) may progress to mucinous borderline tumors (MBTs), and then to MOCs. KRAS is the predominantly mutated gene in MOC; however, other associated mutations and the mechanism underlying carcinogenesis in MOC remain unclear. Here, we assessed molecular genetic alterations in mucinous ovarian tumors and constructed mutation profiles. Methods Using the Sanger sequencing method, we assessed genetic mutations (KRAS, BRAF, TP53, and PIK3CA) in 16 cases of MOC, 10 cases of MBT, and 12 cases of MCA. Results Among MOC cases, the prevalence of G12D and G13D KRAS mutations was 43.8% (7/16). No MOC cases showed V600E BRAF and TP53 mutations. Among MBT cases, the prevalence of G12D KRAS mutation was 20.0% (2/10), those of TP53 and PIK3CA mutations were nil, and that of V600E BRAF mutation was 40% (4/10). None of the genetic mutations assessed were detected among MCA cases. Conclusion These results suggest that MBT with V600E BRAF mutation may rarely progress to MOC, while MBT with G12D or G13D KRAS mutation may more commonly progress to MOC.

Despite the knowledge about numerous genetic mutations essential for the progression of low-grade serous ovarian carcinoma (LGSOC), the specific combination of mutations required remains unclear. Here, we aimed to recognize the oncogenic mutations responsible for the stepwise development of LGSOC using immortalized HOVs-cyst-1 cells, developed from ovarian serous cystadenoma cells, and immortalized via cyclin D1, CDK4R24C, and hTERT gene transfection. Furthermore, oncogenic mutations, KRAS and PIK3CA, were individually and simultaneously introduced in immortalized HOV-cyst-1 cells. Cell functions were subsequently analyzed via in vitro assays. KRAS or PIK3CA double mutant HOV-cyst-1 cells exhibited higher cell proliferation and migration capacity than the wild-type cells, or those with either a KRAS or a PIK3CA mutation, indicating that these mutations play a causative role in LGSOC tumorigenesis. Moreover, KRAS and PIK3CA double mutants gained tumorigenic potential in nude mice, whereas the cells with a single mutant exhibited no signs of tumorigenicity. Furthermore, the transformation of HOV-cyst-1 cells with KRAS and PIK3CA mutants resulted in the development of tumors that were grossly and histologically similar to human LGSOCs. These findings suggest that simultaneous activation of the KRAS/ERK and PIK3CA/AKT signaling pathways is essential for LGSOC development.

The treatment of cervical intraepithelial neoplasia (CIN) can result in under- or overtreatment. The current report describes a case of undertreatment of a cervical tumor. A 72-year-old woman was preoperatively diagnosed with CIN3. Following surgery, the final diagnosis of the excised specimen was keratinizing squamous cell carcinoma that measured 2.5 cm in size. The exocervical margin and deep margin were negative. The patient received adjuvant therapy with concurrent chemoradiotherapy and never had disease recurrence. In elderly patients, making an accurate preoperative diagnosis based on specimens from cervical biopsies with or without colposcopy is difficult. MRI may be an accurate preoperative indicator of early cervical tumor, although some studies have demonstrated that MRI has a limitation with respect to its diagnostic ability. Other studies have reported that it is necessary to perform conization prior to hysterectomy. Physicians must reconsider the determined preoperative diagnosis of an early cervical tumor and establish standard guidelines for deciding when to use surgical treatment in elderly patients.

Recent advances in next-generation sequencing and genome medicine have contributed to treatment decisions in patients with cancer. Most advanced gynecological cancers develop resistance to chemotherapy and have a poor prognosis. Therefore, we conducted genomic tests in gynecological tumors to examine the efficacy and clinical feasibility of genotype-matched therapy. Target sequencing was performed in 20 cases of gynecological cancers (cervical cancer, 6, endometrial cancer, 6, and ovarian cancer, 6). Both actionable and druggable genes were identified in 95% (19/20) of the cases. Among them, seven patients (35%) received genotype-matched therapy, which was effective in three patients. Of the three patients, one patient with a PTEN mutation received everolimus, another patient with a TSC2 mutation received everolimus and letrozole, and the patient with a BRIP1 mutation received olaparib. Subsequently, disease control in these three patients lasted for more than half a year. However, all patients relapsed between 9 and 13 months after the initiation of genotype-matched therapy. In this study, the response rate of genotype-matched therapy was 43% (3/7), which may have contributed to improved prognoses. Therefore, genotype-matched therapies may help patients with refractory gynecological cancers achieve better outcomes.

