Abstract Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer. With improved pharmacokinetic parameters, BNZ-111 effectively disrupts tubulin polymerization through hydrogen bonds and hydrophobic interactions. It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating β-3 tubulin expression to suppress microtubule dynamics. This study suggests that BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology Citation Format: Jeong-Won Lee, Kwangho Lee, Byumseok Koh, Yoo-Young Lee, Duk-Soo Bae. Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7139.

PDF - 1246K, Western blot analysis was used to determine expression levels of MEK1 and p-ERK (1/2) when two ovarian cancer cells were transfected with BRD7 plasmid.

PDF - 856K, Western blot analysis was used to determine expression levels of alpha-catenin when two ovarian cancer cells were transfected with BRD7 plasmid.

PDF - 1091K, A, Western blot analysis was used to determine expression levels of BRD7 in the tumor samples from xenografts that were transfected with BRD7 plasmid or mock vector. B, Semi-quantitative analysis was performed on the basis of relative BRD7/ beta-actin density level using the Image J program. Individual lysates were loaded onto the gel. M1-M6 includes xenografts that were transfected with mock vectors. B1-B6 includes xenografts that were transfected with BRD7 plasmid.

Safety and toxicity in mouse after treatment of linalool with different dose.

PDF - 1513K, BRD7 mediated tumor suppressive effects are not correlated with cell cycle. A, Cell cycle distributions of A2780 (marked as A) and SKOV3 (marked as S) cells measured by flow cytometry. Cell number histograms plot (upper panel) show the distribution of cells on the basis of DNA contents as determined by PI fluorescence intensity. Left peak represents cells in the G1/G0 phases, hatched area represents cells in S phase, and peak on right represents cells in the G2 and M phases. The expression levels of BRD7 mRNA among phases of cell cycle show no significant differences in both A2780 and SKOV3 cell line (.lower panel). Values are expressed as means of three independent experiments plus or minus SD. B, Western blot analysis was used to determine expression levels of Cyclin B1, D1 or E2.

Supplementary Data from Altered MicroRNA Expression in Cervical Carcinomas

PDF - 1244K, BRD7 mediated reduction of MMP2 require beta-catenin pathway. A2780 (A) or SKOV3 (B) cells were co-transfected with BRD7 plasmid and beta-catenin siRNA. After 36 hours, whole mRNA was isolated and cDNA was synthesized. Semi-quantitative PCR was performed to estimate the expression of MMP2 mRNA.

Abstract Purpose: MicroRNAs (miRNA) are small noncoding RNAs that are 18 to 25 nucleotides in length; they regulate the stability or translational efficiency of target mRNAs. Emerging evidence suggests that miRNAs might be involved in the pathogenesis of a variety of human cancers. Experimental Design: In this study, we profiled miRNA expression in 10 early stage invasive squamous cell carcinomas (ISCC) and 10 normal cervical squamous epithelial specimens using TaqMan real-time quantitative PCR array methods. In order to evaluate the role of miR-199a, one of the most significantly overexpressed in ISCCs, we transfected cervical cancer cells (SiHa and ME-180) with anti–miR-199a oligonucleotides and assessed the cell viability. Results: We found 70 genes (68 up-regulated, 2 down-regulated) with significantly different expression in the ISCCs compared with normal samples (P < 0.05). When we analyzed the expression of the 10 most significant miRNAs in 31 ISCCs, increased miR-127 expression was significantly associated with lymph node metastasis (P = 0.006). Transfection of anti–miR-199a oligonucleotides to cervical cancer cells suppressed cell growth in vitro, which was potentiated with the anticancer agent cisplatin. Conclusions: Our results show that miRNA deregulation may play an important role in the malignant transformation of cervical squamous cells. In addition, they may offer new candidate targets to be exploited for both prognostic and therapeutic strategies in patients with cervical cancer.

PDF - 57K, Information of the cell lines used in experiments.

