Published papers

Objective: Hospital treatment volume affects survival in patients with endometrial cancer; notably, initial treatment at high-volume centers improves survival outcomes. Our study assessed the effect of hospital treatment volume on cost-effectiveness and survival outcomes in patients with endometrial cancer in Japan. Methods: A decision-analytic model was evaluated using the following variables and their impact on cost-effectiveness: 1) hospital treatment volume (low-, intermediate-, and high-volume centers) and 2) postoperative recurrent risk factors based on pathological findings (high-and intermediate-risk or low-risk). Data were obtained from the Japan Society of Obstetrics and Gynecology database, systematic literature searches, and the Japanese Diagnosis Procedure Combination database. Quality-adjusted life years (QALY) was used as a measure of effectiveness. The model was built from a public healthcare perspective and the impact of uncertainty was assessed using sensitivity analyses. Results: A base-case analysis showed that the incremental cost-effectiveness ratio at high-volume centers was below a willingness-to-pay (WTP) threshold of ¥5,000,000 with a maximum of ¥3,777,830/4.28 QALY for the high-and intermediate-risk group, and ¥2,316,695/4.57 QALY for the low-risk group. Treatment at the high-volume centers showed better efficiency and cost-effectiveness in both strategies compared to intermediate-or low-volume centers. Sensitivity analyses showed that the model outcome was robust to changes in input values. With the WTP threshold, treatment at high-volume centers remained cost-effective in at least 73.6% and 78.2% of iterations for high-and intermediate-risk, and low-risk groups, respectively. Conclusion: Treatment at high-volume centers is the most cost-effective strategy for guiding treatment centralization in patients with endometrial cancer.

Immune checkpoint inhibitors (ICIs), such as pembrolizumab (PEM), are widely recognized for their antitumor efficacy, but they can also lead to various cutaneous adverse events (CAEs). While most CAEs can be managed with topical corticosteroids, severe cases may necessitate halting immunotherapy. The incidence of severe CAEs is notably higher in combination therapies involving ICIs than in monotherapies, emphasizing the need for stringent, long-term management strategies. This includes potential modifications or discontinuations of the combination therapy. PEM, when added to the conventional paclitaxel + cisplatin (or carboplatin) ± bevacizumab regimen, has shown significant improvements in overall and progression-free survival for patients with Stage IVB metastatic or locally uncontrolled recurrent cervical cancer. This case series retrospectively examined the incidence and management of CAEs in 19 female patients treated with this combination therapy between October 2022 and May 2023. Four patients exhibiting CTCAE grade 3 were identified. The four cases of severe CAEs involved erythema multiforme after the initial course of PEM combination chemotherapy. Notably, three patients experienced immediate hypersensitivity reactions, including anaphylaxis, during subsequent treatments. This observation underscores the necessity for rigorous dermatological monitoring of patients undergoing PEM combination chemotherapy. Such vigilance is crucial for early detection of adverse reactions and timely adjustment of treatment regimens, thereby enhancing patient safety.

Immune checkpoint inhibitor (ICI) therapy has been successfully applied to various cancers; however, not all patients respond to ICI therapy. Tumors with an immune-activated environment are highly responsive to ICIs. To identify the cells and molecules essential to the formation of an immune-activated cancer microenvironment, we focused on the tertiary lymphoid structure (TLS) and performed histological and genomic analyses using endometrial cancer material. In the high immunogenic group, numerous TLSs were observed, and CXCL9 and CXCL13 expression was markedly increased. CXCL9-positive antigen-presenting and CXCL13-positive follicular dendritic cells were distributed in the T- and B-cell zones of TLSs, respectively. A group of molecules whose expression was upregulated along with CXCL9 and CXCL13 expression was strongly associated with cellular immunity. These results suggest that CXCL9-expressing antigen-presenting cells and CXCL13-expressing follicular dendritic cells coordinately shape the immune-activated microenvironment through TLS formation. The current findings will contribute to a better understanding of the mechanisms underlying the activated cancer immune microenvironment, thereby advancing the field of precision cancer medicine.