Background: Recent advances in next-generation sequencing and genome medicine has contributed to treatment decisions in patients with cancer. Most advanced gynecological cancers develop resistance to chemotherapy and have a poor prognosis. Therefore, we conducted genomic tests in gynecological tumors to examine the efficacy and clinical feasibility of genotype-matched therapy. Methods: Target sequencing was performed in 20 cases of gynecological cancers (cervical cancer, 6; endometrial cancer, 6; and ovarian cancer, 6).Results: Both actionable and druggable genes were identified in 95% (19/20) of the cases. Among them, seven patients (35%) received genotype-matched therapy, which was effective in three patients. Of the three patients, one patient with a PTEN mutation received everolimus, another patient with a TSC2 mutation received everolimus and letrozole, and the patient with a BRIP1 mutation received olaparib. Subsequently, disease control in these three patients lasted for more than half a year. However, all patients relapsed between 9 and 13 months after the initiation of genotype-matched therapy. In this study, the response rate of genotype-matched therapy was 43% (3/7), which may have contributed to improved prognoses.Conclusions: Therefore, genotype-matched therapies may help patients with refractory gynecological cancers achieve better outcomes.

Endometriosis-harboring cancer-associated somatic mutations of PIK3CA and KRAS provides new opportunities for studying the multistep processes responsible for the functional and molecular changes in this disease. We aimed to establish a novel in vitro endometriosis model to clarify the functional behavior and molecular pathogenesis of this disorder. Immortalized HMOsisEC10 human ovarian endometriotic epithelial cell line was used in which KRAS and PIK3CA mutations were introduced. Migration, invasion, proliferation, and microarray analyses were performed using KRAS and PIK3CA mutant cell lines. In vitro assays showed that migration, invasion, and proliferation were significantly increased in KRAS and PIK3CA mutant cell lines, indicating that these mutations played causative roles in the aggressive behavior of endometriosis. Microarray analysis identified a cluster of gene signatures, among them, two significantly upregulated cancer-related genes, lysyl oxidase (LOX) and pentraxin3 (PTX3), were associated with cell proliferation, invasion, and migration capabilities. Furthermore, siRNA knockdown of the two genes markedly reduced the metastatic ability of the cells. These results suggest that endometriosis with KRAS or PIK3CA mutations can significantly enhance cell migration, invasion, and proliferation by upregulating LOX and PTX3. We propose that LOX and PTX3 silencing using small molecules could be an alternative therapeutic regimen for severe endometriosis.

Innovation in gynecological surgery is constantly evolving to make procedures less invasive. Minimally invasive single-port laparoscopic surgery (SPLS) is another innovation that may further improve gynecological surgery outcomes. However, SPLS is not widely used due to the technical difficulties of the procedure. Inserting several instruments through the same incision impedes proper use of the devices. Therefore, the present study aimed to find a technique to overcome this problem and make this approach more convenient. Between March 2015 and February 2020, 25 patients were treated with SPLS by a single gynecological surgeon. The range of surgery time was 50-103 min and the mean surgery time was 67.2 min. The mean bleeding volume was small (mean, 10.1 ml). No intraoperative or postoperative complications occurred in the patients. A gel port (GelPOINT® Mini Medical Leaders) was inserted into the peritoneal cavity through a 3-cm Z-shaped intra-umbilical skin incision. Additionally, a small incision (3 mm) was made in the left medial portion of the iliac crest and a bladeless trocar (Versa One®) was inserted. Thus, crowding of the working instruments within one incision was prevented. The addition of a small diameter port (3-mm) at the wound site left practically no scar, thus making SPLS a cosmetically superior option compared with a bigger diameter port (5-mm).

