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Objective: The tumor immune microenvironment in ovarian clear cell carcinoma has not been clearly defined. We analyzed the immunological changes from treatment-naive to recurrence to correlate them with clinical outcomes., Method: We compared the changes in immune infiltration of advanced-stage ovarian clear cell carcinoma samples before treatment and at the time of recurrence via immunohistochemistry (Programmed Cell Death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8+), forkhead box P3 (Foxp3+)), tumor-infiltrating lymphocytes (TIL), and next-generation sequencing (54 patients). We analyzed the association between platinum sensitivity status and tumor immune microenvironment., Results: Immunohistochemistry revealed significantly increased PD-L1 (p=0.048) and CD8+T cells (p=0.022) expression levels after recurrence. No significant differences were observed in TIL density or Foxp3+T cells. There was no significant correlation between TIL, PD-L1, CD8+T cell, and Foxp3+T cell levels in treatment-naive tumors and survival outcomes. The most common genomic alterations were PIK3CA (41.7%) and ARID1A (41.7%) mutations. There were no differences in the immunological changes or survival outcomes according to PIK3CA and ARID1A mutations. Patients with recurrent platinum-sensitive disease showed higher TIL expression levels. There were no significant differences in PD-L1, CD8+T cells, or Foxp3+T cells between platinum-sensitive and platinum-resistant diseases., Conclusion: We characterized the tumor immune microenvironment in patients with advanced-stage ovarian clear cell carcinoma. PD-L1 and CD8+T cell expression significantly increased after recurrence. Whether this could be used to select patients for immunotherapy in the recurrence setting should be investigated., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the efficacy of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting survival outcomes based on breast cancer gene (BRCA) mutational status in epithelial ovarian cancer., Methods: Medical records of 448 patients diagnosed with epithelial ovarian cancer at a single tertiary institution in Korea were retrospectively analyzed. Area under the curve, sensitivity, specificity, and accuracy were assessed using the CA125 and HE4 values after surgery and 3 cycles of chemotherapy to predict 1-year survival based on the BRCA mutational status. Kaplan-Meier analysis was used to obtain progression-free and overall survival to evaluate CA125 and HE4 effectiveness in predicting survival outcomes., Results: A total of 423 patients were analyzed, including 180 (42.6%) who underwent interval debulking surgery (IDS) and 243 (57.4%) who underwent primary debulking surgery (PDS). BRCA mutations were observed in 37 (15.2%) and 44 (22.4%) patients in the PDS and IDS groups, respectively. CA125 and HE4 normalization demonstrated the highest specificity in patients with or without BRCA mutations, with specificities of 97.1% and 99.1% in the PDS group and 78.6% and 86.2% in the IDS group, respectively. Normalizing HE4 alone may be an effective prognostic marker, with an area under the curve of 0.774 and specificity of 75.0%, in patients with BRCA mutations., Conclusion: Normalizing both biomarkers emerged as the most effective predictive marker for the 1-year recurrence rate, regardless of BRCA mutational status. A negative HE4 value can be a useful predictor for 1-year recurrence-free survival in patients with BRCA mutations., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Backgruound: Malignant struma ovarii (MSO) is a very rare disease in which thyroid cancer originates from the ovary. Because it is rare for endocrinologists to encounter patients with MSO, endocrinologists may have a limited understanding of the disease. Therefore, we analyzed and introduced its incidence and clinical course in a tertiary hospital in Korea., Methods: We retrospectively investigated the clinical data of 170 patients who underwent surgery for struma ovarii at the Department of Obstetrics and Gynecology of Samsung Medical Center from 1994 to May 2023., Results: Among 170 patients with struma ovarii, 15 (8.8%) were diagnosed with MSO. The median age of patients with MSO was 48 years (range, 30 to 74), and the median tumor size was 3.3 cm (range, 0.5 to 11.0). Papillary thyroid carcinoma (46.7%) was the most common subtypes followed by follicular thyroid carcinoma (26.7%). All patients were diagnosed after surgery, with no predictions from preoperative imaging. The surgical extent of gynecological surgery was variable. Four patients (26.7%) underwent thyroidectomy for thyroid cancer, while one underwent total thyroidectomy and radioactive iodine therapy for MSO with peritoneal metastasis. Except for one patient who underwent hemithyroidectomy, thyroid stimulating hormone suppression therapy was performed in four patients. Only 53% of MSO patients were consulted by an endocrinologist. With a median follow-up period of 33 months (range, 4 to 156), 11 patients remained disease-free, one experienced progression with peritoneal seeding, and the remaining one was in treatment. There have been no recurrences or deaths due to MSO., Conclusion: An endocrinologist should be involved in establishing a therapeutic plan for MSO, for which the overall prognosis is generally favorable.

Circulating tumor DNA (ctDNA) may aid in personalizing ovarian cancer therapeutic options. Here, we aimed to assess the clinical utility of serial ctDNA testing using tumor-naïve, small-sized next-generation sequencing (NGS) panels. A total of 296 patients, including 201 with ovarian cancer and 95 with benign or borderline disease, were enrolled. Samples were collected at baseline (initial diagnosis or surgery) and every 3 months after that, resulting in a total of 811 blood samples. Patients received adjuvant therapy based on the current standard of care. Cell-free DNA was extracted and sequenced using an NGS panel of 9 genes: TP53, BRCA1, BRCA2, ARID1A, CCNE1, KRAS, MYC, PIK3CA, and PTEN. Pathogenic somatic mutations were identified in 69.2% (139/201) of patients with ovarian cancer at baseline but not in those with benign or borderline disease. Detection of ctDNA at baseline and/or at 6 months follow-up was predictive of progression-free survival (PFS). PFS was significantly poorer in patients with detectable pathogenic mutations at baseline that persisted at follow-up than in patients that converted from having detectable ctDNA at baseline to being undetectable at follow-up; survival did not differ between patients without pathogenic ctDNA mutations in baseline or follow-up samples and those that converted from ctDNA positive to negative. Disease recurrence was also detected earlier with ctDNA than with conventional radiologic assessment or CA125 monitoring. These findings demonstrate that serial ctDNA testing could effectively monitor patients and detect minimal residual disease, facilitating early detection of disease progression and tailoring of adjuvant therapies for ovarian cancer treatment., Significance: In ovarian cancer, serial circulating tumor DNA testing is a highly predictive marker of patient survival, with a significantly improved recurrence detection lead time compared with conventional monitoring tools., (©2023 American Association for Cancer Research.)

Background: Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis) are becoming the standard of care for epithelial ovarian cancer (EOC). Recently, clinical trials of triple maintenance therapy (PARPi+anti-angiogenic agent+anti-PD-1/L1) are actively ongoing. Here, we investigated the immunological effects of PARPi or triple maintenance therapy on T cells and their impact on clinical responses., Methods: We collected serial blood from EOC patients receiving PARPi therapy (cohort 1: PARPi, n = 49; cohort 2: olaparib+bevacizumab+pembrolizumab, n = 31). Peripheral T cells were analyzed using flow cytometry and compared according to the PARPi response. Progression-free survival (PFS) was assessed according to prognostic biomarkers identified in a comparative analysis., Results: Regulatory T cells (Tregs) were suppressed by PARPi therapy, whereas PD-1 was not significantly changed. Short PFS group exhibited a higher percentage of baseline PD-1 + Tregs than long PFS group, and the patients with high percentage of PD-1 + Tregs before treatment showed poor PFS in cohort 1. However, the expression of PD-1 on Tregs significantly decreased after receiving triple maintenance therapy, and the reduction in PD-1 + Tregs was associated with superior PFS in cohort 2 (P = 0.0078)., Conclusion: PARPi suppresses Tregs, but does not affect PD-1 expression. Adding anti-PD-1 to PARPi decreases PD-1 + Tregs, which have negative prognostic value for PARPi monotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The purpose of this study was to confirm the antiproliferative and apoptotic induction potential of a saccharin and caffeine combination in ovarian cancer cells. The cell line used was Ovcar-3, and the cell viability was measured through a WST-8 assay, while a Chou-Talalay assay was used to confirm the synergistic effect of saccharin and caffeine on the ovarian cancer cells. A clonogenic assay, annexin V-FITC/PI-PE double-staining, and RT-PCR were performed to confirm the expression of genes that induce colony formation, cell viability, and apoptosis in ovarian cancer cells treated with the saccharin-caffeine combination. It was demonstrated that both saccharin and caffeine decreased the viability of Ovcar-3 cells, and the cell viability decreased even more significantly when the cells were treated with the combination of saccharin and caffeine. The clonogenic assay results showed that the number of colonies decreased the most when saccharin and caffeine were combined, and the number of colonies also significantly decreased compared to the single-treatment groups. Based on flow cytometry analysis using annexin V-FITC/PI-PE double-staining, it was confirmed that the decrease in cell viability caused by the combination of saccharin and caffeine was correlated with the induction of apoptosis. The results of the RT-PCR confirmed that the combined treatment of saccharin and caffeine promoted cell apoptosis by regulating the expression of apoptosis-inducing genes. These results demonstrate that the combination of saccharin and caffeine more efficiently inhibits the proliferation of Ovcar-3 cells and induces apoptosis in vitro.