Objective: Pulmonary lymphangitic carcinomatosis (PLC) is a rare event of metastatic lung disease in advanced gynecologic malignancy. Nonspecific symptoms of patients and difficulties in detection of PLC often result in a delayed diagnosis. In this study, we evaluated the clinical outcomes of PLC in patients with gynecologic cancer.Materials and methods: We retrospectively reviewed electronic medical records of patients with gyne-cologic cancer who received care from January 1, 2008 through December 31, 2018 in Samsung Medical Center, Seoul, Republic of Korea. We based diagnosis of PLC on chest CT scan and analyzed clinical pa-rameters of cancer type, International Federation of Gynecology and Obstetrics (FIGO) stage, histology, and patient survival.Results: During the study period, 27 cases of PLC in patients with gynecologic malignancy were iden-tified, including 11 cervical, 12 ovarian, and four uterine cancers. The most common histologic type at initial diagnosis was squamous cell in cervical (6/11, 55%), serous in ovarian (1/11, 92%), and serous in endometrial (2/4, 50%) cancer. The average survival time from diagnosis of PLC to death was a mean of 5.7 months (0.7-23.6 months) in all patients and 6.3, 6.6, and 3.6 months for cervical, endometrial, and ovarian cancer, respectively. Conclusion: This study showed that PLC results in extremely poor survival, from several days to a few months, in patients with gynecologic cancer. Clinicians must be aware of these clinical characteristics and consider other novel therapeutic strategies in the future.(c) 2022 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PURPOSE:This study aimed to evaluate the effect of waiting time, from diagnosis to initiation of definitive concurrent chemoradiation (CCRT), on overall survival in cervical cancer patients.MATERIALS AND METHODS:Patients with cervical cancer who were treated with definitive CCRT between 2000 and 2017 were retrospectively reviewed. Time from initial pathological diagnosis to definitive CCRT was analyzed both as a continuous variable (per day) and as a categorical variable in two groups (group 1 ≤ median, group 2 > median). Patients with a waiting time of more than 60 days were excluded.RESULTS:The median waiting time was 14 days (0-60). There were differences between group 1 and group 2 in age and chemotherapy regimens. However, no significant difference was found in the International Federation of Gynecology and Obstetrics stage, cell type, or the number of cycles of chemotherapy received during CCRT. A longer waiting time was associated with poorer overall survival on the Kaplan-Meier curve (group 1 vs. group 2, p=0.042). On multivariate analysis, intervals as either a continuous variable (hazard ratio [HR], 1.023; 95% confidence interval [CI], 1.006 to 1.040; p=0.007) or a categorical variable (HR, 1.513; 95% CI, 1.073 to 2.134; p=0.018), FIGO stage, cell type, and the number of cycles of chemotherapy received during CCRT were significant independent prognostic factors for overall survival.CONCLUSION:A shorter waiting time from pathological diagnosis to definitive CCRT showed benefit on overall survival. Our findings suggest that an effort to minimize waiting times should be recommended in cervical cancer patients who are candidates for CCRT.

Objective. Few studies have been conducted on the relationship between metabolic syndrome (MetS) and persistent human papillomavirus (HPV) infection. We investigated whether MetS and associated factors can predict the persistence of HPV infection. Patients and methods. We performed a retrospective cohort study of 80,993 female cases undergoing general medical screenings at Samsung Medical Center and 51,140 cases were included in final analysis. MetS and associated factors were used to develop a model predicting the persistence of HPV infection which was defined as HPV positivity for at least one year. The performance of the model was internally validated using bootstrapping and externally validated by testing the risk score against the test set. Results. Of the 51,140 cases, there were 5833 (11.4%) cases diagnosed with MetS and 7682 (15.0%) cases diagnosed with HPV infection at baseline. The 12-to 24-month persistence rates of HPV were 50.0% (2846/5691). MetS (OR 1.34, 95% CI 1.04-1.71), globulin (by quintile; OR 1.70, 95% CI 1.25-2.30), fibrinogen (x100 value by quintile; OR 1.07, 95% CI 1.02-1.14), total protein (by quintile; OR 0.91, 95% CI 0.84-0.99) and prothrombin time (by quintile; OR 0.94, 95% CI 0.89-0.99) were significantly associated with the persistence of HPV in multivariate analysis. For validation, a prediction model showed good performance for a range of risk scores and categorized cases into low-, intermediate-and high-risk, which were also correlated with HPV persistence (45.8%, 51.9%, and 60.2% respectively, P < 0.001). Conclusion. MetS and associated factors were associated with an increased risk of persistent HPV infection. (c) 2021 Elsevier Inc. All rights reserved.