Bisphenol A and its derivatives are recognized endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is not well understood. Herein, we identified novel ERβ ligands by screening a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as ERα agonists and ERβ antagonists. Docking simulations suggested that these compounds act as coactivator binding inhibitors (CBIs). Direct binding experiments using wild-type and mutated ERβ demonstrated the presence of a second ligand interaction position at the coactivator binding site in ERβ. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting a critical view point for future ER signaling-based drug development.

The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them.

Malignant transformation of extraovarian endometriosis is rare, with the carcinogenesis mechanism unclear. To clarify the actionable variants of rare-site endometriosis-associated cancer (RSEAC), we performed whole-exome sequencing for the tumor, in two patients. The intestine was affected in both cases, although the histology was that of clear cell carcinoma and undifferentiated carcinoma, respectively. Therefore, the cases were referred to as endometriosis-associated intestinal tumors (EIATs). Actionable variants (all frameshift mutations) were identified in tumor suppressor genes ARID1A, PTEN, and p53, however, no oncogenic variants were identified. Both cases were microsatellite stable. The patient with undifferentiated carcinoma exhibited hypermutator and homologous recombination deficiency phenotypes. The dominant mutation signatures were signature 30 (small subset of breast cancers) and 19 (pilocytic astrocytoma) in patient 1, and signature 5 (small subset of breast cancers) and 3 (breast, ovarian, and pancreatic cancers) in patient 2. Immunohistochemistry revealed positive CD8 and PD-1 expression in both patients, patient 1 also showed positive PDL-1 expression. Our results suggest that RSEAC is associated with variants of tumor suppressor genes as epigenetic alterations. Mutation signature-based whole-exome sequencing could be useful to select an adjuvant chemotherapy regimen. High CD8 and PD-1 expression in RSEAC suggests that immune checkpoint inhibitors are useful for treatment.

Telomere length (TL) influences the development of lifestyle-related diseases, and neonatal TL may influence their prevalence. Various factors have been reported to affect neonatal TL. Although the fetus is exposed to multiple conditions in utero, the main factors affecting the shortening of neonatal TL are still not known. In this study, we sought to identify factors that influence fetal TL. A total of 578 mother-newborn pairs were included for TL analysis. TL was measured in genomic DNA extracted from cord blood samples using quantitative PCR. The clinical factors examined at enrollment included the following intrauterine environmental factors: maternal age, assisted reproductive technology (ART) used, body mass index (BMI), gestational diabetes mellitus (GDM), maternal stress, smoking, alcohol consumption, preterm delivery, small-for-gestational-age, neonatal sex, and placental weight. Univariate and multivariate regression analyses were used to verify the relationship between neonatal TL and these clinical factors. The median neonatal TL to single-copy gene ratio was 1.0. Pregnancy with ART was among the 11 factors associated with shorter neonatal TL. From multiple regression analysis, we determined that neonatal TL was significantly shorter for pregnancies in the ART group than in the other groups. We conclude that pregnancy with ART is associated with shorter neonatal TL.

Background: Lymphocyte telomere length is strongly correlated with patient prognosis in several malignant tumor types and is thought to be related to tumor immunity. However, this correlation has not been studied in gynecological cancers. We determined the prognostic significance of peripheral blood lymphocyte telomere length in gynecologic cancers. Methods: Telomere length of lymphocytes from patients with gynecological malignant tumors (ovarian cancer (OC), N = 72, cervical cancer (CC), N = 63, endometrial cancer (EC), N = 87) was examined by quantitative reverse-transcription PCR of isolated mononuclear cells. Kaplan&ndash, Meier and Cox proportional hazard analyses were used to determine the association between lymphocyte telomere length and clinicopathological factors. Results: The overall survival (OS) and progression-free survival (PFS) of patients were based on the dichotomized lymphocyte telomere length using the median as a threshold (OC: 0.75, CC: 1.94, and EC: 1.09). A short telomere length was significantly correlated with residual tumors (&ge, 1 cm) in OC and with advanced stage (III and IV) of CC. In OC and CC, patients with shorter relative lymphocyte telomere length (RLT) had significantly poorer OS and PFS than patients with longer RLT (p = 0.002, p = 0.003, and p = 0.001, p = 0.001, respectively). However, in EC, RLT was not significantly associated with OS or PFS (p = 0.567 and p = 0.304, log-rank test). Multivariate analysis showed that shorter RLT was a significant independent prognostic factor of PFS and OS for OC (p = 0.03 and p = 0.04, respectively) and CC (p = 0.02 and p = 0.03, respectively). Conclusions: Patients with OC and CC with shorter lymphocyte telomeres have significantly reduced survival, therefore, the peripheral blood lymphocyte telomere length is a prognostic biomarker in OC and CC.