In this multicenter, open-label, single-arm, Phase II study with Simon two-stage optimum design (NCT04361370), we investigate the efficacy and safety of triplet maintenance (olaparib, pembrolizumab, bevacizumab) in patients with platinum-sensitive recurrent ovarian cancer who are wild-type for BRCA 1/2. A total of 44 patients were enrolled, and the median follow-up duration was 22.9 months (interquartile range: 17.4-24.7). The primary outcome was 6-months progression-free survival (PFS), which was 88.6% (95% confidence interval [CI] 75.4-96.2), meeting the pre-specified primary endpoint. The secondary outcomes reported here include median PFS, 12-months PFS, and overall survival and safety. The median PFS was 22.4 months (20.4-∞), with a 12-months PFS rate of 84.0% (95% CI 69.3-92.0). The median overall survival was 28.6 months (27.3-∞). The combination demonstrated tolerable toxicity with manageable side effects. Other secondary outcomes include time-to-progression, time to subsequent treatment, time to second treatment and PFS2; however, this data is not reported, as treatment is still ongoing in a majority of patients. Exploratory analysis shows that patients who were homologous recombination deficiency-positive or had a programmed death-ligand 1 combined positive score ≥1 showed a favorable response (P = 0.043 and P < 0.001, respectively). Thus, triplet maintenance shows durable efficacy with tolerable safety in patients with platinum-sensitive recurrence., (© 2023. Springer Nature Limited.)

Purpose: Patient-specific molecular alterations leading to PARP inhibitor (PARPi) resistance are relatively unexplored. In this study, we analyzed serially collected circulating tumor DNA (ctDNA) from patients with BRCA1/2 mutations who received PARPis to investigate the resistance mechanisms and their significance in postprogression treatment response and survival., Experimental Design: Patients were prospectively enrolled between January 2018 and December 2021 (NCT05458973). Whole-blood samples were obtained before PARPi administration and serially every 3 months until progression. ctDNA was extracted from the samples and sequenced with a 531-gene panel; gene sets for each resistance mechanism were curated., Results: Fifty-four patients were included in this analysis. Mutation profiles of genes in pre-PARPi samples indicating a high tumor mutational burden and alterations in genes associated with replication fork stabilization and drug efflux were associated with poor progression-free survival on PARPis. BRCA hypomorphism and reversion were found in 1 and 3 patients, respectively. Among 29 patients with matched samples, mutational heterogeneity increased postprogression on PARPis, showing at least one postspecific mutation in 89.7% of the patients. These mutations indicate non-exclusive acquired resistance mechanisms-homologous recombination repair restoration (28%), replication fork stability (34%), upregulated survival pathway (41%), target loss (10%), and drug efflux (3%). We observed poor progression-free survival with subsequent chemotherapy in patients with homologous recombination repair restoration (P = 0.003) and those with the simultaneous involvement of two or more resistance mechanisms (P = 0.040)., Conclusions: Analysis of serial ctDNAs highlighted multiple acquired resistance mechanisms, providing valuable insights for improving postprogression treatment and survival., (©2023 American Association for Cancer Research.)

Objective: We evaluated the usefulness of preoperative diagnostic laparoscopy for treatment planning in patients with advanced-stage ovarian cancer., Methods: We retrospectively analyzed 614 patients diagnosed with advanced-stage ovarian cancer between January 2010 and May 2018. Primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) followed by interval debulking surgery were selected based on preoperative laparoscopic (Group 1, n=192) and computed tomography findings (Group 2, n=422). The primary outcomes in the PDS and NAC groups were suboptimal cytoreduction (residual disease >1 cm) rate and non-high-grade serous carcinoma (non-HGSC) rate, respectively., Results: The patients who underwent PDS in group 1 and group 2 were 49 (25.5%) and 279 (66.1%), respectively. The suboptimal cytoreduction rate after PDS was lower in Group 1 than in Group 2 (2.0% vs 11.1%, p=0.023). Moreover, Group 1 showed a tendency toward a lower proportion of non-HGSC patients who underwent NAC than that in Group 2 (9.1% vs. 15.4%, p=0.069). Further, Group 1 showed lower rates of postoperative morbidity than Group 2 (5.2% vs. 10.4%, p=0.033). However, Kaplan-Meier analysis showed no significant differences in survival outcomes between the 2 groups., Conclusion: Diagnostic laparoscopy reduced the suboptimal cytoreduction rate in the PDS group and the implementation rate of NAC in non-HGSC patients. Moreover, it reduced postoperative morbidity without affecting survival in both groups. Thus, diagnostic laparoscopy is a valuable diagnostic tool for determining the primary treatment., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

HOXA cluster antisense RNA 3 (HOXA‑AS3) is considered to be involved in several malignancies, however, its biological function in the progression of epithelial ovarian cancer (EOC) remains unclear. The present study compared the expression of HOXA‑AS3 in ovarian cancer and normal ovarian tissues and analyzed the association between the expression of HOXA‑AS3 and the survival outcomes of patients with ovarian cancer. RNA interference was used to suppress HOXA‑AS3 expression in ovarian cancer cell lines in order to demonstrate the function of HOXA‑AS3 in ovarian cancer progression. The associations between HOXA‑AS3 and epithelial‑mesenchymal transition (EMT) markers were explored to verify the mechanism of action of HOXA‑AS3 in ovarian cancer. The results of the present study revealed that ovarian cancer tissues exhibited higher HOXA‑AS3 expression than normal ovarian tissues. Clinical data indicated that HOXA‑AS3 was a significant predictor of progression‑free survival and overall survival. Patients with high HOXA‑AS3 expression had a poorer prognosis than patients with low HOXA‑AS3 expression. In vitro experiments using HOXA‑AS3‑knockdown ovarian cancer cell lines demonstrated that HOXA‑AS3 knockdown inhibited cell proliferation and migration. HOXA‑AS3 was a potent inducer and modulator of the expression of EMT pathway‑related markers and interacted with both the mRNA and protein forms of HOXA3. Collectively, the findings of the present study demonstrated that HOXA‑AS3 expression is associated with ovarian cancer progression and thus, may be employed as a prognostic marker and therapeutic target in EOC.

Through the wide adaptation of next-generation sequencing (NGS) technology within clinical practice, molecular profiling of the tumor has been the principal component of personalized treatment. In our study, we have generated a large collection of cancer genomes on East Asian epithelial ovarian carcinoma (EOC) patients and demonstrate the feasibility and utility of NGS platforms to explore the dynamic interrelations of major cancer driver alterations and their impacts on clinical prognosis and management. A total of 652 EOC patients have undergone clinical NGS panels to determine the prevalence of germline and somatic mutations. Notably, TP53 was the most frequently altered event (73%), followed by both BRCA1 and BRCA2 (22% each) and MYC (19%) through pan-EOC analysis. When analyzed based on individual histopathological levels, TP53 mutation was highly dominant in high-grade serous and mucinous histology, whereas mutations in PIK3CA and ARID1A were mostly observed in clear cell carcinoma, and KRAS, BRAF, and CDKN2A mutations were enriched in endometrioid, low-grade serous, and mucinous tumors, respectively. The network-based probabilistic model showed significant co-occurrences of TP53 with BRCA1 and ALK with BRCA2, NOTCH1, and ROS1, whereas mutual exclusivity of TP53 with KRAS and PIK3CA was evident. Furthermore, we utilized machine-learning algorithms to identify molecular correlates that conferred increased sensitivity to platinum and olaparib treatments including somatic mutations in BRCA1, ATM, and MYC. Conversely, patients with ALK mutation were considerably resistant to both treatment modalities. Collectively, our results demonstrate the clinical feasibility of prospective genetic sequencing to facilitate personalized treatment opportunities for patients with EOC., (© 2022 UICC.)

Background/aim: The majority of targeted therapies are focused on BRCA mutations, homologous recombination repair deficiency, and BRCA wild-type platinum-sensitive recurrent ovarian cancer. There is a growing need for platinum-resistant patients without BRCA mutations. Herein, we conducted a phase II multicenter study evaluated the efficacy and safety of bortezomib plus pegylated liposomal doxorubicin (PLD) in patients with BRCA wild-type platinum-resistant recurrent ovarian cancer (NCT03509246)., Patients and Methods: Ovarian cancer patients with wild-type BRCA who experienced platinum-resistant recurrence after three or less prior treatment cycles from three Institutions were included. All patients received bortezomib, 1.3 mg/m 2 subcutaneously (days 1, 4, 8, and 11), and PLD, 40 mg/m 2 intravenously (day 4), every 4 weeks. The primary endpoint was best objective response rate (ORR), and secondary endpoints included disease control rate, progression-free survival (PFS), overall survival, and safety. Targeted sequencing was performed to evaluate biomarkers and their potential association with response to treatment., Results: The trial was terminated after 23 patients were recruited because of slow accrual. The median follow-up was 29.5 months. The overall ORR was 8.7% (2/23); partial response was observed in two patients. The median duration of response was 10.5 months, and median PFS was 2.9 months. Treatment-related adverse events (TRAEs) of grade 3/4 were reported in 43.5% of patients. One patient who exhibited TRAEs discontinued treatment. However, grade 4/5 TRAEs were not observed. Mutations in TP53 and CDK12 were detected in 67% (14/21) and 24% (12/21) of patients, respectively. Two patients with partial response harbored mutations in genes related to homologous recombination repair deficiency, including BRCA2, ATM, and CDK12., Conclusion: The combination of bortezomib and PLD was well tolerated; however, antitumor activity was not sufficient to warrant further investigation in ovarian cancer., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management., Methods: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment., Results: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers., Conclusion: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs., Competing Interests: Timothy R. RebbeckHonoraria: AstraZeneca (I)Consulting or Advisory Role: AstraZeneca (I) Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise. Norbert ArnoldHonoraria: AstraZeneca Åke BorgHonoraria: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, AstraZeneca Sandrine CaputoResearch Funding: AstraZeneca/France (Inst) Wendy K. ChungConsulting or Advisory Role: RegeneronResearch Funding: Biogen Chrystelle ColasConsulting or Advisory Role: AstraZeneca/Merck, Pfizer Miguel de la HoyaConsulting or Advisory Role: AstraZenecaResearch Funding: AstraZeneca D. Gareth EvansHonoraria: AstraZeneca Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche George FountzilasStock and Other Ownership Interests: GENPREX Inc (I), ARIAD (I), Deciphera Pharmaceuticals Inc (I), Daiichi Sankyo, RFL Holdings, FORMYCONHonoraria: AstraZenecaConsulting or Advisory Role: Pfizer, Roche, NovartisSpeakers' Bureau: Roche (I), LEO Pharma (I), Pfizer (I)Travel, Accommodations, Expenses: Merck (I), Pfizer (I), K.A.M Oncology/Hematology (I) Megan FronePatents, Royalties, Other Intellectual Property: Receive royalties for being a codeveloper of CancerGene Connect Eric HahnenConsulting or Advisory Role: AstraZeneca Helen HansonHonoraria: Pfizer Beth Y. KarlanConsulting or Advisory Role: Roche Pharma AG, Merck, Mercy Bioanalytics, GRAILResearch Funding: GOG Foundation (Inst), NCI-NRG Oncology (Inst), Genentech/Roche (Inst)Patents, Royalties, Other Intellectual Property: US and EU patent on gene signatureOther Relationship: Elsevier Irene KonstantopoulouSpeakers' Bureau: AstraZenecaResearch Funding: AstraZeneca Ava KwongHonoraria: Stryker, AstraZeneca Taiwan Limited, Roche Singapore, Pfizer, AstraZeneca Hong Kong Ltd Joanne Ngeow Yuen YieResearch Funding: AstraZeneca Rita K. SchmutzlerHonoraria: AstraZeneca, Clovis, MSD/AstraZenecaConsulting or Advisory Role: AstraZeneca, MSD/AstraZenecaResearch Funding: Amgen Leigha SenterConsulting or Advisory Role: AstraZeneca/MerckSpeakers' Bureau: AstraZeneca/Merck Christian F. SingerHonoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead Sciences, Sanofi/Aventis, NovartisSpeakers' Bureau: Novartis, AstraZeneca/MedImmuneResearch Funding: Novartis, Sanofi, Myriad Genetics, Roche, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Novartis Dominique Stoppa-LyonnetHonoraria: AstraZeneca/Merck (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, Roche Sebastian A. WagnerConsulting or Advisory Role: Bayer Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. May receive royalties if commercialization is realized.No other potential conflicts of interest were reported.

Objective: We investigated the prognostic value of complete metabolic response (CMR) on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) after 3 cycles of neoadjuvant chemotherapy (NAC) in advanced high-grade serous ovarian cancer (HGSC)., Methods: PET/CT at baseline and after 3 cycles of NAC were performed; peak standardized uptakes were measured. PET parameters were compared with NAC parameter: cancer antigen-125 (CA-125) normalization before interval debulking surgery (IDS) and chemotherapy response score (CRS) to predict platinum-sensitivity. Kaplan-Meier analysis was used to determine correlations between PET parameters and survival. Prognostic factors were obtained by multivariate Cox regression analysis., Results: Between 2007 and 2020, 102 patients were recruited: 19 (18.6%) were designated as CMR group and 83 (81.4%) as non-CMR group. CMR after 3 cycles of NAC showed the highest accuracy in predicting platinum-sensitivity (area under the curve [AUC]=0.729; 95% confidence interval [CI]=0.552-0.823; p=0.017), compared with CA-125 normalization before IDS (AUC=0.626; 95% CI=0.542-0.758; p=0.010) and CRS (AUC=0.613; 95% CI=0.490-0.735; p=0.080). CMR demonstrated better prognosis than non-CMR in progression-free survival (PFS) (median PFS, 23.9 months vs. 16.4 months; p=0.021) and overall survival (OS) (median OS, not reached vs. 69.7 months; p=0.025). In multivariate analysis, CMR was associated with a lower risk of recurrence (adjusted hazard ratio [aHR]=0.50; 95% CI=0.27-0.92; p=0.027) and death (aHR=0.23; 95% CI=0.05-0.99; p=0.048)., Conclusion: CMR after 3 cycles of NAC can be a prognostic factor for both recurrence and death in advanced HGSC., Competing Interests: No potential conflict of interest relevant to this article was reported, (Copyright © 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: This study aimed to determine the incidence of thrombotic events in ovarian cancer patients following a de-escalated prophylactic strategy and to stratify risk groups., Methods: We reviewed the records of patients who underwent debulking surgery for ovarian cancer at a single institution between January 2007 and May 2019. We identified clinically diagnosed and radiologically confirmed cases of thrombotic events-classified as pulmonary thromboembolism (PE), deep vein thrombosis (DVT), and other thrombotic events-within 6 months of debulking surgery., Results: After excluding 13 patients diagnosed with thromboembolism at the baseline or during neoadjuvant chemotherapy, 799 were analyzed. Since the introduction of medical prophylaxis at our institution in 2009, 482 patients (60%) received medical prophylaxis with subcutaneous injection of low molecular weight heparin for 5 days with mechanical prophylaxis, whereas 317 (40%) received mechanical prophylaxis only. After debulking surgery, thrombotic events occurred in 28 patients (3.5%) including PE (n = 11), DVT (n = 10), and other thrombotic events (n = 7). Multivariable analysis identified age, body mass index (BMI), and operative duration as independent risk factors associated with thrombotic events. A thrombotic event was an independent prognostic factor for overall survival (HR 2.17, 95% CI 1.16-4.1). A cut-off analysis for pre-operative identifiable risk factors showed age < 57 years and BMI < 21 could help define low-risk groups. One patient from 172 low-risk patients (0.58%) experienced a thrombotic event., Conclusions: The thrombotic event incidence was low in our cohort. A de-escalated prophylaxis strategy may be considered in young (age < 57 years) and lean (BMI < 21) patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This study investigated the attitudes toward risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) as cancer prevention options for BRCA1/2 carriers in healthy, young, unmarried Korean women., Materials and Methods: A nationally representative sample of 600 women, aged 20-39 years, completed a questionnaire on sociodemographic variables, preference for genetic testing, and intention to undergo risk-reducing surgeries after receiving information on the cancer risk of BRCA1/2 mutations and benefits of risk-reducing surgeries., Results: A total of 54.7% and 57.7% had the intention to undergo RRM and RRSO, respectively, on the assumption that they were BRCA1/2 carriers. Older age and no intention to undergo genetic testing were associated with a reduced likelihood of undergoing RRM (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.14 to 0.61 for age 35-39 years and OR, 0.35; 95% CI, 0.20 to 0.62 for no intention for genetic testing) and RRSO (OR, 0.39; 95% CI, 0.19 to 0.79 for age 35-39 years and OR, 0.30; 95% CI, 0.17 to 0.53 for no intention for genetic testing). Women who chose to be single were likely to undergo risk-reducing surgeries (OR, 1.67; 95% CI, 1.07 to 2.60 for RRM and OR, 1.56; 95% CI, 1.00 to 2.44 for RRSO)., Conclusion: More than 50% of healthy, unmarried, young Korean women were inclined to undergo prophylactic surgeries if they were BRCA1/2 mutation carriers. Further studies on decision-making process for cancer prevention in individuals at high risk for cancer need to be conducted.

