CD109 Promotes Drug Resistance in A2780 Ovarian Cancer Cells by Regulating the STAT3-NOTCH1 Signaling Axis.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy owing to relapse caused by resistance to chemotherapy. We previously reported that cluster of differentiation 109 (CD109) expression is positively correlated with poor prognosis and chemoresistance in patients with EOC. To further explore the role of CD109 in EOC, we explored the signaling mechanism of CD109-induced drug resistance. We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. In EOC cells (A2780 and A2780-R), the expression level of CD109 was positively correlated with the expression level of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, and paclitaxel (PTX) resistance. Using a xenograft mouse model, it was confirmed that PTX administration in xenografts of CD109-silenced A2780-R cells significantly attenuated in vivo tumor growth. The treatment of CD109-overexpressed A2780 cells with cryptotanshinone (CPT), a signal transducer and activator of transcription 3 (STAT3) inhibitor, inhibited the CD109 overexpression-induced activation of STAT3 and neurogenic locus notch homolog protein 1 (NOTCH1), suggesting a STAT3-NOTCH1 signaling axis. The combined treatment of CD109-overexpressed A2780 cells with CPT and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a NOTCH inhibitor, markedly abrogated PTX resistance. These results suggest that CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.

TRRAP Enhances Cancer Stem Cell Characteristics by Regulating NANOG Protein Stability in Colon Cancer Cells.

NANOG, a stemness-associated transcription factor, is highly expressed in many cancers and plays a critical role in regulating tumorigenicity. Transformation/transcription domain-associated protein (TRRAP) has been reported to stimulate the tumorigenic potential of cancer cells and induce the gene transcription of NANOG. This study aimed to investigate the role of the TRRAP-NANOG signaling pathway in the tumorigenicity of cancer stem cells. We found that TRRAP overexpression specifically increases NANOG protein stability by interfering with NANOG ubiquitination mediated by FBXW8, an E3 ubiquitin ligase. Mapping of NANOG-binding sites using deletion mutants of TRRAP revealed that a domain of TRRAP (amino acids 1898-2400) is responsible for binding to NANOG and that the overexpression of this TRRAP domain abrogated the FBXW8-mediated ubiquitination of NANOG. TRRAP knockdown decreased the expression of CD44, a cancer stem cell marker, and increased the expression of P53, a tumor suppressor gene, in HCT-15 colon cancer cells. TRRAP depletion attenuated spheroid-forming ability and cisplatin resistance in HCT-15 cells, which could be rescued by NANOG overexpression. Furthermore, TRRAP knockdown significantly reduced tumor growth in a murine xenograft transplantation model, which could be reversed by NANOG overexpression. Together, these results suggest that TRRAP plays a pivotal role in the regulation of the tumorigenic potential of colon cancer cells by modulating NANOG protein stability.

Absent or impaired rectoanal inhibitory reflex as a diagnostic factor for high-grade (grade III-V) rectal prolapse: a retrospective study.

BACKGROUND: Clinically diagnosing high-grade (III-V) rectal prolapse might be difficult, and the prolapse can often be overlooked. Even though defecography is the significant diagnostic tool for rectal prolapse, it is noticed that rectoanal inhibitory reflex (RAIR) can be associated with rectal prolapse. This study investigated whether RAIR can be used as a diagnostic factor for rectal prolapse. METHODS: In this retrospective study, we evaluated 107 patients who underwent both anorectal manometry and defecography between July 2012 and December 2019. Rectal prolapse was classified in accordance with the Oxford Rectal Prolapse Grading System. Patients in the high-grade (III-V) rectal prolapse (high-grade group, n = 30), and patients with no rectal prolapse or low-grade (I, II) rectal prolapse (low-grade group, n = 77) were analyzed. Clinical variables, including symptoms such as fecal incontinence, feeling of prolapse, and history were collected. Symptoms were assessed using yes/no surveys answered by the patients. The manometric results were also evaluated. RESULTS: Frequencies of fecal incontinence (p = 0.002) and feeling of prolapse (p < 0.001) were significantly higher in the high-grade group. The maximum resting (77.5 vs. 96 mmHg, p = 0.011) and squeezing (128.7 vs. 165 mmHg, p = 0.010) anal pressures were significantly lower in the high-grade group. The frequency of absent or impaired RAIR was significantly higher in the high-grade group (19 cases, 63% vs. 20 cases, 26%, p < 0.001). In a multivariate analysis, the feeling of prolapse (odds ratio [OR], 23.88; 95% confidence interval [CI], 4.43-128.78; p < 0.001) and absent or impaired RAIR (OR, 5.36; 95% CI, 1.91-15.04, p = 0.001) were independent factors of high-grade (III-V) rectal prolapse. In addition, the percentage of the absent or impaired RAIR significantly increased with grading increase of rectal prolapse (p < 0.001). The sensitivity of absent or impaired RAIR as a predictor of high-grade prolapse was 63.3% and specificity 74.0%. CONCLUSIONS: Absent or impaired RAIR was a meaningful diagnostic factor of high-grade (III-V) rectal prolapse. Furthermore, the absent or impaired reflex had a positive linear trend according to the increase of rectal prolapse grading.

