Jae Hoon Kim

Radiotherapy patterns of care for recurrent ovarian cancer by gynecologic and radiation oncologists: a Korean Gynecologic Oncology Group study (KGOG-3064S1)

A Comparative Study of Performance Between Federated Learning and Centralized Learning Using Pathological Image of Endometrial Cancer

Federated learning, an innovative artificial intelligence training method, offers a secure solution for institutions to collaboratively develop models without sharing raw data. This approach offers immense promise and is particularly advantageous for domains dealing with sensitive information, such as patient data. However, when confronted with a distributed data environment, challenges arise due to data paucity or inherent heterogeneity, potentially impacting the performance of federated learning models. Hence, scrutinizing the efficacy of this method in such intricate settings is indispensable. To address this, we harnessed pathological image datasets of endometrial cancer from four hospitals for training and evaluating the performance of a federated learning model and compared it with a centralized learning model. With optimal processing techniques (data augmentation, color normalization, and adaptive optimizer), federated learning exhibited lower precision but higher recall and Dice similarity coefficient (DSC) than centralized learning. Hence, considering the critical importance of recall in the context of medical image processing, federated learning is demonstrated as a viable and applicable approach in this field, offering advantages in terms of both performance and data security.

Serum Lipidome Profiling Reveals a Distinct Signature of Ovarian Cancer in Korean Women

Abstract Background: Distinguishing ovarian cancer from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of ovarian cancer pathogenesis. Accumulating evidence suggests a link between ovarian cancer and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved ovarian cancer diagnosis and prevention. Methods: Here, we profiled the serum lipidome of 208 ovarian cancer, including 93 early-stage patients with ovarian cancer and 117 nonovarian cancer (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning (ML) approaches. Results: We found that lipidome alterations unique to ovarian cancer were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in ovarian cancer in comparison with other gynecological diseases. ML methods selected a panel of 17 lipids that discriminated ovarian cancer from nonovarian cancer cases with an AUC value of 0.85 for an independent test set. Conclusions: This study provides a systemic analysis of lipidome alterations in human ovarian cancer, specifically in Korean women. Impact: Here, we show the potential of circulating lipids in distinguishing ovarian cancer from nonovarian cancer conditions.

Stratifying the risk of ovarian cancer incidence by histologic subtypes in the Korean Epithelial Ovarian Cancer Study (Ko‐EVE)

AbstractIntroductionThis study aimed to verify the association between ovarian cancer (OC) and reproductive‐ and lifestyle‐related risk factors stratified by the subtype of OC.MethodsIn this matched case–control study derived from the Korean epithelial ovarian cancer study (Ko‐EVE), we calculated the risk of OC subtypes using odds ratios (ORs) and 95% confidence intervals (95% CIs) in a logistic regression model.ResultsAs a result of matching, 531 cases and 2,124 controls were selected. Smoking had positive association with high‐grade serous (HGS) OC (OR = 2.69, 95% CI = 1.15–6.30), whereas alcohol consumption had positive association with mucinous type (MUC) (OR = 3.63, 95% CI = 1.39–9.49). Obesity (≥30 kg/m2) was associated with clear cell type (CLC) (OR = 4.57, 95% CI = 1.06–19.77). Spontaneous abortion was negatively associated with CLC (OR = 0.34, 95% CI = 0.13–0.90), in contrast to HGS (OR = 1.43, 95% CI = 0.96–2.15). Tubal ligation, hysterectomy, and oophorectomy were associated with decreased risk of HGS (OR = 0.14, 95% CI = 0.05–0.39; OR = 0.23, 95% CI = 0.07–0.73; OR = 0.28, 95% CI = 0.08–0.97, respectively). Early menarche was strongly associated with increased risk of CLC, but not MUC (OR = 6.11, 95% CI = 1.53–24.42; OR = 3.23, 95% CI = 0.98–10.86). Further, childbirth (≥2 times) was negatively associated with endometrioid type OC and CLC (OR = 0.11, 95% CI = 0.04–0.35; OR = 0.12, 95% CI = 0.02–0.37, respectively). Oral contraceptives and hormone replacement therapy were negatively associated with OC (OR = 0.61, 95% CI = 0.40–0.93; OR = 0.51, 95% CI = 0.32–0.80, respectively), and similar negative associations were also observed in HGS (OR = 0.69; OR = 0.60, respectively). Associations between family history of breast cancer and OC, regular exercise (≥5/week), and artificial abortion and OC were similar across all subtypes (OR = 3.92; OR = 0.41; OR = 0.72, respectively).ConclusionA heterogeneous association between some risk factors and the incidence of each subtype of epithelial OC was observed, suggesting that the carcinogenic mechanisms of each subtype may be partly different.