Ovarian cancer stem-like cells (CSCs) have been implicated in tumor recurrence, metastasis, and drug resistance. Accumulating evidence has demonstrated the antitumor effect of plasma-activated medium (PAM) in various carcinomas, including ovarian cancer. Thus, PAM represents a novel onco-therapeutic strategy. However, its impact on ovarian CSCs is unclear. Here, we show that ovarian CSCs resistant to high-dose conventional chemotherapeutic agents used for ovarian cancer treatment exhibited dose-dependent sensitivity to PAM. In addition, PAM treatment reduced the expression of stem cell markers and sphere formation, along with the aldehyde dehydrogenase- or CD133-positive cell population. We further investigated the effect of PAM in combination with other chemotherapeutics on ovarian CSCs in vitro. PAM exhibited synergistic cytotoxicity with cisplatin (CDDP) but not with paclitaxel and doxorubicin. In a peritoneal metastasis xenograft model established via intraperitoneal spheroid injection, PAM intraperitoneal therapy significantly suppressed peritoneal carcinomatosis (tumor size and number), with a more significant decrease observed due to the combined effects of PAM and CDDP with no side effects. Taken together, our results indicate that PAM inhibits ovarian CSC traits and exhibits synergetic cytotoxicity with CDDP, demonstrating PAM as a promising intraparietal chemotherapy for enhancing antitumor efficacy and reducing side effects., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

A 35-year-old woman presented with abdominal discomfort at 26 weeks gestation. The magnetic resonance imaging demonstrated a huge unilocular cystic mass with mural nodules originated from body and tail of pancreas. There was also a cystic mass in the left ovary with suppressed intensity on fat saturated image. One week later, she complained of worsening left lower abdominal pain and dyspnea as a new symptom. Hence, distal pancreatectomy with splenectomy and left ovarian cystectomy were performed. The huge cystic mass of pancreas was compressing the diaphragm, and left tubo-ovarian torsion was observed. This is the second case wherein an MCN of the pancreas with mature cystic teratoma of the ovary caused different symptoms. The management of MCNs in pregnant women should consider multiple aspects such as the malignancy potential of imaging findings, severity of symptoms, and fetal well-being., (© 2021 Japan Society of Obstetrics and Gynecology.)

The current paradigm of cancer medicine focuses on patient- and/or cancer-specific treatments, which has led to continuous progress in the development of patient representatives (e.g., organoids) and cancer-targeting carriers for drug screening. As breakthrough concepts, i) living cancer tissues convey intact profiles of patient-specific microenvironmental signatures. ii) The growth mechanisms of cancer mass with intense cell-cell interactions can be harnessed to develop self-homing nano-targeting by using cancer cell-derived nanovesicles (CaNVs). Hence, a tissueoid model of ovarian cancer (OC) is developed by culturing OC patient tissues in a 3D gel chip, whose microchannel networks enable perfusion to maintain tissue viability. A novel model of systemic cancer responses is approached by xenografting OC tissueoids into ischaemic hindlimbs in nude mice. CaNVs are produced to carry general chemotherapeutics or new drugs under pre/clinical studies that target the BRCA mutation or energy metabolism, thereby increasing the test scope. This pioneer study cross-validates drug responses from the OC clinic, tissueoid, and animal model by demonstrating the alignment of results in drug type-specific efficiency, BRCA mutation-dependent drug efficiency, and metabolism inhibition-based anti-cancer effects. Hence, this study provides a directional foundation to accelerate the discovery of patient-specific drugs with CaNV application towards future precision medicine., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: This study aimed to compare the quality of life (QOL), psychosocial status, sexual function, and menopausal symptoms between the risk-reducing salpingo-oophorectomy (RRSO) and non-RRSO groups comprising BRCA mutation carriers and to evaluate the effect of timing of RRSO on those aspects., Methods: This cross-sectional study recruited BRCA mutation carriers aged ≥35 years between September 2015 and September 2016. Demographic data of carriers were collected. Outcomes were measured using the questionnaires addressing QOL, anxiety, depression, optimism, sexual function, and menopausal symptoms., Results: Of 52 participants, 30 (57.7%) underwent RRSO, whereas 22 (42.3%) did not. In the RRSO group, 16 (53.3%) and 14 (46.7%) women underwent RRSO before and after menopause, respectively. The mean age in the RRSO group was higher than that in the non-RRSO group (49.8 vs. 42.1 years, respectively, p = 0.002). The scores for QOL, anxiety, depression, optimism, sexual function, and menopausal symptoms were similar between both groups. In the multivariate analysis, RRSO uptake was associated with worse physical QOL (coefficient, -5.350; 95% confidence interval, -10.593 to -0.108). With respect to the timing of RRSO, only the mental QOL was significantly lower in the postmenopausal RRSO group than in the premenopausal RRSO group (39.2 vs. 43.7, respectively, p = 0.043)., Conclusion: We could not find any difference in mental QOL, psychosocial status, sexual function, and menopausal symptoms between the RRSO and non-RRSO groups. RRSO uptake only affected worse physical QOL. These results will help physicians counsel BRCA mutation carriers about the effect of RRSO on QOL., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

Objective: Immunotherapy for programmed cell death 1 (PD-1) and its ligand, PD-L1, has been considered an effective treatment for ovarian cancer. 18 F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) is a widely used noninvasive imaging tool for diagnosing several cancers. In this study, we investigated the association between PD-L1 expression and the maximum standardized uptake value (SUVmax) using 18 F-FDG PET/CT., Methods: We retrospectively analyzed clinical data of patients with ovarian cancer who underwent 18 F-FDG PET/CT. Patients were categorized into two groups according to PD-L1 expression results. The relationship between clinicopathological characteristics of patients with ovarian cancer and PD-L1 expression was examined., Results: SUVmax was significantly higher in PD-L1-positive tumors than in PD-L1-negative tumors (16.1 ± 5.2 and 12.7 ± 7.0, respectively; p = 0.026). There were no significant differences in age, histologic type, and tumor grade between the PD-L1-negative and PD-L1-positive groups. The receiver operating characteristic curve analysis demonstrated that the highest accuracy (61.8%) for predicting PD-L1 expression was obtained with an SUVmax cutoff value of 10.5., Conclusion: There was a significant correlation between 18 F-FDG uptake and PD-L1 expression, suggesting a role of 18 F-FDG PET/CT in selecting ovarian cancer candidates for anti-PD-L1 antibody therapy.

Introduction: Subcutaneous negative pressure wound drains have been used to reduce wound complication rates in various surgical procedures. However, research on the benefits of subcutaneous drains on wound healing after ovarian cancer surgery is limited. The aim of this study was to assess the effects of subcutaneous negative pressure drains on wound healing after abdominal surgery for ovarian cancer., Methods: Patients who underwent surgery with a midline incision for ovarian cancer between February 2015 and May 2019 were retrospectively examined. Patients were divided into two groups according to the presence (group 1; n=99) or absence (group 2; n=213) of subcutaneous wound drains. The primary endpoint was the incidence of wound complications within 8 weeks after abdominal surgery. The secondary endpoints were time interval from surgery to adjuvant chemotherapy and survival., Results: Patients in group 1 were older (mean 58.5 vs 55.4 years; p=0.02), and had higher rates of previous abdominal surgery (66.7% vs 47.9%; p=0.002), bowel surgery (47.5% vs 34.3%; p=0.026), and had a high surgical complexity score (53.5% vs 33.8%; p<0.001) compared with patients in group 2. Median body mass index was not different between the two groups: group 1, 22.9 kg/m 2 (range 16.0 to 33.3) and group 2, 22.8 kg/m 2 (range 16.4 to 37.5) (p=0.858). A higher rate of clear wound healing (82.8% vs 71.8%; p=0.036) and a lower rate of seroma formation (6.1% vs 16.0%; p=0.015) were observed in group 1 compared with group 2. After multivariate analysis, subcutaneous wound drain placement was identified as an independent predictive factor for preventing wound complications (adjusted odds ratio 0.43; 95% confidence interval 0.21 to 0.87). Time interval from surgery to adjuvant treatment was significantly longer in patients with wound complications than in those with clear wound healing (mean 23.6 vs 19.2 days; p=0.003). Kaplan-Meier analysis, however, showed no significant differences in progression free or overall survival between the two groups (p=0.35 and p=0.96, respectively)., Conclusion: The prophylactic use of subcutaneous negative pressure drains after abdominal surgery for ovarian cancer significantly reduced the incidence of wound complications in this study., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on the Korean Hereditary Breast Cancer Research at this time.

Carcinosarcoma of the fallopian tube is an exceptionally rare gynecological neoplasm. It tends to have high metastatic potential, to frequently recur, and has a poor prognosis. For these reasons, treatment is difficult and there is no standardized therapy schedule for this disease. Here, we report a case of carcinosarcoma of the fallopian tube mimicking ovarian cancer, initially presenting as a rupture of a growth and subsequent hemoperitoneum. The 55-year-old woman underwent cytoreductive surgery and postoperative conventional platinum-based combination therapy. The anti-angiogenic drug bevacizumab was added, and no evidence of disease was found on follow-up images or tumor markers 51 months after surgical resection. We describe a rare case of carcinosarcoma of the fallopian tube, include an in-depth histopathological review with genetic analysis, and propose treatment with a platinum-based combination therapy including bevacizumab.

Purpose: The aim of this study was to evaluate the ability of sequential 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) after one cycle of neoadjuvant chemotherapy (NAC) to predict chemotherapy response before interval debulking surgery (IDS) in advanced-stage ovarian cancer patients., Materials and Methods: Forty consecutive patients underwent 18F-FDG-PET/CT at baseline and after one cycle of NAC. Metabolic responses were assessed by quantitative decrease in the maximum standardized uptake value (SUVmax) with PET/CT. Decreases in SUVmax were compared with cancer antigen 125 (CA-125) level before IDS, response rate by Response Evaluation Criteria in Solid Tumors criteria before IDS, residual tumor at IDS, and I chemotherapy response score (CRS) at IDS., Results: A 40% cut-off for the decrease in SUVmax provided the best performance to predict CRS 3 (compete or near-complete pathologic response), with sensitivity, specificity, and accuracy of 81.8%, 72.4%, and 72.4%, respectively. According to this 40% cut-off, there were 17 (42.5%) metabolic responders (≥ 40%) and 23 (57.5%) metabolic non-responders (< 40%). Metabolic responders had higher rate of CRS 3 (52.9% vs. 8.7%, p=0.003), CA-125 normalization (< 35 U/mL) before IDS (76.5% vs. 39.1%, p=0.019), and no residual tumor at IDS (70.6% vs. 31.8%, p=0.025) compared with metabolic non-responders. There were significant associations with progression-free survival (p=0.021) between metabolic responders and non-responders, but not overall survival (p=0.335)., Conclusion: Early assessment with 18F-FDG-PET/CT after one cycle of NAC can be useful to predic response to chemotherapy before IDS in patients with advanced-stage ovarian cancer.