Therapeutic Strategies for Targeting Ovarian Cancer Stem Cells.

Ovarian cancer is a fatal gynecological malignancy. Although first-line chemotherapy and surgical operation are effective treatments for ovarian cancer, its clinical management remains a challenge owing to intrinsic or acquired drug resistance and relapse at local or distal lesions. Cancer stem cells (CSCs) are a small subpopulation of cells inside tumor tissues, and they can self-renew and differentiate. CSCs are responsible for the cancer malignancy involved in relapses as well as resistance to chemotherapy and radiation. These malignant properties of CSCs are regulated by cell surface receptors and intracellular pluripotency-associated factors triggered by internal or external stimuli from the tumor microenvironment. The malignancy of CSCs can be attenuated by individual or combined restraining of cell surface receptors and intracellular pluripotency-associated factors. Therefore, targeted therapy against CSCs is a feasible therapeutic tool against ovarian cancer. In this paper, we review the prominent roles of cell surface receptors and intracellular pluripotency-associated factors in mediating the stemness and malignancy of ovarian CSCs.

Prognostic factors of oncologic outcomes after fertility-preservative management with progestin in early-stage of endometrial cancer.

BACKGROUND: The aim of this study was to evaluate efficacy of various fertility-preservative treatments with progestin and analyze prognostic factors in Stage 1A of endometrial cancer. MATERIALS AND METHODS: This retrospective study involved four Korean university hospitals. Data were collected from 43 women who were under the age of 40 with presumed stage IA endometrial cancer determined by magnetic resonance imaging and treated from January 2014 to December 2017. All of the patients were administered hormonal therapy for fertility preservation. Twenty-five patients received oral progestin with a levonorgestrel-releasing intrauterine system (LNG-IUS) for 6-24 months, and 18 patients received high-dose oral progestin for the same period of time. Oncologic outcomes were evaluated. Prognostic factors for pathologic response to progestin were identified by logistic regression analysis. RESULTS: Complete response (CR) was achieved by 72.1% of patients (31/43), and the average time to CR was 4.2 (Stable disease [SD] 3.4) months (range, 3-9 months). Partial response was achieved by 7.0% of patients (3/43), SD by 9.3% (4/43), and progressive disease by 11.6% (5/43). Of the CR patients, 41.9% (13/31) achieved pregnancy with the median follow-up period of 12.5 (SD 7.6) months (range: 3-50 months). No irreversible toxicity or therapy-associated death occurred. Multivariate analysis showed that high endometrial thickness ratio of pre- and posttreatment measured at 2 months from the treatment initiation (≥0.55, Odds ratio [OR]: 19.018; 95% confidence intervals (CI): 1.854-195.078; P = 0.013) and oral progestin without LNG-IUS (OR: 13.483; 95% CI: 1.356-134.069; P = 0.026) might be related with unfavorable prognostic factors for CR. CONCLUSION: This study shows that progestin-based fertility-preservative treatment might be a feasible option for stage 1A endometrial cancer. It also identifies that low endometrial thickness ratio and oral progestin with LNG-IUS combination therapy might be related with favorable response to hormonal treatment.

Comparison of long-term survival of total abdominal radical hysterectomy and laparoscopy-assisted radical vaginal hysterectomy in patients with early cervical cancer: Korean multicenter, retrospective analysis.

PURPOSE: The aim of this study was to compare survival outcomes of total abdominal radical hysterectomy (TARH) versus laparoscopy-assisted radical vaginal hysterectomy (LARVH) in stage IA2-IB2 cervical cancer. METHODS: 812 patients who underwent RH between 2008 and 2017 were evaluated in 3 institutions. Progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier method and compared by log-rank test. The clinical noninferiority of the LARVH to TARH was assessed with a margin of -7.2%. Noninferiority was demonstrated if the low limit of 95% confidence interval (CI) exceeded its predefined margin. RESULTS: 258 patients were treated with TARH and 252 patients with LARVH. TARH and LARVH group had similar 5-year PFS (84.4% vs 86.6%, p = 0.467) and OS rates (85.8% vs 88.0%, p = 0.919). Noninferiority of LARVH to TARH were confirmed with 5-year PFS and OS difference rates of 2.2% (95% CI -2.9-7.3, p = 0.001) and 2.2% (95% CI -2.7-7.1, p = 0.001), respectively. In subgroup of patients with tumors size >2 cm, 5-year PFS (77.6% vs 79.0%, p = 0.682) and OS rates (79.2% vs 81.5%, p = 0.784) did not differ statistically between the two groups. Noninferiority of LARVH to TARH were also confirmed with 5-year PFS and OS difference rates of 1.4% (95% CI -7.0-9.8, p = 0.046) and 2.3% (95% CI -5.8-10.4, p = 0.027), respectively. CONCLUSION: LARVH showed significant noninferiority for PFS and OS versus TARH in early cervical cancer, suggesting the potential oncologic safety of LARVH.