Integrative Multi-Omics Analysis Reveals Molecular Signatures of Recurrence in Paired Primary and Recurrent High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive form of epithelial ovarian cancer and is characterized by high recurrence rates and poor clinical outcomes. In this study, we identify molecular signatures associated with recurrence by conducting integrative transcriptomic and proteomic analyses on paired primary and recurrent HGSOC tissues from 34 patients. RNA sequencing and proteomic profiling revealed 185 differentially expressed genes (DEGs) and 36 differentially expressed proteins (DEPs) linked to recurrence. Pathway enrichment and Ingenuity pathway analyses highlighted the involvement of immune cell trafficking, cell signaling, and MAPK pathway activation in recurrent tumors. A survival analysis identified seven DEGs that correlated significantly with recurrence-free survival; among them, IL7R, IRF8, and PTPRC were upregulated in recurrent tumors and associated with poor prognosis, and NSG1 was downregulated and linked to favorable outcomes. Immunohistochemistry validated the differential expression of these markers at the protein level. The proteomic analysis demonstrated that recurrent tumor-specific DEGs are functionally linked to MAPK signaling. Co-expression analyses revealed dynamic regulatory interactions between the DEGs and DEPs, suggesting context-dependent molecular shifts during recurrence. This integrative multi-omics approach reveals that key molecular alterations underlie HGSOC recurrence and identifies IL7R, IRF8, PTPRC, and NSG1 as potential prognostic biomarkers and therapeutic targets. Our findings provide a foundation for targeted strategies to improve outcomes for patients with recurrent HGSOC.

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT)

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

High-Dose Selenium Induces Ferroptotic Cell Death in Ovarian Cancer

Selenium is a promising multi-target chemotherapeutic agent with controversial clinical results. Hence, reassessing the anticancer effects of Se is necessary to clearly understand the potential of high-dose selenium in cancer treatment. Here, we observed that high-dose sodium selenite (SS) significantly decreased the proliferation and increased the death of ovarian cancer cells, mediated by an increased generation of reactive oxygen species. Notably, high-dose SS decreased the levels of glutathione peroxidase (GPx), a selenoprotein with antioxidant properties, without altering other selenoproteins. Furthermore, high-dose SS triggered lipid peroxidation and ferroptosis, a type of iron-dependent cell death, due to dysregulated GPx4 pathways. We demonstrated that intravenous high-dose SS significantly reduced the tumor growth and weight in SKOV3-bearing mice. Consistent with our in vitro results, mice with SKOV3 cells treated with high-dose SS showed decreased GPx4 expression in tumors. Therefore, we highlight the significance of high-dose SS as a potential chemotherapeutic agent for ovarian cancer. High-dose SS-mediated ferroptotic therapy integrating glutathione depletion and ROS generation is a promising strategy for cancer therapy.

Tetraspanin 1 promotes endometriosis leading to ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) reportedly develops from endometriosis. However, the molecular mechanism underlying its malignant progression to OCCC remains elusive. This study aimed to identify an essential gene in the malignant transformation of endometriosis to OCCC. We performed RNA sequencing in formalin‐fixed, paraffin‐embedded (FFPE) tissues of endometriosis (n = 9), atypical endometriosis (AtyEm) (n = 18), adjacent endometriosis to OCCC (AdjEm) (n = 7), and OCCC (n = 17). We found that tetraspanin 1 (TSPAN1) mRNA level was significantly increased by 2.4‐ (DESeq2) and 3.4‐fold (edgeR) in AtyEm and by 80.7‐ (DESeq2) and 101‐fold (edgeR) in OCCC relative to endometriosis. We confirmed that TSPAN1 protein level was similarly overexpressed in OCCC tissues and cell lines. In immortalized endometriosis cell lines, TSPAN1 overexpression enhanced cell growth and invasion. Mechanistically, TSPAN1 triggered AMP‐activated protein kinase (AMPK) activity, promoting endometriosis and cell growth. Upregulated levels of TSPAN1 are considered an early event in the development of high‐risk endometriosis that could progress to ovarian cancer. Our study suggests the potential of TSPAN1 as a screening candidate for high‐risk endometriosis.

Clinical Significance of Tumor Infiltrating Lymphocytes in Association with Hormone Receptor Expression Patterns in Epithelial Ovarian Cancer

Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor-infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Here we found that ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERβ expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease-free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while the Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.

Cost-Effectiveness Analysis of Germline and Somatic BRCA Testing in Patients With Advanced Ovarian Cancer

We developed a decision model comprising five Assuming a willingness-to-pay of $20,000 per progression-free life-year gain (PF-LYG), all five strategies were considered cost-effective. Strategy 4 was the most cost-effective option, with an incremental cost-effectiveness ratio (ICER) of $2,547.7 per PF-LYG, followed by strategy 1, with an ICER of $3,978.4 per PF-LYG. Even when the parameter values were varied within the possible range, the ICERs of all strategies did not exceed the willingness-to-pay threshold. Considering the importance of knowing a patient's

East Asian Gynecologic Oncology Trial Group (EAGOT): founding history and future perspective

Racial and regional differences exist in morbidity, histology, drug response, toxicity, and prognosis of gynecologic cancer. However, most large-scale phase III studies have been conducted in Western countries, and these data on Asians, who account for more than half of the world's population, are limited. To build a global clinical trial network in Asia, four clinical trial groups with high expertise and international competitiveness in East Asia, namely the Japanese Gynecologic Oncology Group in Japan, the Korean Gynecologic Oncology Group in Korea, the Taiwanese Gynecologic Oncology Group in Taiwan, and the Chinese Gynecologic Cancer Society in the People's Republic of China, established a new group called the East Asia Gynecologic Oncology Trial Group (EAGOT) on November 19, 2021. It includes four committees: the Cervical Cancer Committee, Uterine Corpus Cancer Committee, Ovarian Cancer Committee, and Translational Research Committee. The purpose of EAGOT is to conduct international clinical trials in an effort to provide the best treatments for Asian women affected by gynecologic cancer. Discussions on new collaborative clinical trials have already begun. The first Annual EAGOT Meeting was held on May 25-27, 2023 in Niigata, Japan. EAGOT, the largest healthcare/investigational innovation network in Asia in the area of gynecologic cancers, will become a platform for establishing standards of care and lead to guidelines for Asian women suffering from gynecologic cancer. The harmonization of regulatory/investigator-initiated clinical trials, simultaneous approval of unapproved drugs in the four countries under a common protocol, and expansion of indications will improve the prognosis of gynecologic cancers in Asia in the near future.

Biobanking of gynecologic cancer biospecimens: Development, quality control, and translational applications

Introduction This study presents a nationwide infrastructure for the collection and utilization of gynecologic cancer biospecimens, established through the Korea Biobank Project. We comprehensively describe the biobanking strategy, quality control protocols, and development of secondary resources to support future translational and discovery-based research. Methods We established a gynecologic cancer biobank within the Korea Biobank Project (KBP) through a multi-institutional consortium. Biospecimens, including blood, tumor tissue, urine, and ascites, were collected from 294 patients with endometrial, cervical, or ovarian cancers. Pre-analytical variables were documented using the Standard PREanalytical Code (SPREC), and all samples were tracked with 2D barcodes. Secondary resources were developed, including whole-genome sequencing (WGS) datasets, immortalized human ovarian surface epithelial (IHOSE) cell lines, patient-derived xenografts (PDX), tumor organoids, and tissue microarrays (TMAs). Results A total of 6,168 biospecimens were archived. WGS was performed on 386 cancer samples, including 172 paired tumor–normal sets. Four IHOSE cell lines were authenticated and validated for stability, 14 PDX models retained histological fidelity across passages, and patient-derived ovarian cancer organoids demonstrated drug sensitivity consistent with clinical response patterns. TMAs were constructed from 519 tumors, supporting large-scale molecular profiling. Industry collaborations further highlighted the translational utility of these resources. Conclusions This study describes the development and application of a gynecologic cancer biobank that integrates standardized biospecimen collection, rigorous QC, and the generation of diverse secondary resources. By linking these resources with clinical and epidemiological data, the biobank provides a scalable and accessible platform for precision oncology and academic–industry collaboration.