• Context.—Diagnostic strategies for endometrial cancer have been evolving, with cytologic analysis being considered a key method in integrated oncologic diagnostics because of its less invasive nature and adaptability to various assessments. Liquid-based cytology (LBC) has emerged as a promising method for intact DNA preservation; it exhibits improved efficiency in advanced sequencing applications such as next-generation sequencing. However, despite the use of LBC in panel assays, its application in whole-exome sequencing (WES) for comprehensive genomic profiling remains underexplored. Objective.—To investigate whether molecular classification is possible based on WES using DNA derived from LBC specimens. Design.—We combined WES with targeted gene panel analysis to compare genomic findings of LBC and traditional tissue samples obtained from 7 cases of endometrial cancer. We investigated pathogenic mutations, tumor mutational burden, and microsatellite instability, and achieved molecular classification with high accuracy. Results.—We found a substantial concordance between LBC and traditional tissue samples in terms of pathogenic mutation detection, with a 95% match in the LBC samples and 94% in the tissue samples. Notably, our results highlight the importance of combining WES with panel-based analysis in identifying the ultramutated status of a case that had been missed during panel analysis. Conclusions.—Our findings emphasize the potential of LBC samples in the precise and noninvasive genomic analysis of cases of endometrial cancer and offer a new avenue for developing diagnostic and therapeutic strategies in precision oncology.

Objective: DUO-E/GOG-3041/ENGOT-EN10 (NCT04269200) demonstrated statistically significant and clinically meaningful progression-free survival (PFS) improvement with durvalumab plus carboplatin/paclitaxel, followed by durvalumab with or without olaparib, vs. carboplatin/paclitaxel alone (intention-to-treat [ITT] population) in patients with newly diagnosed advanced or recurrent endometrial cancer. We evaluated efficacy and safety in the Japan subset of DUO-E. Methods: Patients with newly diagnosed International Federation of Gynecology and Obstetrics stage III/IV or recurrent endometrial cancer were randomized 1:1:1 to control arm (carboplatin/paclitaxel + durvalumab placebo [6 cycles] followed by durvalumab placebo + olaparib placebo), durvalumab arm (carboplatin/paclitaxel + durvalumab [1,120 mg every 3 weeks] [6 cycles] followed by durvalumab [1,500 mg every 4 weeks] + olaparib placebo), or durvalumab + olaparib arm (carboplatin/paclitaxel + durvalumab [6 cycles] followed by durvalumab + olaparib [300 mg twice a day]). Dual primary endpoints were investigator-assessed PFS for durvalumab and durvalumab + olaparib arms vs. control. This prespecified exploratory analysis evaluated PFS and safety in the Japan subset. Results: In the Japan subset (n=88) PFS favored durvalumab (hazard ratio=0.61, 95% confidence interval [CI]=0.32–1.12) and durvalumab + olaparib (0.44, 95% CI=0.22–0.85) vs. control; median PFS was 9.9 and 15.1 vs. 9.5 months, and the 18-month PFS rate was 37.0% and 42.1% vs. 22.2%, respectively. The safety profile in the Japan subset was generally consistent with the full safety analysis set and the established profiles of the individual agents. Conclusion: Efficacy and safety in the Japan subset were generally consistent with outcomes in the DUO-E ITT population. This Japanese subset analysis of DUO-E supports carboplatin/ paclitaxel + durvalumab followed by durvalumab with or without olaparib as new treatment options in patients with advanced or recurrent endometrial cancer and is the first to report on these regimens in Japanese patients alone.

There are currently no effective treatments available for clear cell ovarian cancer (CCC). In this study, we aimed to identify effective drugs for CCC through high-throughput drug screening (HTDS) using ovarian cancer organoids and determine novel therapeutic targets based on the biological characteristics of CCC through omics analysis. An ovarian cancer organoid biobank was established, and HTDS was conducted using CCC organoids based on libraries of 361 and 4,560 compounds. The efficacy of the identified drugs was verified in in vitro and in vivo experiments using a patient-derived organoid xenograft mouse model. Transcriptome analysis was performed to identify genes related to the pathways targeted by the identified drugs in CCC and to assess their potential as therapeutic targets. Proteasome inhibitors and dinaciclib were extracted using HTDS and shown to inhibit tumorigenesis in vitro and in vivo. CCC, like multiple myeloma, exhibited activated endoplasmic reticulum (ER) stress and unfolded protein response (UPR), and treatment with proteasome inhibitors further enhanced ER stress and UPR, ultimately leading to cell death. Transcriptome analysis identified anterior gradient-2 (AGR2) as a key gene involved in UPR in CCC. CRISPR knockout of AGR2 suppressed cell proliferation, increased sensitivity to proteasome inhibitors, and reversed platinum resistance in CCC. AGR2 knockout also upregulated Schlafen 11, contributing to platinum sensitivity. ER stress and the UPR are activated in CCC, and proteasome inhibitors disrupt this balance, ultimately leading to cell death. AGR2 may serve as a potential therapeutic target in CCC.