Objective: Uterine artery ligation (UAL) at the time of myomectomy has shown to decrease blood loss during the operation. However, little is known about the efficacy and feasibility of UAL during single-port access (SPA) myomectomy. The present study was performed to investigate the clinical benefits of UAL in SPA myomectomy and to provide details of the surgical techniques. Materials and methods: A retrospective and comparative review on the surgical outcomes of the patients who underwent SPA myomectomy with UAL and those who underwent SPA myomectomy without UAL was conducted. UAL was performed at its origin from the internal iliac artery via a retroperitoneal approach. Results: A total of 56 women who received SPA myomectomy were reviewed (24 patients received SPA myomectomy with UAL while 32 patients received SPA myomectomy only). The median weight of total resected leiomyomas was heavier for the patients who received UAL than those who did not receive UAL [210.0 g (range: 171.5-335.0 g) vs. 119.0 g (62.5-265.0 g), p = 0.023]. However, no differences in total operative time, estimated blood loss, perioperative hemoglobin changes, use of postoperative analgesics and postoperative complications between the two groups were seen. Conclusion: Obtaining similar surgical outcomes between the patients who received UAL with larger leiomyomas and those who did not receive UAL with smaller leiomyomas suggests that UAL is a feasible surgical approach to reduce blood loss during SPA myomectomy. Detailed descriptions of the surgical techniques are provided in the present report. (C) 2021 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V.

Objective: Unlike cervical squamous cell carcinoma, there are no consensus criteria for serum tumor markers in cervical adenocarcinoma. This study aimed to identify the prognostic value of preoperative carbohydrate antigen 125 (CA125) levels in cervical adenocarcinoma patients with adverse pathologic features. Methods: A total of 105 patients who underwent radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiation therapy were included. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were evaluated using the Cox proportional hazard regression model. Results: Using a cutoffvalue of 50 U/mL, 83 and 22 patients had low- and high-CA125, respectively. Patients with high-CA125 had a larger tumor size, more frequent parametrial extension, and more frequent lymph node metastasis than those with low-CA125. During a median follow-up of 59.3 (interquartile range, 32.7-97.8) months, patients with high-CA125 showed inferior 5-year LRFS, DMFS, and OS rates compared to those with low-CA125 (38.5% vs. 70.0%; 37.0% vs. 69.4%; 43.6% vs. 78.1%, respectively, all p<0.05). In multivariable analysis, the high-CA125 remained significant prognostic factor for LRFS, DMFS, and OS (all p<0.05). Furthermore, 12 patients with high-CA125 at recurrence exhibited lower 5-year OS rates than 21 patients with low-CA125 at recurrence (0.0% vs. 51.3%, p=0.003). Conclusion: In this retrospective analysis, the serum CA125 level at diagnosis and recurrence was related to the extent of disease and prognosis of cervical adenocarcinoma with adverse pathologic features. A CA125 level of >= 50 U/mL may be a prognostic surrogate marker for cervical adenocarcinoma in patients with the presence of adverse factors.

5512 Background: BVAC-C is a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, which was well tolerated in HPV positive recurrent cervical carcinoma in phase I study (J Clin Med. 2020 Jan 5;9(1):147). This phase IIa study sought to determine the antitumor activity of BVAC-C. Methods: Twenty-one patients with HPV 16 or 18 positive recurrent cervical cancer who had experienced recurrence after one prior platinum-based combination chemotherapy were enrolled. They were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks (1x108 cells/dose); Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks (5x107 cells/dose); Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks (5x107 cells/dose) with topotecan at 2, 6, 10, 14 weeks (0.75 mg/m2 for 3 days). Results: The overall response rate was 21% (Arm 1: 29% (2/7), Arm 2: 25% (1/4), Arm 3 : 0 % (0/3)) among the evaluable patients (N = 14), and the median duration of response was 18 months (range, 9 – 26 months). The disease control rate was 43% (Arm 1: 29% (2/7), Arm 2: 50% (2/4), Arm 3 : 67 % (2/3)) and the median duration of stable disease were 12 months (range, 6 - 26 months). The median progression-free survival in all patients was 4 months (95% CI, 2 to Infinite months). Immune responses of patients after vaccination were shown to be correlated with clinical responses of them. Consistent with Phase I study, all evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α), which might be mediated by the activation of natural killer cells and natural killer T cells, but also potent E6/E7-specific T cell responses upon vaccinations. Conclusions: BVAC-C demonstrated a durable antitumor activity with an immune response in HPV 16- or 18-positive recurrent cervical carcinoma patients who failed 1st line platinum based chemotherapy. Clinical trial information: NCT02866006.