Metastatic Cervical Cancer in the Asia-Pacific Region: Current Treatment Landscape and Barriers

Abstract Despite treatment advances for metastatic cervical cancer (mCC), the Asia-Pacific region faces significant barriers in treatment accessibility, availability, and healthcare infrastructure. This study explored the treatment landscape and barriers for mCC in the Asia-Pacific. A descriptive, cross-sectional, web-based study evaluating cervical cancer treatment patterns was conducted among medical, radiation, and gynecologic oncologists and gynecologists in the Chinese mainland (n = 80), Australia, the Philippines, South Korea, and Taiwan (n = 20 each). Eligible respondents were primarily involved in direct patient care (≥60%) and were key treatment deciders with ≥5 years of experience. Among patients with cervical cancer of 160 physicians, 10.9% had metastatic disease, of which 50.3% were aged 41 to 60 years and had Eastern Cooperative Oncology Group scores of 0 to 2 (78.7%). Top treatment modalities included systemic therapy (ST) alone (43.6%) and radiotherapy + ST (33.4%). Top first-line regimens were carboplatin/cisplatin + paclitaxel ± bevacizumab (42.3% and 33.1%, respectively), and the top second-line treatment regimens were carboplatin + paclitaxel + bevacizumab (12.0%) and cisplatin + paclitaxel + bevacizumab (11.5%). PD-L1 testing was more common in South Korea (80.8%) than in the Chinese mainland (48.8%) and Taiwan (26.4%). Treatment drivers included National Comprehensive Cancer Network guidelines (82.7%), disease stage (87.4%), Eastern Cooperative Oncology Group status (83.5%), comorbidities (59.1%), drug efficacy (88.2%), safety (84.3%), and accessibility (66.9%). Treatment challenges included poor prognosis (26.8%), patient affordability (21.3%), and limited treatment option availability (19.7%). In bevacizumab-reimbursed locations, patient tolerability and insufficient medical resources persisted. In conclusion, approximately 11% of cervical cancer cases were metastatic. Treatment preferences were radiotherapy and ST, with funding, cost, accessibility, and availability challenges. Policies supporting reimbursement and accessibility could encourage the adoption of effective alternative therapies. Significance: The findings offer valuable insights about current treatments and the related unmet needs in funding, cost, accessibility, and availability across the Asia-Pacific region. These further highlight areas of importance and the need for implementing reimbursement policies and enhancing accessibility to support the adoption of effective, advanced treatments.

Therapeutic effects of surgical debulking of metastatic lymph nodes in cervical cancer IIICr: a trial protocol for a phase III, multicenter, randomized controlled study (KGOG1047/DEBULK trial)

Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.

Lugol's Solution Reduces Positive Margins and Residual Disease After the Large Loop Excision of Transformation Zone

Objective This study aimed to examine whether the intraoperative use of Lugol's solution reduces the proportion of positive resection margins (RMs) using the data of women who underwent large loop excision of the transformation zone (LLETZ). Materials and Methods A total of 1,751 consecutive women with cervical intraepithelial neoplasia (CIN) who underwent LLETZ with or without Lugol's solution were retrospectively retrieved from each database of 3 university hospitals in South Korea. Outcomes included positive RMs and residual disease pathologically confirmed within 6 months after LLETZ. Results Positive RMs were noted in 345 cases (19.7%). Among 1,507 women followed up, residual disease was diagnosed in 100 cases (6.6%) (69/308 cases with positive RMs; 31/1,199 cases with negative RMs). The Lugol's solution group was less likely to have positive RMs (11.8% vs 25.5%, p < .01), to require additional surgical intervention (5.4% vs 10.2%, p < .01), and to have residual disease (4.9% vs 8.0%, p = .02). On multiple logistic regression analysis, Lugol's solution reduced the proportion of positive RMs (adjusted odds ratio [aOR], 0.31). Age (50 years or older; aOR, 1.64), preconization cervical cytology (aOR, 1.53), high-risk human papillomavirus (aOR, 1.75), and CIN 2 or 3 (aOR, 2.65) were independent risk factors for margin positivity (p < .01 for all except high-risk human papillomavirus of p = .05). Conclusions Lugol's solution optimizes CIN treatment by reducing the proportion of positive RMs and residual disease after LLETZ.

Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study

Abstract Purpose: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). Patients and Methods: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). Results: The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% [95% confidence interval (CI), 81.1–97.8] in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5–43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2–86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥ 3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. Conclusions: Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.