Hitomi Yamashita

Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer

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.

KRAS/BRAF Analysis in Ovarian Low-Grade Serous Carcinoma Having Synchronous All Pathological Precursor Regions

Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains unclear as to how these mutations contribute to tumor progression. This is the first report to track the histopathological progression of serous adenofibroma to low-grade serous carcinoma. Each stage was individually analyzed by pathological and molecular genetic methods to determine what differences occur between the distinct stages of progression.

Affinity-purified DNA-based mutation profiles of endometriosis-related ovarian neoplasms in Japanese patients

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.

Long‑term outcomes of microwave endometrial ablation for treatment of patients with menorrhagia: A retrospective cohort study

This study aimed to describe the long-term outcomes of patients with menorrhagia treated with microwave endometrial ablation (frequency, 2.45 GHz), as well as to identify factors associated with recurrence or re-surgery. This retrospective cohort study was conducted from 2007 to 2015 at Shimane University Hospital in Japan. Patients with severe menorrhagia and a desire to preserve their uterus were included in the study. Clinical factors associated with recurrence of menorrhagia or re-surgery were analyzed with a multivariable logistic regression model. Of 160 microwave endometrial ablation candidates, 100 had uterine myomas, 20 adenomyosis, 26 functional excessive menstruation, and 12 endometrial polyps. In the full cohort, age (<40) and uterine cavity length (≥10) were associated with recurrence of menorrhagia and re-surgery. Among patients with myomas, age (<48) and number of myomas (≥4) were associated with recurrence, and largest myoma size (≥5) and preoperative hemoglobin level (<9 mg/dl) were associated with re-surgery. Among subjects with adenomyosis, uterine cavity length (≥10) was associated with recurrence. Microwave endometrial ablation is thought to be a highly efficacious method to control menorrhagia caused by functional bleeding and endometrial polyps. However, microwave endometrial ablation may be less effective for patients younger than 48 years with myomas, especially those with 4 or more myomas, or with a myoma 5 cm or larger in size, and for patients with adenomyosis who have a thickened myometrium. These clinical factors may be useful predictors of success in selecting candidates for microwave endometrial ablation.

Preoperative tumor size is associated with deep myometrial invasion and lymph node metastases and is a negative prognostic indicator for patients with endometrial carcinoma

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.

Genetic analysis and phosphoinositide 3‑kinase/protein kinase B signaling pathway status in ovarian endometrioid borderline tumor samples

Ovarian endometrioid borderline tumors (EBTs) are extremely rare, and are thought to be precursors of endometrioid carcinoma, beginning as adenofibroma or endometriosis and progressing in a slow, stepwise manner. In endometrioid carcinomas, a high frequency of activating mutations in phosphatase and tensin homolog (PTEN), β-catenin or AT-rich interaction domain 1A (ARID1A) genes, and the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway have been observed. However, the frequency of these alterations in EBTs and how they contribute to tumor progression remain unclear. To the best of our knowledge, this is the first study to assess the status of the PI3K/AKT signaling pathway in EBTs, in association with PTEN and ARID1A mutations. PTEN mutations were observed in EBTs and also in the area of endometriosis without atypia. However, the PI3K/AKT signaling pathway was revealed to be activated only in EBTs. The observations of the present study suggest that the PTEN mutation represents an early event in EBT tumorigenesis, while additional genetic alterations may be necessary to activate the PI3K/AKT signaling pathway and induce the development of the invasive carcinoma.

High preoperative Glasgow prognostic score is a negative prognostic factor for patients with endometrial carcinoma

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 Coxs proportional hazards regression model. A high pretreatment GPS was associated with advanced clinical stage, histological type and tumor grade (P<0.001, P=0.007 and P=0.006, respectively). Multivariate analysis identified a high GPS as an independent negative prognostic factor for PFS and OS (P=0.025 and P=0.044, respectively). Therefore, a high pretreatment GPS has prognostic value and the potential to be a predictive marker for surgical outcome in patients with EC. Evaluation of pretreatment GPS may aid in the identification of high-risk populations, which may improve treatment selection and patient outcomes.

Prognostic significance of pre‑treatment neutrophil‑to‑lymphocyte and platelet‑to‑lymphocyte ratios in non‑surgically treated uterine cervical carcinoma

The aim of the present study was to assess the prognostic significance of the pre-treatment neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and other clinicopathological characteristics in patients with non-surgically treated uterine cervical carcinoma. The correlations of clinicopathological characteristics with overall and progression-free survival were determined in 98 Japanese patients who received non-surgical treatment for uterine cervical carcinoma between January 1997 and July 2013. Survival rates were calculated using the Kaplan-Meier method and potential prognostic indicators were assessed using a Cox proportional hazards model. A total of 68 patients (69.4%) had a high pre-treatment NLR (≥3.5) and 34 patients (34.7%) had a high pre-treatment PLR (≥212). Both NLR and PLR were found to be positively correlated with pre-treatment platelet counts. Multivariate analysis identified NLR and carcinoembryonic antigen level, but not PLR, as independent predictors of overall and progression-free survival. In conclusion, the present study identified two prognostic indicators for uterine cervical carcinoma, both of which can be easily and cost-effectively monitored via blood testing.

Ultrasound-guided intranodal lymphangiography with lipiodol for treatment of chylous ascites following surgery for ovarian cancer: A case report

Although lymphadenectomy for gynecological cancer is often associated with chylous leakage, the proper management of this complication remains a matter of debate. In the present study a case of chylous leakage successfully treated with lipiodol lymphangiography is described. A 33-year-old patient with ovarian cancer experienced chylous leakage following total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy. The volume of fluid in the abdominal drainage tube increased to 800–1,000 ml/day on postoperative day (POD)3. The patient was started on a fat-restricted diet on POD3 and octreotide on POD21, but the volume of the discharge remained unchanged. Lipiodol lymphangiography was performed on POD62, which reduced the leakage, and the patient was discharged on POD95. Therefore, lipiodol lymphangiography effectively resolved chylous leakage following surgery for gynecological cancer. The aim of the present study was to report the clinical effectiveness of lipiodol lymphangiography in resolving chylous leakage in such cases, and to summarize the methods used and complications encountered.

Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report

Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2 (PMS2)). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers.