Kaoru Niimi

Mesothelial cells promote peritoneal invasion and metastasis of ascites-derived ovarian cancer cells through spheroid formation

Patients with epithelial ovarian cancer (EOC) are often diagnosed with peritoneal metastasis and ascites, the accumulation of intraperitoneal fluid containing nonmalignant cells. However, the interactions between EOC and nonmalignant cells before peritoneal metastasis remain unclear. To investigate this, whole EOC spheroids were observed using a multiphoton microscope, and their invasion ability was assessed. Mesothelial cells were identified as notable components of ascites through morphological assessment, immunohistochemical/immunofluorescence staining, and single-cell RNA sequencing analyses. Almost all EOC cells were spheroids, with 60% containing mesothelial cells. EOC cells quickly generate aggregated spheroids with mesothelial cells, and these aggregated cancer-mesothelial spheroids (ACMSs) invade collagen or mesothelial layers. Mesothelial cells forming ACMSs initiated the invasion. RNA sequencing analysis revealed marked RNA expression changes in mesothelial cells, whereas the changes in EOC cells were minor. Transforming growth factor–β1–stimulated mesothelial cells showed increased invadopodium formation along with fascin-1 up-regulation. These findings suggest that EOC cells alter mesothelial cells through ACMSs, thereby elucidating the rapid spread of EOC in the abdominal cavity.

Update on the oncologic and obstetric outcomes of medroxyprogesterone acetate treatment for atypical endometrial hyperplasia and endometrial cancer

Abstract Aims To evaluate the safety and effectiveness of high‐dose oral medroxyprogesterone acetate (MPA) therapy as a fertility‐sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence. Methods We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post‐MPA therapy pregnancies were examined. Results MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post‐CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved. Conclusions High‐dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment.

Spatial distribution of tumor‐resident macrophages as predictive biomarkers in endometrial cancer

Abstract Background To investigate the role of CD47 expression and its relationship with tumor‐resident macrophages, specifically at the tumor margin, in patients with type II endometrial cancer. This study aims to elucidate whether CD47 could serve as a prognostic marker and to understand the dynamics between CD47 and macrophages, which could inform new therapeutic strategies. Methods A retrospective cohort study was conducted involving 75 patients of type II endometrial. Immunohistochemical analysis was performed to assess CD47 expression and macrophage markers (CD68 and CD163). Results The study found no direct correlation between CD47 expression levels and overall survival ( p  = 0.32), challenging its role as an independent prognostic marker in type II endometrial cancer. The higher expression of CD47 had significantly less incidence of endometrioid carcinoma G3 ( p  = 0.047). The negative correlation between CD47 H‐score and the density of CD68‐positive macrophages at tumor margin was statistically significant ( p  = 0.049). A high density of CD68‐positive macrophages at the tumor margin but a low density of CD163‐positive macrophages at the tumor margin were associated with poorer prognosis ( p  = 0.036). Conclusions The complex interaction between CD47 and macrophages, particularly at the tumor margin, suggests new avenues for targeted therapy in type II endometrial cancer.

Downregulation of Chromosome 19 miRNA Cluster and the Tumor‐Suppressive Role of miR ‐517a‐3p in Choriocarcinoma

ABSTRACT Choriocarcinoma is a rare gynecologic malignancy. MicroRNAs, which are noncoding RNAs approximately 22 nucleotides in length, are known to regulate gene expression and play important roles in various cancers; however, their functions in choriocarcinoma remain largely unknown. This study aimed to identify disease‐specific microRNAs involved in choriocarcinoma development. Eleven cases of choriocarcinoma and five cases of complete hydatidiform mole treated at our institution were analyzed. Total RNA was extracted from trophoblast cells in formalin‐fixed, paraffin‐embedded specimens using laser capture microdissection, and microRNA sequencing was performed. The analysis revealed that 87 microRNAs were significantly upregulated, whereas 28 were downregulated in choriocarcinoma compared to complete hydatidiform mole. Notably, 13 of the 28 downregulated microRNAs belonged to the chromosome 19 microRNA cluster. In vitro experiments demonstrated that overexpression of miR‐517a‐3p, a representative member of this cluster, significantly suppressed cell proliferation, migration, and invasion in JEG‐3 and BeWo cell lines. Further transcriptome sequencing and computational analysis identified SRSF1 as a target gene of miR‐517a‐3p, which was validated by dual‐luciferase reporter assays. Knockdown of SRSF1 also led to significant reductions in proliferation, migration, and invasion, supporting its functional relevance. Immunohistochemical analysis confirmed that SRSF1 protein was highly expressed in choriocarcinoma tissues compared to complete hydatidiform mole. These findings indicate that downregulation of the chromosome 19 microRNA cluster is a characteristic feature of choriocarcinoma and that miR‐517a‐3p functions as a tumor suppressor by directly regulating SRSF1 expression.

Tumor growth direction predicts surgical difficulty in large uterine fibroids: A retrospective imaging‐based study

Abstract Objective To identify preoperative imaging features associated with retroperitoneal growth of large uterine fibroids and evaluate their impact on surgical outcomes. Methods This retrospective study included 20 patients who underwent hysterectomy for uterine fibroids measuring ≥10 cm between 2014 and 2024. Preoperative CT or MRI was evaluated for four features: bladder displacement, sigmoid colon deviation, cecal displacement, and hydronephrosis. Tumor growth direction (intraperitoneal vs. retroperitoneal) was determined intraoperatively. Operative time, blood loss, and complications were compared between groups. Results Eight tumors exhibited retroperitoneal growth. Bladder displacement, cecal shift, sigmoid colon deviation, and hydronephrosis were significantly more common in retroperitoneal cases (all p  < 0.05). Retroperitoneal tumors were associated with significantly greater median blood loss (1591 mL vs. 651 mL, p  = 0.043), although operative time did not differ significantly (301 vs. 232 min, p  = 0.237). Organ injury or resection occurred only in the retroperitoneal group. A bubble plot illustrated the trend of increased surgical burden in retroperitoneal cases. Conclusion Retroperitoneal growth of large uterine fibroids is associated with increased intraoperative blood loss and surgical complexity. Four simple imaging features may serve as reliable indicators of growth direction and help guide preoperative planning.

Outcomes of cases with complete hydatidiform mole coexisting with a fetus: a single-center study

Abstract Background Complete hydatidiform moles coexisting with a fetus (CHMCF) are uncommon. Although CHMCF is associated with perinatal complications and post-molar gestational trophoblastic neoplasia (GTN), necessitating post-delivery chemotherapy, live birth remains feasible. This report presents 14 cases of CHMCF in Japan. Methods  We reviewed medical records of patients with CHMCF treated at our hospital from 2000 to 2020 and summarized clinical data, including maternal age, pregnancy details, delivery outcomes, fertility treatments, serum human chorionic gonadotropin (hCG) levels, and ultrasonography findings. Results Fourteen cases of CHMCF were diagnosed. The average age of the mothers was 30.6 years, with the majority conceiving following fertility treatment. The mean gestational age at diagnosis was 12 weeks. Six patients maintained their pregnancies, leading to two live births through emergency cesarean section. Eight patients exhibited spontaneous regression following treatment and pregnancy interruption, achieving negative serum hCG levels within 17.4 weeks. Six patients experienced post-molar GTN, including the two who had live births. One patient presented with FIGO stage I disease, while five patients had stage III lung metastases. All patients received chemotherapy, averaging nine courses, achieving remission within 13.7 weeks. Conclusion  The occurrence of GTN was higher after CHMCF than after typical complete hydatidiform moles. Despite the heightened risk of premature birth, some patients with CHMCF who maintain their pregnancies can successfully deliver live babies. Informed consent is essential for patients with CHMCF when considering pregnancy continuation. A team approach involving gynecological oncologists, obstetricians, and neonatologists is essential for effective diagnosis and treatment.

Utility of manual vacuum aspiration followed by curettage in the treating hydatidiform mole: A retrospective analysis

AbstractAimWhile manual vacuum aspiration (MVA) is commonly employed for early first‐trimester abortions, its effectiveness in treating hydatidiform mole is still unclear. This study sought to evaluate the efficacy and safety of MVA in comparison to dilation and curettage (D&C) for managing hydatidiform mole.MethodsWe conducted a retrospective review of medical records for 198 patients with hydatidiform mole treated at Nagoya University Hospital between 2004 and 2023. After excluding cases with incomplete data, we compared 106 patients who underwent D&C with 60 patients treated with MVA followed by curettage. We evaluated the surgical duration, intraoperative blood loss, and the occurrence of post‐molar gestational trophoblastic neoplasia (GTN) in both groups.ResultsThe surgical duration and blood loss were similar between the MVA and D&C groups. The average surgical time was 13.2 min for D&C and 11.8 min for MVA (p = 0.145). Most cases in both groups experienced blood loss of less than 10 mL, with no significant difference (p = 0.066). Over a median follow‐up period of 33.4 months, 25 cases developed post‐molar GTN. All GTN cases originated from complete hydatidiform mole (25 of 132 cases, 18.9%), and none were from partial hydatidiform mole. Kaplan–Meier analysis, focusing only on patients with complete hydatidiform mole, indicated no significant difference in the time to onset of GTN between the D&C and MVA groups (p = 0.632).ConclusionsMVA followed by curettage is a viable approach for treating molar pregnancy.

Niraparib as a therapeutic agent for the treatment of ovarian cancer meningeal dissemination with BRCA1 mutation

AbstractThis study analyzed a 63‐year‐old woman with hereditary BRCA1 mutation. She underwent interval debulking surgery after neoadjuvant chemotherapy for high‐grade serous ovarian carcinoma (HGSOC). After 2 years of postoperative chemotherapy, she developed headache and dizziness, and a suspected metastatic cerebellar mass in left ovary was detected. Pathological analysis of the mass revealed HGSOC, which was removed surgically. Eight months and another 6 months after the surgery, local recurrence was noted; hence, she underwent CyberKnife treatment. After 3 months, cervical spinal cord metastasis was found, evidenced by left shoulder pain. Moreover, meningeal dissemination was present around the cauda equina. Chemotherapy treatment, including bevacizumab, was ineffective and increased lesions were observed. After CyberKnife treatment for the cervical spinal cord metastasis, niraparib was initiated for the meningeal dissemination. The cerebellar lesions and meningeal dissemination improved within 8 months of niraparib treatment. Although meningeal dissemination is challenging to treat, niraparib may be useful in BRCA‐mutated HGSOC.

An update of oncologic and obstetric outcomes of radical trachelectomy for early‐stage cervical cancer: The need for further minimally invasive treatment

AbstractAimsTo investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early‐stage cervical cancer and to evaluate the potential role of fertility‐preserving treatments in improving pregnancy outcomes while oncologic status is stable.MethodsIn this single‐institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early‐stage cervical cancer who underwent RT at Nagoya University Hospital.ResultsThe cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies.ConclusionsRT is a viable treatment option for selected patients with early‐stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable.

In‐Tumor CRISPR ‐Cas9 Knockout Screening and Novel Therapy Development for Malignant Transformation of Ovarian Teratoma

ABSTRACT Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare but aggressive malignancy for which no standardized chemotherapy or effective targeted therapies currently exist. To identify therapeutic vulnerabilities in MTMCT, we performed a genome‐wide CRISPR‐Cas9 knockout screen using the MTMCT‐derived NOSCC1 cell line. Two parallel selective pressures were applied: in vivo tumorigenicity in immunodeficient mice and cisplatin exposure in vitro. From this screen, 67 negatively selected genes were identified, among which SOD1 and NDUFB4 emerged as top candidates based on high basal expression levels and clinical relevance. Integration with spatial transcriptomic data from three independent MTMCT patient tumors further supported the prioritization of these targets. SOD1 was selected for further investigation due to the availability of known pharmacological inhibitors. Both siRNA‐mediated knockdown and small‐molecule inhibition of SOD1 using LCS‐1 significantly suppressed MTMCT cell proliferation in vitro by inducing oxidative stress and impairing cell cycle progression. This antiproliferative effect was reversed by co‐treatment with N ‐acetylcysteine, a reactive oxygen species scavenger. In vivo validation using patient‐derived xenograft models demonstrated that oral administration of LCS‐1 led to significant tumor growth suppression and increased expression of apoptotic and DNA damage markers, including cleaved caspase‐3 and γH2AX. These findings establish SOD1 as a critical vulnerability in MTMCT and provide preclinical evidence supporting redox modulation as a therapeutic strategy for this highly chemoresistant and understudied ovarian cancer subtype. Our integrative approach combining functional genomics, spatial transcriptomics, and pharmacologic validation offers a framework for the discovery of novel targets in rare gynecologic malignancies.