The acceptance of MEA in Japan is well demand due to its outstanding effectiveness and safety. Infrequently, a repeat MEA or hysterectomy is needed for recurrent menorrhagia in case of failure ablation. The reasons of recurrent menorrhagia subsequent MEA treatment are unclear. The objective of current study is to identify the possible causes of menorrhagia repetition following MEA, together with the observation of histological changes in the endometrium due to this treatment compared with normal cycling endometrial tissue. A total of 170 patients, 8 (4.7%) of them carried out hysterectomy after 16.8 months (range, 2–29 months) of MEA treatment. Normal (n = 47) and MEA (n = 8) treated paraffin embedded endometrial tissue were prepared for hematoxylin and eosin (H&E) and immunostaining study to recognize the histological changes in the endometrium as a result of MEA treatment. The histological features observed increased tubal metaplasia (TM) including negative expression of the estrogen receptor (ER) and progesterone receptor (PR) in the endometrium subsequent MEA treatment. Increased TM together with the absence of ER and PR expression might be a reasonable explanation for repetition menorrhagia in cases of failure ablation. Further study is required to clarify the molecular mechanisms of tubal metaplasia and the expression loss of hormone receptor in the endometrium as a result of MEA treatment. Current studies propose that low dose estrogen-progestin may not be effective with recurrent menorrhagia patient’s due to the inadequacy of hormone receptor expression in the endometrium following MEA.

Previous studies have largely failed to clarify the relationship between p16INK4A status and cervical adenocarcinoma prognosis. The current study aimed to examine the clinical and pathological significance of p16INK4A expression in several cervical adenocarcinoma subtypes. Eighty-two samples collected from patients with cervical adenocarcinoma were formalin fixed and paraffin embedded. Next, p16INK4A levels were analyzed with immunohistochemistry. Additionally, the relationship between p16INK4A expression and clinicopathological factors as well as prognosis was evaluated. The expression of p16INK4A was mostly detected in all usual cervical adenocarcinoma subtypes. In the gastric type, only a few cases were positive for p16INK4A expression. Results of the Kaplan–Meier analysis indicated that the positive p16INK4A expression in tumor cells was significantly associated with favorable progression-free survival and overall survival in patients with cervical adenocarcinoma (p = 0.018 and p = 0.047, respectively, log-rank test). Our findings suggest that the status of p16INK4A expression may influence prognosis. Thus, p16INK4A expression could be used as a biomarker for improving the prognosis of patients with cervical adenocarcinoma.

PurposeThe effectiveness of immunotherapy for cervical adenocarcinoma (CA) has not been demonstrated yet. Programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and CD8 may be used as biomarkers of response to immune therapy in CA patients. In the present study, we aimed to investigate whether the expression levels of PD-1, PD-L1, and CD8 can predict the prognosis of patients with CA and their response to immune checkpoint inhibition therapy.MethodsIn the present study, the clinical stage for all 82 patients with cervical adenocarcinoma was classified according to the guidelines of the International Federation of Gynecology and Obstetrics (FIGO); there were 5, 48, 5, 14, 8, and 2 patients with stage IA, IB, IIA, IIB, IIIB, and IVB disease, respectively. The levels of PD-1, PD-L1, and CD8 were analyzed by the immunohistochemical analysis of the formalin-fixed paraffin-embedded tumor samples. The correlation between the expression levels and patient prognosis was analyzed using the Kaplan–Meier method and univariate and multivariate Cox proportional hazard regression models.ResultsWe observed a significant inverse correlation between the expression of PD-1 and CD8 (p = 0.001, chi-square test). We also found a significant inverse correlation between the expression of PD-L1 and CD8 (p = 0.027). The overall survival and progression-free survival rates were significantly worse in patients with positive PD-1 expression (p = 0.031;p = 0.087, respectively).ConclusionOur results suggest that a high PD-1 expression is associated with a poor prognosis in patients with CA. Further research is necessary to identify the molecular mechanisms that mediate this association.

// Kohei Nakamura 1 , Kentaro Nakayama 1 , Noriyoshi Ishikawa 2 , Toshiko Minamoto 1 , Tomoka Ishibashi 1 , Kaori Ohnishi 1 , Hitomi Yamashita 1 , Ruriko Ono 1 , Hiroki Sasamori 1 , Sultana Razia 1 , Mohammad Mahmud Hossain 1 , Shanta Kamrunnahar 1 , Masako Ishikawa 1 and Satoru Kyo 1 1 Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 6938501, Japan 2 Department of Organ Pathology, Shimane University School of Medicine, Izumo 6938501, Japan Correspondence to: Kentaro Nakayama, email: kn88@med.shimane-u.ac.jp Keywords: endometrial carcinoma; tumor size; overall survival; progression-free survival; myometrial invasion Received: January 31, 2018 Accepted: April 07, 2018 Published: May 01, 2018 ABSTRACT We examined the usefulness of evaluating tumor size determined using preoperative magnetic resonance imaging (MRI) for prognosis in patients with endometrial carcinoma (EC). Patients ( N = 184) with EC who underwent surgery at Shimane University Hospital between 1997 and 2013 were enrolled. We investigated the association between the tumor size of EC assessed prior to surgery by MRI (anteroposterior [AP], transverse [TV], and craniocaudal [CC] diameters) and various clinical parameters including deep myometrial invasion and lymph node metastases. We subsequently examined the prognostic significance of tumor size in patients with EC. Survival analysis was performed using the Kaplan-Meier method, and prognostic factors were evaluated using the Cox’s proportional hazards regression model. Multivariate analysis identified increased AP diameter as an independent negative prognostic factor for overall survival (OS) ( P = 0.037). A long AP diameter has prognostic value and the potential to be a predictive marker for surgical outcomes in patients with EC. Furthermore, AP diameter exhibited the greatest area under the curve (AUC) (0.727) for deep myometrial invasion, and CC diameter had the greatest AUC for lymph node metastases (0.854). Evaluation of tumor size parameters may aid in the identification of high-risk populations, which could improve treatment selection and patient outcomes.

// Masako Ishikawa 1 , Kentaro Nakayama 1 , Kohei Nakamura 1 , Ruriko Ono 1 , Kaori Sanuki 1 , Hitomi Yamashita 1 , Tomoka Ishibashi 1 , Toshiko Minamoto 1 , Kouji Iida 1 , Sultana Razia 1 , Noriyoshi Ishikawa 2 and Satoru Kyo 1 1 Department of Obstetrics and Gynecology, Shimane University School of Medicine, 6938501 Izumo, Japan 2 Department of Organ Pathology, Shimane University School of Medicine, 6938501 Izumo, Japan Correspondence to: Kentaro Nakayama, email: kn88@med.shimane-u.ac.jp Keywords: ovarian clear cell carcinoma; ovarian endometrioid carcinoma; ARID1A ; POLE ; liquid microdissection Received: September 05, 2017 Accepted: February 13, 2018 Epub: February 22, 2018 Published: March 13, 2018 ABSTRACT Aim: Endometriosis-related ovarian neoplasms (ERONs) have recently attracted considerable attention; however, the prevalence and patterns of ARID1A and POLE mutations in ERONs have not been studied in detail. The aim of this study was to investigate not only the carcinogenesis of ERONs, but also the prognostic significance of several gene mutations in this cohort. We used DNA purified from only tumor epithelial cells, from which fibroblasts were removed, using a specific method we called “liquid microdissection”. Methods: Tissue samples from 22 ovarian carcinomas (13 endometrioid, and nine clear cell) were used. Tumor cells were isolated using a cell sorting system and DNA was purified from tumor epithelial cells. Nucleotide sequencing was conducted to analyze the mutational status of ARID1A, p53, PTEN, POLE, PIK3CA , and KRAS . Results: In ERONs, the frequencies of somatic mutations in ARID1A, p53, POLE, PTEN, PIK3CA , and KRAS were 19/20 (95.0%), 7/19 (36.8%), 9/22 (40.9%), 13/19 (68.4%), 3/19 (15.8%), and 1/9 (11.1%). The frequency of ARID1A mutations was significantly higher than that reported previously. Kaplan-Meier survival analysis revealed that mutations in all genes, including POLE , were not associated with patient prognosis in our Japanese cohort. Conclusions: Our results suggest that the frequency of ARID1A mutations in ERONs may be higher than that previously reported. In addition, the “liquid microdissection” method that we chose for DNA purification could be used to obtain high-quality sequencing results. The findings suggest that ARID1A mutations represent the basis of ERON carcinogenesis; other subsequent gene mutations may result in the progression of carcinogenesis.

The aim of the present study was to determine the prognostic value of the Glasgow prognostic score (GPS) in endometrial carcinoma (EC). Patients with EC who underwent surgery at the Shimane University Hospital between January 1997 and December 2013 were enrolled (n=118). The associations between pretreatment GPS and clinical parameters, including age, histological type, International Federation of Gynecology and Obstetrics stage, tumor grade, carbohydrate antigen 19-9 and carcinoembryonic antigen levels, progression-free survival (PFS), and overall survival (OS), were investigated. Survival analysis was performed with the Kaplan-Meier method, and prognostic factors were evaluated with Cox's proportional hazards regression model. A high pretreatment GPS was associated with advanced clinical stage, histological type and tumor grade (P

Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ERα agonists and ERβ antagonists. Docking simulations of these compounds and ERβ suggested that they bound not only to the canonical binding site of ERβ but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor-ligand binding experiments using WT and mutated ERβ support the presence of a second ligand-interaction position at the coactivator-binding site in ERβ, and direct binding experiments of ERβ and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling-based drugs and their potential to function as endocrine disruptors.

In recent years, it has become evident that tumor cells have immune escape mechanisms, and immune checkpoint inhibitor therapy (anti-PD-1/PD-L1 antibody) has shown benefit in various cancers. In endometrial tumors with microsatellite-instability (MSI), somatic mutations have the potential to encode ‘’non-self’’ immunogenic antigens, and lymphocytes have been shown to infiltrate the tumor. Therefore, immune checkpoint inhibitor therapy might be effective in endometrial cancers with MSI. Expression of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), the presence of tumor-infiltrating lymphocytes (CD8+), and PD-1/PD-L1 expression were assessed by immunohistochemistry in 149 patients with endometrial cancer. We examined whether tumors with MSI had an enhanced immune microenvironment and whether MSI could be a predictor of the therapeutic effect of PD-1/PD-L1 immunotherapy in endometrial cancer. Loss of MMR protein expression was identified in 42 (28.2%) of 149 patients (MSI group) with endometrial cancer. There was no significant relationship between MSI status and age (p = 0.193), histological grade (p = 0.097), FIGO stage (p = 0.508), pelvic lymph node metastasis (p = 0.139), or depth of myometrial invasion (p = 0.494). However, the presence of tumor-infiltrating lymphocytes (CD8+) and PD-L1/PD-1 expression were significantly higher in the MSI group compared to the microsatellite-stable group (p = 0.002, p = 0.001, and p = 0.008, respectively). These results suggest that immune checkpoint inhibitors (anti-PD-1/PD-L1 antibody) could be effective in endometrial cancers with MSI. The presence of MSI may be a biomarker for good response to PD-1/PD-L1 immunotherapy in endometrial cancer.