Introduction: The spleen plays a role in the immune and coagulative responses, yet a splenectomy may be required during ovarian cancer surgery to achieve complete cytoreduction. The aim of the study was to correlate hematologic changes with the development of infection and venous thromboembolism in patients undergoing splenectomy., Methods: This single-institution retrospective review includes all patients undergoing splenectomy during cytoreductive surgery for advanced ovarian cancer, March 2001 to December 2016. We compared postoperative hematologic changes (evaluated daily before discharge) in patients developing infection within 30 days' post-surgery (Infection group) with those who did not (No-Infection group). We also compared patients developing venous thromboembolism with those without., Results: A total of 265 patients underwent splenectomy. Median age was 64 years (range 22-88): 146 (55%) patients had stage IIIC and 114 (43%) patients had stage IV. The majority, 201 (76%) patients underwent splenectomy during primary debulking. A total of 132 (50%) patients comprised the Infection group (most common: urinary tract infection, 54%). Median time from surgery to infection was 8 days (range, 0-29). After initial rise in white blood cell count in both groups, the Infection group had a second peak on postoperative day 10 (median 16.6K/mcL, IQR 12.5-21.2) not seen in the No-Infection group (median 12K/mcL, IQR 9.3-16.3). A total of 40 (15%) patients developed venous thromboembolism, median time of 6.5 days (range, 1-43). All patients demonstrated a continuous rise in platelets during postoperative days 0-15. Thrombocytosis was present in 38/40 (95%) patients with venous thromboembolism vs 183/225 (81%) patients without (P=0.036). Median days with thrombocytosis was higher in venous thromboembolism (8 days, range 1-15) vs non groups (6 days, range 1-16, P=0.049)., Conclusion: We identified initial leukocytosis after splenectomy in all patients. The Infection group had a second peak in white blood cell count on postoperative day 10, not present in the No-Infection group. Among patients with venous thromboembolism, thrombocytosis was more frequent and of longer duration., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We evaluated whether adding bevacizumab to current platinum-based chemotherapy could improve clinical outcomes without affecting safety., Materials and Methods: We retrospectively reviewed medical records of patients with pathologically confirmed ovarian cancer who received neoadjuvant chemotherapy (NAC) at Yonsei Cancer Hospital. We divided the patients into groups based on the use of bevacizumab for NAC (CP group: carboplatin+paclitaxel vs. BCP group: bevacizumab+carboplatin+paclitaxel) and compared patient characteristics, responses to NAC, and surgical and survival outcomes between the two groups. Overall, 88 patients in the CP group and 16 patients in the BCP group received NAC. The primary endpoint was survival outcomes. Complete resection rate after interval debulking surgery (IDS), cancer antigen 125 (CA-125) normalization after NAC, and chemotherapy response score were secondary endpoints., Results: After NAC treatment, all patients underwent IDS. There were no significant differences in adverse events during NAC or postoperative complications between the two groups ( p =0.293 and p =0.485, respectively). There were also no significant differences in CA-125 normalization after NAC (42.0% vs. 43.8%, p =0.899) or complete resection rate after IDS (47.7% vs. 56.3%, p =0.530). However, although the BCP group did not show longer overall survival (OS) (log-rank p =0.854), they had significantly longer progression-free survival (PFS) than the CP group (log-rank p =0.048)., Conclusion: Bevacizumab-containing NAC might be safe and provide longer PFS than chemotherapy alone in patients with advanced ovarian cancer. However, further study is necessary to investigate the impact of bevacizumab-containing NAC on OS., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Background: Poly (ADP-ribose) polymerase inhibitors targeting BRCA1/2 mutations are available for treating patients with high-grade serous ovarian cancer. These treatments may be more appropriately directed to patients who might respond if the tumor tissue is additionally tested by next-generation sequencing with a multi-gene panel and Sanger sequencing of a blood sample. In this study, we compared the results obtained using the next-generation sequencing multi-gene panel to a known germline BRCA1/2 mutational state determined by conventional Sanger sequencing to evaluate the landscape of somatic mutations in high-grade serous ovarian cancer tumors., Methods: Cancer tissue from 98 patients with high-grade serous ovarian cancer who underwent Sanger sequencing for germline BRCA1/2 analysis were consecutively analyzed for somatic mutations using a next-generation sequencing 170-gene panel., Results: Twenty-four patients (24.5%) showed overall BRCA1/2 mutations. Seven patients (7.1%) contained only somatic BRCA1/2 mutations with wild-type germline BRCA1/2, indicating acquired mutation of BRCA1/2. Three patients (3.1%) showed reversion of germline BRCA1 mutations. Among the 14 patients (14.3%) with both germline and somatic mutations in BRCA1/2, two patients showed different variations of BRCA1/2 mutations. The next-generation sequencing panel test for somatic mutation detected other pathogenic variations including RAD51D and ARID1A, which are possible targets of poly (ADP-ribose) polymerase inhibitors. Compared to conventional Sanger sequencing alone, next-generation sequencing-based tissue analysis increased the number of candidates for poly (ADP-ribose) polymerase inhibitor treatment from 17.3% (17/98) to 26.5% (26/98)., Conclusions: Somatic mutation analysis by next-generation sequencing, in addition to germline BRCA1/2 mutation analysis, should become the standard of care for managing women with high-grade serous ovarian cancer to widen the indication of poly (ADP-ribose) polymerase inhibitors.

Background: To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS)., Methods: We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated., Results: BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients., Conclusion: In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients.

Objective: To compare the efficacy and toxicity of dose-dense weekly paclitaxel and 3-weekly carboplatin (ddPC) as neoadjuvant chemotherapy (NAC) with the standard 3-weekly regimen., Methods: A retrospective study of patients diagnosed with stage IIIc and IV ovarian cancer who received at least one cycle of NAC followed by interval debulking surgery between August 2015 and January 2018 was conducted. Patient characteristics, clinical and pathological response to NAC, surgical and survival outcome, and adverse event were compared., Results: A total of 23 patients in the ddPC group and 50 patients in the standard group received a median of 3 cycles of NAC. Rate of grade ≥3 neutropenia was significantly higher in the ddPC group than the standard (82.6% vs. 22.0%, p<0.001). Patients in the ddPC group underwent dose-reduction more frequently (34.8% vs. 4.00%, p=0.001). Normalization of cancer antigen-125 post-NAC occurred more frequently in the ddPC group (73.9% vs. 46.0%, p=0.030). No residual disease rate (43.5% vs. 60.0%, p=0.188) and chemotherapy response score of 3 (34.8% vs. 26.0%, p=0.441) were not statistically different between two groups. There was no statistical difference in progression free survival (PFS) at 2 years (36.3% vs. 28.4%, p=0.454). Cox proportional hazard model showed that ddPC was not a significant determinant of PFS (p=0.816)., Conclusion: There was no difference between both regimens in terms of NAC response and survival outcomes. However, ddPC group showed higher hematologic toxicity requiring dose reduction., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Purpose: Few efforts have been made to integrate a next generation sequencing (NGS) panel into standard clinical treatment of ovarian cancer. The aim of this study was to investigate the clinical utility of NGS and to identify clinically impactful information beyond targetable alterations., Materials and Methods: We conducted a retrospective review of 84 patients with ovarian cancer who underwent NGS between March 1, 2017, and July 31, 2018, at the Yonsei Cancer Hospital. We extracted DNA from formalin-fixed, paraffin-embedded tissue samples of ovarian cancer. The TruSight Tumor 170 gene panel was used to prepare libraries, and the MiSeq instrument was used for NGS., Results: Of the 84 patients, 55 (65.1%) had high-grade serous carcinomas. Seventy-three (86.7%) patients underwent NGS at the time of diagnosis, and 11 (13.3%) underwent NGS upon relapse. The most common genetic alterations were in TP53 (64%), PIK3CA (15%), and BRCA1/2 (13%), arising as single nucleotide variants and indels. MYC amplification (27%) was the most common copy number variation and fusion. Fifty-seven (67.9%) patients had more than one actionable alteration other than TP53 . Seven (8.3%) cases received matched-target therapy based on the following sequencing results: BRCA1 or 2 mutation, poly ADP ribose polymerase inhibitor (n=5); PIK3CA mutation, AKT inhibitor (n=1); and MLH1 mutation, PD-1 inhibitor (n=1). Fifty-three (63.0%) patients had a possibility of treatment change, and 8 (9.5%) patients received genetic counseling., Conclusion: Implementation of NGS may help in identifying patients who might benefit from targeted treatment therapies and genetic counseling., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2019.)

Objectives: In our institutional experience, involved-field radiation therapy (IFRT) yields favorable outcomes in patients with recurrent epithelial ovarian cancer (EOC). This retrospective study aimed to investigate the clinical benefits of IFRT in this patient population., Methods: Among patients treated with IFRT for recurrent EOC between 2010 and 2017, 61 patients with 90 treatments were included. IFRT encompassed all treatable lesions identified via imaging studies with 10-15-mm margins. Prescribed doses were ≥45 Gy (equivalent dose in 2 Gy/fraction)., Results: Patients were followed up for a median of 19.0 (Interquartile range, 8.6-34.9) months after IFRT. The 2-year in-field control, progression-free survival, and overall survival (OS) rates were 42.7%, 24.2%, and 78.9%, respectively. Fifty-three IFRT sessions (58.9%) were followed by systemic chemotherapy, and the median chemotherapy-free interval (CFI) was 10.5 (95% confidence interval=7.3-13.7) months. A higher carbohydrate antigen-125 (CA-125) level correlated with a worse 2-year OS (69.2% vs. 91.0%; p=0.001) and shorter median CFI (4.7 vs. 11.9 months; p<0.001). Twenty-eight (31.1%) of 90 treatments yielded a long-term CFI >12 months. For patients with a normal CA-125 level and/or platinum-sensitive tumor, IFRT prolonged CFI regardless of pre-existing carcinomatosis, gross tumor volume, and number of treatment sites., Conclusion: Our early experience demonstrates the safety and feasibility of IFRT as an effective salvage therapy and enables a "chemotherapy holiday" in selected recurrent EOC settings. The CA-125 value before IFRT (within normal range) and/or platinum sensitivity could be used as selection criteria for IFRT., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Purpose: Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing., Materials and Methods: To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA)., Results: Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25, HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845)., Conclusion: We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.

Aims: We evaluated the prognostic significance of postoperative re-elevation of cancer antigen-125 (CA-125) levels in patients with ovarian cancer and preoperative normalization of CA-125 levels after neoadjuvant chemotherapy (NAC)., Methods: The data of 103 patients with preoperative CA-125 normalization after NAC at the Yonsei Cancer Hospital (2006-2017) were analyzed. We compared the clinical characteristics and survival outcomes among patients with normal postoperative CA-125 levels and those with re-elevated CA-125 levels after interval debulking surgery (IDS). CA-125 elevation was defined as levels >35 U/mL., Results: Among 103 patients, 52 (50.5%) and 51 (49.5%) had normal and re-elevated CA-125 levels after IDS, respectively. Patients with CA-125 re-elevation underwent more radical surgeries during IDS than those with normal CA-125 levels (p = 0.018). We found no significant differences in progression-free survival (PFS; p = 0.726) or overall survival (OS; p = 0.293) between the two groups. Moreover, patients with persistent CA-125 elevation (3 weeks after IDS) did not have inferior PFS (p = 0.171 and p = 0.208, respectively) or OS (p = 0.128 and p = 0.095, respectively) compared to patients with early normalization (within 3 weeks of IDS) or normal CA-125 levels. Multivariate regression showed that CA-125 re-elevation had no effect on recurrence (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.43-1.30) or death (HR, 0.99; 95% CI, 0.33-2.98)., Conclusion: Among patients with preoperative CA-125 normalization after NAC, postoperative CA-125 re-elevation had no prognostic value. Novel and reliable biomarkers reflecting the tumor response after IDS should be identified., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The aim of this study was to investigate the prognostic significance of lymphocytopenia in advanced-stage ovarian cancer. We retrospectively reviewed 506 patients with advanced-stage ovarian cancer at Yonsei Cancer Hospital. This study included two cohorts of patients: a neoadjuvant chemotherapy (NAC) group (N = 247) and a primary debulking surgery (PDS) group (N = 259). The absolute lymphocyte count was recorded before treatment. A receiver operating characteristic (ROC) curve analysis was used to determine the cutoff for defining lymphocytopenia in the NAC cohort and followed by multivariate analysis. Subsequently, lymphocytopenia was assessed in the PDS cohort by multivariate analysis. A further analysis was performed to evaluate the absolute lymphocyte count as a continuous variable. An absolute lymphocyte count of 1.49 × 109/L was determined as the cutoff for the ROC curve analysis in the NAC cohort, and the multivariate analysis revealed that lymphocytopenia was an independent prognostic factor for poor progression-free survival (PFS) [hazard ratio (HR), 1.50; 95% confidence interval (CI), 1.07-2.11] and overall survival (OS) (HR, 2.02; 95% CI, 1.21-3.40). In the PDS cohort, the multivariate analysis showed that lymphocytopenia was an independent prognostic factor for poor PFS (HR, 1.73; 95% CI, 1.20-2.49) and OS (HR, 1.87; 95% CI, 1.27-2.75). The absolute lymphocyte count was a significant factor when analyzed as a continuous variable in both the NAC and PDS cohorts. Pretreatment lymphocytopenia is an independent adverse prognostic factor in patients with advanced-stage ovarian cancer., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The aim of this study is to analyze the long-term relapse-free survival and overall survival outcomes of primary ovarian cancer patients using adenosine triphosphate-based chemotherapy response analysis., Methods: In total, 162 primary epithelial ovarian cancer patients who underwent chemotherapy response assay for carboplatin, cisplatin, and paclitaxel by adenosine triphosphate-based chemotherapy response analysis prior to chemotherapy between December 2006 and November 2016 were retrospectively reviewed. Chemosensitivity with single or combined three agents and clinical characteristics of patients were studied to understand their correlation with long-term relapse-free survival and overall survival., Results: Median follow-up time was 61.4 (range 1 - 130) months. Univariate analysis showed the paclitaxel-sensitive group (HR = 0.625, 95%CI = 0.393 to 0.994), combined carboplatin and paclitaxel-sensitive group (HR = 0.574, 95%CI = 0.352 to 0.937), and combined carboplatin, cisplatin, and paclitaxel-sensitive group (HR = 0.489, 95%CI = 0.295 to 0.810) were highly associated with better relapse-free survival than their corresponding non-sensitive groups. The carboplatin-sensitive group (HR = 0.533, 95%CI = 0.303 to 0.939), cisplatin-sensitive group (HR = 0.433. 95%CI = 0.251 to 0.748), and combined carboplatin- and cisplatin-sensitive group (HR = 0.286, 95%CI = 0.142 to 0.576) were highly associated with better overall survival than their corresponding non-sensitive groups. Combined carboplatin, cisplatin, and paclitaxel chemosensitivity, together with International Federation of Gynecology and Obstetrics (FIGO) stage were independent predictors for relapse-free survival. Single or combined chemosensitivity of cisplatin and/or carboplatin, together with residual tumor size and FIGO stage, were significant independent predictors for overall survival on a multivariate hazard model., Conclusion: Paclitaxel sensitivity is a prognostic factor of long-term relapse-free survival in patients with epithelial ovarian cancer, but platinum sensitivity is a more important prognostic factor for long-term overall survival., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We conducted a protocol-based cohort study to evaluate the outcomes of interval debulking surgery (IDS) followed by paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of advanced-stage ovarian cancer., Methods: From October 2015 to May 2018, 65 patients with stages IIIC-IV ovarian cancer were treated according to the study protocol. HIPEC was performed with paclitaxel (175 mg/m²) for 90 minutes, only in cases of optimal cytoreduction., Results: Of 65 patients, 40 (61.5%) patients underwent neoadjuvant chemotherapy (NAC), 34 (52.3%) patients had a high tumor burden with a Fagotti score ≥8 at diagnostic laparoscopy, and 6 (9.2%) had definite stage IV metastasis and/or poor performance status before NAC. Twenty-seven (41.5%) patients underwent IDS followed by HIPEC. The mean duration of IDS with HIPEC was 543.8 (range, 277.0-915.0) minutes. Grade III/IV perioperative complications occurred in 7.4% (n=2)/3.7% (n=1) of patients and no cases of mortality were reported within 30 days postoperatively. The median progression-free survival was 21.3 months, and the median overall survival was not reached for those who received HIPEC., Conclusions: According to our study protocol, IDS followed by paclitaxel-based HIPEC as a first-line treatment appears to be feasible and safe for the treatment of advanced-stage ovarian cancer. Further evaluations of this procedure are required to assess its survival benefits., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objective: To investigate the prognostic value of the expressions of programmed cell death ligand 1 (PD-L1) and immune checkpoint markers in residual tumors after neoadjuvant chemotherapy (NAC) for advanced high-grade serous ovarian cancer (HGSOC)., Methods: We collected pre- and post-NAC tumor samples from patients with advanced HGSOC between 2006 and 2017. Post-NAC tumor tissue samples were available for immunostaining from 131 patients. The expressions of PD-L1 and immune checkpoint markers were assessed by immunohistochemical staining and the status of tumor-infiltrating lymphocytes (TILs) was also evaluated. We examined whether there are significant associations between protein expression status and patient outcomes and whether significant changes in protein expression levels occurred in response to NAC., Results: PD-L1 expression in the tumor cells was evaluated in 113 patients, 12 (10.6%) of whom had high PD-L1 expression (≥25%) in post-NAC tissues. However, these high levels were not associated with progression-free survival (PFS; P = 0.348) or overall survival (OS; P = 0.699). Similarly, high stromal TILs [≥50%; n = 16 (15.0%)] among the 107 patients evaluated did not show any significant impact on PFS (P = 0.250) or OS (P = 0.800). Moreover, an abundance of TILs (intraepithelial, CD8+, and Foxp3+) and the expression of immune checkpoint markers (PD-1, ICOS, and LAG-3) in residual tumors did not confer any significant survival benefit. The impact of NAC on PD-L1 expression and stromal TILs varied considerably among individual patients., Conclusion: Although the expression of PD-L1 and immune checkpoint markers in residual tumors after NAC had no prognostic impact on survival in patients with HGSOC, post-NAC evaluation of these proteins in chemoresistant tumors may help select patients for immunotherapy trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/aim: This study aimed to determine the effect of different BRCA1 exonal mutations on the clinical course of epithelial ovarian cancer (EOC)., Patients and Methods: Clinicopathological variables and survival outcomes were compared among 53 primary EOC patients with pathogenic BRCA1 mutations in exons 1-11 (5' mutations) and in exons 12-24 (3' mutations)., Results: BRCA1 5' exonal mutations were found in 35 (66.0%) patients. The median follow-up period was 40 months. Clinicopathological variables remained unchanged between the two groups. Patients with 5' mutations had a significantly longer progression-free survival than those with C-terminal mutations (p=0.034), better predicting progression-free survival [2.923 (1.402-6.093), p=0.004], but not overall survival in cases of multiple relapses (p=0.497)., Conclusion: N-terminal BRCA1 mutations in EOC patients are associated with favourable primary progression-free survival, a trend observed only in primary progression-free survival, not in overall survival., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Outcomes in patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied; however, there is limited information on responses to chemotherapy among patients with non-HGSC. The aim of this study was to compare the survival outcomes of patients with advanced-stage non-HGSC and HGSC treated with NAC., Materials and Methods: This study was a retrospective analysis of patients with advanced-stage ovarian cancer treated at Yonsei Cancer Hospital between 2006 and 2017. The demographics, chemotherapy response, and survival rates were compared between patients with non-HGSC and those with HGSC., Results: Among 220 patients who underwent NAC, 25 (11.4%) patients had non-HGSC histologic subtypes, and all received a taxane-platinum combination regimen for NAC. Patients with non-HGSC had lower baseline cancer antigen-125 levels ( p <0.001), poorer response rates ( p <0.001), lower rates of optimal cytoreduction ( p =0.003), and poorer progression-free survival (PFS) (median PFS 10.3 months vs. 18.3 months; p =0.009) and overall survival (OS) (median OS 25.5 months vs. 60.6 months; p <0.001), compared to those with HGSC. In multivariate analysis, non-HGSC was a negative prognostic factor for both PFS [hazard ratio (HR), 3.19; 95% confidence interval (CI), 1.73-5.88] and OS (HR, 4.22; 95% CI, 2.07-8.58)., Conclusion: In this study, poorer survival outcomes were observed in patients who underwent NAC for treatment of non-HGSC versus those treated for HGSC. Different treatment strategies are urgently required to improve survival outcomes for patients with non-HGSC undergoing NAC., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018.)

Objective: To evaluate the efficacy and safety of involved-field radiation therapy (IFRT) in patients with locoregionally confined recurrent or persistent epithelial ovarian cancer., Methods: This study included patients with recurrent epithelial ovarian cancer eligible for IFRT either during diagnosis of the recurrence or after salvage therapies. IFRT was performed at a dose of ≥45 Gy for all tumors with 10-15-mm margins as seen on standard imaging. The primary endpoint was progression-free survival (PFS); the secondary endpoints were safety, response rate, local control, and overall survival (OS)., Results: Thirty patients with a mean number of 5.7 metastatic lesions each were enrolled between 2014 and 2016. Seventeen were treated with 3-D conformal radiation therapy (RT) and 13 with intensity-modulated RT. IFRT was well tolerated in all patients, and acute toxicity ≥ grade 2 was not observed. One case of grade 3 abdominal pain was reported 10 months post-RT. The overall and complete response rates were 85.7% and 50%, respectively. After a median follow-up of 28 (range, 17-42) months, the median PFS was 7 months. The 2-year PFS rate was 39.3%. Six of the 16 patients who developed outfield disease progression after IFRT were successfully treated with repeat IFRT as salvage treatment. The 3-year local control and OS rates were 84.4% and 55.8%, respectively., Conclusions: Although the primary endpoint was not met, IFRT might be safe and effective for in-field tumor control in patients with persistent epithelial ovarian cancer with a limited number of metastatic foci. We plan to conduct a larger scale multi-center phase II prospective study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Various kinetic parameters of serum CA-125 have been reported to have better correlation with outcomes for patients treated with neoadjuvant chemotherapy (NAC). This study aimed to compare the available kinetic parameters of serum CA-125 in an external cohort of advanced-stage ovarian cancer. Using the cancer registry databases from the Yonsei Cancer Hospital, we retrospectively reviewed 210 patients with advanced-stage ovarian cancer, treated with NAC followed by interval debulking surgery. We compared area under the receiver-operating characteristics curves (AUCs), false negative rate, and negative predictive value (NPV) using 10 different models for optimal cytoreduction and platinum resistance. In addition, we compared incremental AUC for progression-free survival (PFS) and overall survival (OS). No gross residual tumor was observed in 37.0% and residual tumors <1 cm in 82.2% of patients. No model using CA-125 kinetic parameters had an AUC higher than >0.6 for predicting optimal cytoreduction. After adjusting for age, BMI, disease stage, and histologic subtypes, all models had an AUC >0.70 for predicting platinum resistance. However, no model had a high enough NPV (highest value = 82.0%) to avoid chemotherapy futility. For survival outcomes, no model had an incremental AUC >0.70 for predicting either PFS or OS. None of the proposed serum CA-125 kinetic parameters showed high accuracy in predicting optimal cytoreduction, platinum resistance, or survival in patients receiving NAC. For advanced-stage ovarian cancer treated with NAC, there is a need to discover reliable biomarkers to better stratify patient response groups for optimal treatment decision-making., Competing Interests: The authors have declared that no competing interests exist.

Objective: The choice between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NAC) in advanced ovarian cancer remains controversial. We evaluated NAC use in our center before and after results from a randomized trial were published, with the aim to determine the impact of changes in the neoadjuvant strategy on survival in advanced-stage ovarian cancer., Methods: We retrospectively investigated the clinical course of 435 patients with ovarian, tubal, or peritoneal carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV). According to the period of treatment, we stratified patients into a control group (n=216; diagnosed between 2006 and 2010; 83.8% underwent PDS) and a study group (n=219; diagnosed between 2011 and 2014; 48.9% received NAC followed by interval debulking surgery [IDS])., Results: There were no between-group differences in age, body mass index, histology findings, or tumor grade. Compared to patients in the control group, those in the study group were more likely to receive NAC followed by IDS as first-line treatment (48.9% vs. 16.2%; p<0.001), cytoreductive surgery to no-residual disease (21.5% vs. 10.2%; p<0.001), or radical surgery (57.5% vs. 35.6%; p<0.001). However, there was no between-group difference in postoperative morbidity. Kaplan-Meier analysis showed no between-group differences in progression-free or overall survival (p=0.449 and 0.952, respectively)., Conclusion: NAC incorporation resulted in increased optimal cytoreduction rates although no significant differences in survival outcomes were noted. NAC is advantageous for patients with high perioperative morbidity or unresectable disease., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Purpose: Although the use of xenograft models is increasing, few studies have compared the clinical features or outcomes of epithelial ovarian cancer (EOC) patients according to the tumorigenicity of engrafted specimens. The purpose of this study was to evaluate whether tumorigenicity was associated with the clinical features and outcomes of EOC patients., Materials and Methods: Eighty-eight EOC patients who underwent primary or interval debulking surgery from June 2014 to December 2015 were included. Fresh tumor specimens were implanted subcutaneously on each flank of immunodeficient mice. Patient characteristics, progression-free survival (PFS), and germline mutation spectra were compared according to tumorigenicity., Results: Xenografts were established successfully from 49 of 88 specimens. Tumorigenicity was associated with lymphovascular invasion and there was a propensity to engraft successfully with high-grade tumors. Tumors from patientswho underwent non-optimal (residual disease ≥ 1 cm) primary orinterval debulking surgery had a significantly greater propensity to achieve tumorigenicity than those who received optimal surgery. In addition, patients whose tumors became engrafted seemed to have a shorter PFS and more frequent germline mutations than patients whose tumors failed to engraft. Tumorigenicity was a significant factor for predicting PFS with advanced International Federation of Gynecology and Obstetrics stage and high-grade cancers., Conclusions: Tumorigenicity in a xenograft model was a strong prognostic factor and was associated with more aggressive tumors in EOC patients. Xenograft models can be useful as a preclinical tool to predict prognosis and could be applied to further pharmacologic and genomic studies on personalized treatments.