With rapid advances in disease diagnosis and treatment, patients with cancer will achieve longer survival. Among female cancer survivors, oncologic treatments often lead to premature ovarian insufficiency, negatively impacting their health and quality of life. Hormone replacement therapy (HRT) may mitigate these effects; however, concerns remain regarding its impact on oncologic outcomes. Updating the evidence base could help healthcare providers identify patients who may benefit from HRT without an increased risk of recurrence. This review provides an updated overview of HRT in women with a history of cervical, endometrial, ovarian, and breast cancers. For cervical cancer, HRT is not contraindicated in either squamous cell carcinoma or adenocarcinoma, regardless of stage. For endometrial cancer, HRT is not contraindicated in early-stage disease with no residual tumor, although it should be avoided in low-grade endometrial stromal sarcoma. HRT is not contraindicated in epithelial ovarian cancer regardless of stage, except in low-grade serous carcinoma. Currently, HRT is contraindicated for breast cancer. This review highlights the need to promote long-term healthcare strategies for cancer survivors. A shift in focus beyond cancer cure toward lifelong health management is warranted.

High-grade serous carcinoma (HGSC), the most aggressive subtype of epithelial ovarian cancer, is strongly associated with hereditary breast and ovarian cancer (HBOC) syndrome and is primarily linked to germline BRCA1/2 pathogenic variants (PVs). The cumulative risks of ovarian cancer by the age of 70 years are 40% and 18% for carriers of BRCA1 and BRCA2 PVs, respectively. Risk-reducing salpingo-oophorectomy (RRSO) is a recommended preventive strategy that reduces the risk of ovarian cancer by more than 80% and may improve overall survival. However, surgical menopause after RRSO poses several challenges, including infertility and hormonal deficiency. Although the use of hormone replacement therapy may alleviate symptoms, it requires careful consideration of breast cancer risk. Emerging strategies, such as prophylactic salpingectomy with delayed oophorectomy, are being investigated to balance cancer prevention and patient quality of life. Further research is required to refine personalized prevention and management approaches for HBOC-associated ovarian cancer.

Objective: Medroxyprogesterone acetate (MPA) is an effective fertility-preserving treatment for early endometrial cancer and atypical endometrial hyperplasia (AEH), and rarely leads to the development of extrauterine lesions (ELs). We aimed to clarify the characteristics of patients who developed ELs post-MPA therapy. Methods: We analyzed the clinicopathological factors and prognoses of 319 patients with endometrioid carcinoma grade 1 (EMG1) and AEH treated with MPA at our institution. All patients underwent imaging before MPA treatment to rule out ELs. Results: Seven patients (2.2%) with EMG1 showed EL after MPA treatment. Two patients developed EL during the initial treatment, 2 during repeated treatment, and 3 during follow-up. Two patients had peritoneal dissemination, 3 had regional lymph node metastasis, 1 had distant metastasis at the Virchow lymph node, and 1 had ovarian metastasis. ELs were diagnosed using imaging tests in 6 patients and elevated tumor markers in 3 (overlapping) patients. One patient was diagnosed with ELs pathologically after hysterectomy. Upon EL diagnosis, patients underwent standard treatment, including hysterectomy and chemotherapy, that was followed by a diagnosis of EMG1 for 5, EMG2 for 1, and EMG3 for 1 patient. One patient died 15 months after start of therapy and another died 119 months post-treatment initiation, while the others have been survived. Conclusion: Only 2.2% of all patients developed ELs post-MPA treatment, but some cases were fatal. It is essential to conduct imaging tests and screen for tumor markers during and after MPA treatment regularly and also when cancer progression is suspected.

Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive immunotherapy potentially applicable to many types of solid tumors. Although gynecologic malignancies are promising targets for TIL therapy, its objective efficacy has not been established. Current TIL culture typically involves incubation of dissociated samples with high-dose IL-2 (HD-IL2) for weeks to enrich tumor-reactive T cells. While this protocol has been successfully used for melanoma TIL, it has not necessarily been optimized for other cancers. Here we investigated the method of efficiently expanding TILs derived from patients with gynecological cancers. TILs were incubated with HD-IL2 (HD-IL2-TILs) or stimulated with K562 cells expressing anti-CD3 mAb and CD80 (αCD3/CD80-TILs). We found that the αCD3/CD80-TILs showed significantly better proliferation than HD-IL2-TILs. The TIL populations that predominantly expanded upon αCD3/CD80 stimulation expressed high levels of PD-1 and CD28. CD28 co-stimulation was essential to overcome PD-1-mediated signals for growth suppression. We also identified DUSP4 as a negative regulator of TIL proliferation by downregulating ERK phosphorylation. The αCD3/CD80-TILs were reactive to tumor cells as shown by IFN-γ secretion and CD107a expression. Moreover, the αCD3/CD80-TILs were efficiently transduced with a chimeric cytokine receptor that we had previously developed to provide constitutive IL-7 signaling, resulting in superior in vivo persistence and antitumor effects without exogenous cytokine support in mouse models. Collectively, this study shows that direct stimulation of TILs with anti-CD3 mAb and CD28 co-stimulation achieves efficient expansion of tumor-reactive TILs. Genetic engineering of cytokine signaling in TILs may further enhance TIL functions and replace cytokine administration after TIL infusion.

Aim: There is an increasing demand for fertility-sparing treatment (FST) among young women with gynecological cancer. This study aimed to clarify the current status of FST implementation across Japan by focusing on institutional practice patterns and clinical protocols for cervical, endometrial, and ovarian cancers. Methods: A nationwide cross-sectional survey was conducted between August and September 2024. An online questionnaire was distributed to 481 gynecologic tumor registry institutions through the Japan Society of Obstetrics and Gynecology mailing list. Data on institutional characteristics, specific FST eligibility criteria, treatment methods, and post-treatment management were collected. Results: Responses were received from 226 institutions (response rate: 47.0%), and all respondent institutions (100%) performed FST for at least one gynecological cancer. Although FST is widely available, significant heterogeneity in clinical protocols was observed across all three cancers. Key variations among respondent institutions included a low implementation rate of radical trachelectomy for cervical cancer (20.8%), a high rate of post-FST hysterectomy for endometrial cancer (63.6%) compared to cervical cancer and ovarian cancer, and exclusion criteria for patients with hereditary cancer syndromes. Conclusion: FST is an established practice in Japan; however, there is a lack of consensus regarding its clinical application. These findings provide a critical benchmark for future efforts to standardize care and develop collaborative networks to optimize this essential treatment modality for young patients with gynecological cancer.

Tumor sensitivity to platinum (Pt)-based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency-causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan-cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan-cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell-free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events—BRCA1 (n = 3), BRCA2 (n = 18)—including eight pure deletions, one single-nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology-mediated end-join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies.

Purpose DNA polymerase epsilon ( POLE ) exonuclease domain-mutated endometrial cancer (EC) is associated with a favorable prognosis and significant immune cell infiltration. Cancers with significant immune cell infiltration often exhibit higher maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT). This study aimed to evaluate the correlation between POLE status and FDG-PET/CT imaging in patients with EC. Methods This retrospective study enrolled 102 patients (mean age, 56.2 ± 11.8 years) with EC who underwent preoperative FDG-PET/CT between July 2018 and August 2023. Patients were categorized into molecular subtypes based on molecular profiling. SUVmax of the primary tumor and lymph nodes was measured, and correlations with molecular subtypes were examined. Results The SUVmax in the primary tumor of POLE -mutated ECs was higher than that in non- POLE -mutated ECs (mean ± SD, 13.21 ± 4.78 vs 9.82 ± 3.78; p = 0.001). Multiple regression analysis showed that POLE status was associated with SUVmax in primary tumors (B = 2.30, p = 0.031). The SUVmax in non-metastatic lymph nodes of POLE -mutated ECs was higher than that in non -POLE- mutated ECs (median SUVmax, 1.31 [IQR, 1.05–2.21] vs. 1.06 [IQR, 0.91–1.20]; p = 0.003). Multiple regression analysis revealed that POLE status was the only factor associated with SUVmax in non-metastatic lymph nodes (B = 0.339, p = 0.046), while age, BMI, blood glucose level, histological type, and primary tumor size showed no significant association. Conclusion Patients with POLE -mutated EC exhibit high SUVmax in primary tumors and also tend to show elevated uptake in non-metastatic lymph nodes.