Haematogenous metastases of breast cancer tumors has previously been demonstrated to frequently occur at the sites of the lung, bones, liver and brain, however presence in the uterine remains a rare occurrence. Metastatic carcinoma of the uterus usually originates from other genital sites, most frequently from the ovaries. The current review presents the first reported case of lobular breast carcinoma metastasizing to an endometrial polyp, the cervix and a leiomyoma simultaneously. The patient (58 years, female) first presented with abnormal uterine bleeding. Invasive ductal carcinoma had previously been diagnosed in her right breast, with lobular and ductal cancer cells observed to be present in her lymph nodes. A hysteroscopic procedure to examine the postmenopausal bleeding revealed an endometrial polyp, which was subsequently resected. The morphology and immunohistochemical studies confirmed the diagnosis of metastasis of lobular breast carcinoma to an endometrial polyp. An 18F fludeoxyglucose positron emission tomography/computed tomography (PET-CT) scan performed following the diagnosis, revealed a slightly increased uptake in the myoma, which is often observed in benign uterine leiomyoma. The patient then underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy and partial colectomy. Pathology results demonstrated that the uterine leiomyoma and cervix shared the same histopathological features as those presented by the primary lobular breast carcinoma. Although rare, breast tumors may metastasize to an endometrial polyp, cervix and leiomyoma concurrently in patients, therefore physicians may now consider the potential of the diagnosis of metastatic spread to the genital tract, in a patient with abnormal uterine bleeding and a history of lobular breast cancer. Gynecologists planning a laparoscopic hysterectomy for a patient with a history of lobular breast carcinoma may consider abdominal rather than laparoscopic hysterectomy, as lobular carcinoma is difficult to detect. The use of PET-CT may be beneficial for the identification of an unexpected mass.

The prognosis of patients with recurrent/persistent endometrial cancer, particularly type II cancer, remains poor, and effective treatment has not yet been established. We herein present the case of a patient with recurrent type II endometrial cancer who received bevacizumab + chemotherapy continued beyond progression, after previously receiving bevacizumab + chemotherapy. This patient experienced recurrence after first- and second-line adjuvant chemotherapy followed by modified radical hysterectomy and she was administered bevacizumab + paclitaxel + carboplatin therapy. After six cycles of treatment, all metastatic lesions shrunk, indicating partial response. The patient next received single-agent bevacizumab as maintenance therapy. After 12 cycles of bevacizumab monotherapy, disease progression was detected; therefore, combination therapy consisting of bevacizumab, doxorubicin and carboplatin was initiated. After six cycles of this combination therapy, the patient exhibited disease stabilization. Finally, 18 months after the initial bevacizumab treatment, the patient remained on combination chemotherapy, without complaints or signs of tumor progression (last follow-up, October 2014).

Ureterolysis is a surgical method with a high level of difficulty, which may be necessary when performing total laparoscopic hysterectomy (TLH) for large cervical myoma, despite the benign nature of this tumor. The aim of the present study was to introduce techniques that are commonly applied in malignant tumor surgery in order to safely perform TLH for large cervical myoma. Between 2014 and 2016, TLH was performed at the Shimane University Hospital (Izumo, Japan) in 153 patients with benign tumors, including 25 cases with a large uterus (uterine weight ≥500 g). The surgical methods applied in 3 of these large uterine cervical myoma cases were investigated in detail, including techniques devised by our department. TLH was performed without enucleating myomectomy in all 3 cases; however, all 3 cases required ureterolysis, transection of the anterior layer of the vesicouterine ligament and isolation of the ureter. In conclusion, although radical laparoscopic hysterectomy is commonly performed for cervical cancer at our department, techniques used for malignant tumor surgery may prove useful for benign cases with a high level of difficulty.

We evaluated the efficacy of gonadotropin-releasing hormone agonist (GnRHa) therapy for improving the myometrial thickness in women with thin (less than 1 cm) uterine walls, a contraindication for microwave endometrial ablation (MEA). The normal myometrium thickness was 0.5 cm, 0.7 cm and 0.9 cm. After the third GnRHa dose, the myometrial thickness increased to over 1 cm in all the three patients, and all were able to undergo MEA. The VAS score for menorrhagia improved in all the cases. The patient satisfaction levels were 10 in 2 of the 3 patients, and 5 in the other. There was no symptom recurrence, and no adjuvant therapy was administered. GnRHa therapy in women with submucous leiomyomata and a myometrial thickness of less than 1 cm could effectively thicken the myometrium, allowing for the use of MEA.