Purpose This study aimed to identify the prognostic value of early metabolic response assessed using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) during radiation therapy (RT) for cervical cancer. Materials and Methods We identified 116 patients treated with definitive RT, including FDG-PET/CT–guided intracavitary brachytherapy, between 2009 and 2018. We calculated parameters including maximum (SUVmax) and mean standardized uptake values (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for baseline FDG-PET/CT (PETbase) and image-guided brachytherapy planning FDG-PET/CT (PETIGBT). Multivariable analyses of disease-free survival (DFS) and overall survival (OS) were performed. Results We observed a time-dependent decrease in PET parameters between PETbase and PETIGBT; ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG were 65%, 61%, 78%, and 93%, respectively. With a median follow-up of 59.5 months, the 5-year DFS and OS rates were 66% and 79%, respectively. Multivariable analysis demonstrated that ΔSUVmax ≥ 50% was associated with favorable DFS (hazard ratio [HR], 2.56; 95% confidence interval [CI], 1.14 to 5.77) and OS (HR, 5.14; 95% CI, 1.55 to 17.01). Patients with ΔSUVmax ≥ 50% (n=87) showed better DFS and OS than those with ΔSUVmax < 50% (n=29) (DFS, 76% vs. 35%, p < 0.001; OS, 90% vs. 41%, p < 0.001, respectively). Adenocarcinoma was frequently observed in ΔSUVmax < 50% compared to ΔSUVmax ≥ 50% (27.6% vs. 10.3%, p=0.003). In addition, models incorporating metabolic parameters showed improved accuracy for predicting DFS (p=0.012) and OS (p=0.004) than models with clinicopathologic factors. Conclusion Changes in metabolic parameters, especially those in SUVmax by > 50%, can help improve survival outcome predictions for patients with cervical cancer treated with definitive RT.

Objective To evaluate the long-term outcomes, including the pregnancy outcome and recurrence rate after single-port laparoscopic myomectomy (LM) using a modified suture technique with a Hem-o-lok clip (Choi's LM) and conventional 4-port LM. Methods A retrospective study of patients who underwent Choi's LM (n=55) and 4-port LM (n=102) in a single institutional hospital was conducted. Patients with <3 symptomatic myomas sized <10 cm each and operated on by a single surgeon were included. Recurrence was confirmed when a myoma measuring ≥3 cm was detected. Results The patients in both groups had similar demographic characteristics. Single (76.4% vs. 62.7%) and intramural (52.7% vs. 56.9%) tumors were commonly detected in both groups in the mean diameter (6.8±1.5 cm vs. 7.0±1.6 cm; P=0.40). In Choi's LM, 16 patients (29.1%) needed an additional port; those who were nulliparous and/or had a large leiomyoma more frequently required an additional port (P=0.023 and 0.04, respectively). During a median follow-up period of 69 months, 17 patients (7.1% vs. 14.6%) had recurrence. The size of dominant myomas at recurrence was significantly smaller in patients who underwent Choi's LM (3.4±0.7 cm vs. 5.7±2.4 cm; P=0.004). All 13 patients in both groups who successfully conceived had a full-term delivery. No major complications occurred during pregnancy. Conclusion Although an additional port was frequently used, the long-term outcomes of patients who experienced recurrence and pregnancy after Choi's LM were acceptable. Considering its usability, Choi's LM is feasible for the treatment of uterine leiomyoma.

Objective: To compare laparoscopic surgery to laparotomy for harvesting para-aortic lymph nodes in presumed stage I-II, high-risk endometrial cancer patients. Methods: Patients with histologically proven endometrial cancer, presumed stage I-II with high-risk tumor features who had undergone hysterectomy, bilateral salpingoophorectomy, or pelvic and para-aortic lymphadenectomy by either laparoscopy or laparotomy in Samsung Medical Center from 2005 to 2017 were retrospectively investigated. The primary outcome was para-aortic lymph node count. Secondary outcomes were pelvic lymph node count, perioperative events, and postoperative complications. Results: A total of 90 patients was included (35 for laparotomy, 55 for laparoscopy) for analysis. The mean (±SD) para-aortic lymph node count was 10.66 (±7.596) for laparotomy and 10.35 (±5.848) for laparoscopy (p = 0.827). Mean pelvic node count was 16.8 (±6.310) in the laparotomy group and 16.13 (±7.626) in the laparoscopy group (p = 0.664). Lower estimated blood loss was shown in the laparoscopy group. There was no difference in perioperative outcome between the groups. Additional multivariate analysis showed that survival outcome was not affected by surgical methods in presumed stage I-II, high-risk endometrial cancer patients. Conclusions: Study results demonstrate comparable para-aortic lymph node count with less blood loss in laparoscopy over laparotomy. In women with presumed stage I-II, high-risk endometrial cancer, laparoscopy is a valid treatment modality.