Objective: Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery. Methods: We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks). Results: Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity (p =.014) was higher and a history of preterm delivery (p =.0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma in situ (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group (p =.0099 and.0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26–13.68, p =.019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88–46.42, p <.0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55–34.86, p =.012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24–20.73, p =.024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11–16.62, p =.035) increased the risk of preterm delivery in the multiple regression models in primiparous women. Conclusion: Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGES Prior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization. The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.

Background: Fertility preserving therapy using medroxyprogesterone acetate (MPA) is an important option for young patients with endometrial cancer or atypical endometrial hyperplasia (AEH). However, the effectiveness and feasibility of repeated MPA therapy for patients with intrauterine recurrence following initial MPA therapy is controversial. Only a few single-institution retrospective studies have been conducted on repeated MPA therapy, therefore, multicenter prospective studies for repeated MPA therapy are highly needed. The aim of this study is to assess whether repeated MPA therapy is effective and feasible for patients with intrauterine recurrence following initial MPA therapy. Methods: This is a prospective, single-arm, a multicenter phase II trial on repeated MPA therapy for intrauterine recurrence following fertility-preserving therapy for AEH or stage IA (the International Federation of Gynecology and Obstetrics [FIGO] 2008) non-myoinvasive endometrioid carcinoma grade 1. Patients are treated with oral MPA (500–600 mg/day). Pathologically assessment via dilation and curettage will be performed every 2 months until complete response. The major inclusion criteria are 1) intrauterine recurrence of AEH or stage IA (FIGO 2008) endometrioid carcinoma grade 1 without myometrial invasion or extrauterine spread confirmed by imaging tests after complete remission with the previous MPA therapy. 2) The number of recurrences should be up to twice. 3) histologically diagnosed as AEH or endometrioid carcinoma grade 1, 4) 20–42 years of age, and 5) strong desire and consent for fertility-sparing treatment. The primary endpoint is 2-year recurrence-free survival rate. A total of 115 patients will be enrolled from multiple institutions in Japan and Korea within 4 years and followed up for 2 years.

Background: Artificial intelligence (AI) is increasingly applied to colposcopy to enhance the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer. We conducted a systematic review to summarize the diagnostic performance achieved by AI‑based colposcopic systems. Methods: Following the PRISMA 2020 guidelines, the PubMed database was searched using the search terms ‘artificial intelligence’ and ‘colposcop*’ for articles published between 2019 and 2024. From the initial 43 articles retrieved, 19 studies were selected based on specific inclusion criteria: original research articles, written in the English language, and relevant to CIN or cervical cancer diagnosis. For each, we extracted the sample size, AI architecture (e.g., convolutional neural networks, U-Net/DeepLab V3 + segmentation models, multimodal fusion networks), reference standard, and reported metrics (sensitivity, specificity, accuracy, and area under the curve). Results: Across multiple studies, AI systems demonstrated superior diagnostic accuracy, sensitivity, and specificity, particularly for early detection of high-risk lesions and classification of cervical abnormalities. Deep-learning models, such as convolutional neural networks, consistently outperformed conventional methods by reducing diagnostic variability and offering robust performance even in low-resource settings. The review also highlights the potential of AI for real-time diagnostics and its capacity to support clinical decision-making via automated systems. Conclusion: AI has the potential to revolutionize cervical cancer diagnosis and management by enhancing the accuracy and efficiency of colposcopic evaluations. However, challenges remain, including the development of standardized datasets, validation in diverse populations, and ethical considerations surrounding data privacy and access to technology. Continued research and development are crucial to harness AI’s global potential to improve patient outcomes.