Purpose: Next-generation sequencing (NGS) allows simultaneous sequencing of multiple cancer susceptibility genes and may represent a more efficient and less expensive approach than sequential testing. We assessed the frequency of germline mutations in individuals with epithelial ovarian cancer (EOC), using multi-gene panels and NGS., Materials and Methods: Patients with EOC (n=117) with/without a family history of breast or ovarian cancer were recruited consecutively, from March 2016 toDecember 2016.GermlineDNAwas sequenced using 35-gene NGS panel, in order to identify mutations. Upon the detection of a genetic alteration using the panel, results were cross-validated using direct sequencing., Results: Thirty-eight patients (32.5%) had 39 pathogenic or likely pathogenic mutations in eight genes, including BRCA1 (n=21), BRCA2 (n=10), BRIP1 (n=1), CHEK2 (n=2), MSH2 (n=1), POLE (n=1), RAD51C (n=2), and RAD51D (n=2). Among 64 patients with a family history of cancer, 27 (42.2%) had 27 pathogenic or likely pathogenic mutations, and six (9.3%) had mutations in genes other than BRCA1/2, such as CHECK2, MSH2, POLE, and RAD51C. Fifty-five patients (47.0%) were identified to carry only variants of uncertain significance., Conclusion: Using the multi-gene panel test, we found that, of all patients included in our study, 32.5% had germline cancer-predisposing mutations. NGS was confirmed to substantially improve the detection rates of a wide spectrum of mutations in EOC patients compared with those obtained with the BRCA1/2 testing alone.

MicroRNA-630 (miR-630) has been implicated in the development and progression of multiple cancers. The current study aimed to investigate the role of miR-630 in chemoresistant epithelial ovarian cancer. MiR-630 expression levels were detected in ovarian cancer cell line SKOV3 and paclitaxel-resistant SKOV3 (SKOV3-TR) via microarray and qRT-PCR. MiR-630 inhibitors and negative controls were transfected into SKOV3 and SKOV3-TR cells. Wound healing, invasion, chemosensitivity, and cell apoptosis assays were performed to determine proliferation and migration rates. Chemoresistant patient-derived xenograft (PDX) models were established and utilized to verify the effect of miR-630 on chemoresistant ovarian cancer. Inhibition of miR-630 decreased cell proliferation and enhanced the sensitivity of SKOV3-TR and SKOV3 cells to paclitaxel. In the chemosensitivity assay, we observed that the miR-630 inhibitor exhibited a synergistic effect with paclitaxel on SKOV3-TR cells. Inhibition was correlated with enhanced expression of apoptosis-related proteins. APAF-1 was predicted to be a potential target of miR-630. An in vivo PDX study showed that the miR-630 inhibitor sensitized chemoresistant ovarian cancer to paclitaxel. Thus, miR-630 inhibitor sensitizes chemoresistant epithelial ovarian cancer to chemotherapy by enhancing apoptosis. Our findings suggest that miR-630 might be a potential therapeutic target for chemotherapy-resistant ovarian cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the relationship of the time interval from the completion of neoadjuvant chemotherapy (NAC) to the initiation of postoperative adjuvant chemotherapy (POAC) with the survival outcomes in patients with ovarian cancer., Methods: We retrospectively investigated 220 patients with pathologically confirmed epithelial ovarian cancer who received NAC at Yonsei Cancer Hospital between 2006 and 2016. The time interval was defined as the period from the completion of NAC, spanning interval debulking surgery (IDS), to the initiation of POAC., Results: The median time interval was 42 (range 16-178) days; 103 patients (53.1%) received POAC within 42days after NAC while 91 patients (46.9%) received it after 42days. There were no significant differences in patient characteristics between these 2 groups. Kaplan-Meier analysis showed that patients with longer time intervals (>42days) had poorer progression-free survival and overall survival (P=0.039 and 0.005, respectively). In the multivariate analysis, patients with longer time intervals had significantly poorer progression-free (hazard ratio, 1.41; 95% confidence interval, 0.98-2.03; not significant) and overall survivals (hazard ratio, 2.03; 95% confidence interval, 1.16-3.54). When the patients were categorized according to time interval quartiles (≤37, 38-42, 43-50, and >50days), longer time intervals were associated with higher risks of recurrence and death (P for trend: 0.006 and <0.001, respectively)., Conclusion: The time interval from the completion of NAC to the initiation of POAC appears to influence survival. Efforts to reduce the time interval might improve the outcomes in ovarian cancer patients undergoing NAC., (Copyright © 2017. Published by Elsevier Inc.)

In epithelial ovarian cancer (EOC), intraperitoneal (IP) administration of chemotherapy is an effective first-line treatment and may improve outcomes, compared with intravenous (IV) chemotherapy. We used Kaplan-Meier survival analysis to compare long-term survival between propensity score-matched patients with advanced EOC receiving IP (n = 34) vs. IV (n = 68) chemotherapy. Additionally, clinical features associated with carboplatin-based (n = 21) and cisplatin-based (n = 16) IP chemotherapy were analyzed and compared with those associated with IV chemotherapy. The IP and IV chemotherapy groups had a median follow-up duration of 67 (range, 3-131) and 62 (range, 0-126) months, respectively, with no significant difference in progression-free survival (PFS) (P = 0.735) and overall survival (OS) (P = 0.776). A significantly higher proportion of patients in the IV (91.2%) than in the IP (67.6%) chemotherapy group (P = 0.004) received ≥ 6 cycles. However, the frequency of toxic events (anemia, granulocytopenia, nausea/vomiting, abdominal pain, hepatotoxicity, neuromuscular effects) was significantly higher in the IP than in the IV group. Within the IP group, no significant differences were observed in PFS (P = 0.533) and OS (P = 0.210) between the cisplatin-based and carboplatin-based chemotherapy subgroups. The 10-year OS was 28.6% and 49.2% in carboplatin-based and cisplatin-based IP chemotherapy groups, respectively. Toxic events (granulocytopenia, leukopenia, nausea/vomiting, abdominal pain, hepatotoxicity, neuromuscular effects) were significantly more common in the cisplatin-based subgroup. In patients with EOC, cisplatin-based IP chemotherapy may be an acceptable alternative to IV chemotherapy regarding long-term survival, but toxicity must be addressed., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2017 The Korean Academy of Medical Sciences.)

Objective: The chemotherapy response score (CRS) system based on histopathological examination has been recently proposed for tubo-ovarian high-grade serous carcinoma (HGSC) to assess response to neoadjuvant chemotherapy (NAC). This study was aimed at validating the CRS system in an external cohort of tubo-ovarian HGSC patients., Methods: This study included 110 tubo-ovarian HGSC patients who underwent NAC followed by interval debulking surgery. The 3-tiered CRS of the omental and adnexal tissue sections was determined by 3 independent pathologists. Differences in patient outcomes according to CRS were analyzed., Results: The CRS system was highly reproducible among the 3 pathologists. Fleiss' kappa value and Kendall's coefficient of concordance for the omental CRS were 0.656 and 0.669, respectively. The omental CRS significantly predicted progression-free survival (PFS). The median PFS of patients whose tumors exhibited the omental CRS 1-2 (15 months) was significantly shorter than that of patients with an omental CRS of 3 (19 months; p=0.016). In addition, after adjusting for age, stage, and debulking status, the omental CRS was an independent prognostic factor for PFS of tubo-ovarian HGSC patients who were treated with NAC (adjusted hazard ratio [HR]=1.74; 95% confidence interval [CI]=1.05-2.87)., Conclusion: The CRS system for assessing NAC response was a reproducible prognostic tool in our cohort. The application of the CRS system after NAC can improve survival estimation in HGSC patients., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology)

Background: There is currently no consensus regarding the optimal number of chemotherapy cycles to be administered before and after interval debulking surgery (IDS) in patients with advanced ovarian cancer. This study aimed to evaluate the impact of the number of neoadjuvant chemotherapy (NAC) and postoperative adjuvant chemotherapy (POAC) cycles on the survival of patients with advanced ovarian cancer undergoing NAC/IDS/POAC., Methods: We retrospectively reviewed data from 203 patients who underwent NAC/IDS/POAC at Yonsei Cancer Hospital between 2006 and 2016. All patients underwent taxane plus carboplatin chemotherapy for NAC and POAC. The patient outcomes were analyzed according to the number of NAC, POAC, and total chemotherapy (NAC+POAC) cycles., Results: Patients who received fewer than 6 cycles of total chemotherapy (n = 8) had poorer progression-free survival (PFS) and overall survival (OS) than those completing at least 6 cycles (p = 0.005 and p<0.001, respectively). Among patients who completed at least 6 cycles of total chemotherapy (n = 189), Kaplan-Meier analysis revealed no significant difference in either PFS or OS according to the number of NAC cycles (1-3 vs. ≥4; p = 0.136 and p = 0.267, respectively). Among patients who experienced complete remission after 3 cycles of POAC (n = 98), the addition of further POAC cycles did not improve the PFS or OS (3 vs. ≥4; p = 0.641 and p = 0.104, respectively)., Conclusion: IDS after 4 cycles of NAC may be a safe and effective option when completing 6 cycles of total chemotherapy. Furthermore, the addition of more than 3 cycles of POAC does not appear to influence the survival of patients achieving completion remission after 3 cycles of POAC.