The association between expression of p53 and aggressiveness of serous adenocarcinoma of the uterine cervix.

BACKGROUND: Serous adenocarcinoma of the uterine cervix is an extremely rare variant of cervical adenocarcinoma. This study aimed to evaluate the clinicopathological and molecular features and outcomes of serous adenocarcinoma of the uterine cervix (SACC). MATERIALS AND METHODS: This was a retrospective study conducted based on the clinical and pathological data of seven patients diagnosed with SACC after hysterectomy, who were evaluated at the gynecologic oncologic centers between 2010 and 2019. RESULTS: Five cases were diagnosed at Stage IB and two at Stage IV. All patients underwent radical hysterectomy with bilateral salpingo-oophorectomy and subsequently received postoperative radiotherapy or chemotherapy. One patient showed persistent disease, and two patients suffered recurrence. Immunohistochemical study showed that three (43%) of the seven patients were positive for p53, and among these three patients, two with diffuse strong p53 expression experienced an aggressive course with recurrences at pelvic lymph nodes, lung, and brain. CONCLUSION: High p53 expression and advanced stage may be associated with poorer clinical outcomes in SACC, which suggest that immunohistochemistry may contribute to the prediction of prognosis.

Role of autotaxin in cancer stem cells.

Stem cells are a rare subpopulation defined by the potential to self-renew and differentiate into specific cell types. A population of stem-like cells has been reported to possess the ability of self-renewal, invasion, metastasis, and engraftment of distant tissues. This unique cell subpopulation has been designated as cancer stem cells (CSC). CSC were first identified in leukemia, and the contributions of CSC to cancer progression have been reported in many different types of cancers. The cancer stem cell hypothesis attempts to explain tumor cell heterogeneity based on the existence of stem cell-like cells within solid tumors. The elimination of CSC is challenging for most human cancer types due to their heightened genetic instability and increased drug resistance. To combat these inherent abilities of CSC, multi-pronged strategies aimed at multiple aspects of CSC biology are increasingly being recognized as essential for a cure. One of the most challenging aspects of cancer biology is overcoming the chemotherapeutic resistance in CSC. Here, we provide an overview of autotaxin (ATX), lysophosphatidic acid (LPA), and their signaling pathways in CSC. Increasing evidence supports the role of ATX and LPA in cancer progression, metastasis, and therapeutic resistance. Several studies have demonstrated the ATX-LPA axis signaling in different cancers. This lipid mediator regulatory system is a novel potential therapeutic target in CSC. In this review, we summarize the evidence linking ATX-LPA signaling to CSC and its impact on cancer progression and metastasis. We also provide evidence for the efficacy of cancer therapy involving the pharmacological inhibition of this signaling pathway.

Outcomes of non-high grade serous carcinoma after neoadjuvant chemotherapy for advanced-stage ovarian cancer: a Korean gynecologic oncology group study (OV 1708).

BACKGROUND: Outcomes of patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied, but there is limited information on the outcomes of patients with non-HGSC. This study aimed to evaluate the outcomes of NAC in non-HGSC patients with advanced-stage ovarian cancer. METHODS: We conducted a retrospective cohort study of patients who underwent NAC for advanced stage non-HGSC between 2002 and 2017 in 17 institutions. Demographics, surgical outcomes, and survival rates were evaluated according to histological subtypes. RESULTS: A total of 154 patients were included in this study, comprising 20 cases (13.0%) of mucinous adenocarcinoma, 31 cases (20.1%) of endometrioid adenocarcinoma, 28 (18.2%) cases of clear cell carcinoma, 29 (18.8%) cases of low-grade serous carcinoma and 12 cases (7.8%) of carcinosarcoma. Complete remission/partial remission after the third cycle of NAC was achieved in 100 (64.9%) patients and optimal debulking surgery (residual disease ≤1 cm) at interval debulking surgery was achieved in 103 (66.9%) patients. The most common reason for performing NAC was high tumor burden (n = 106, 68.8%). The median progression-free survival (PFS) was 14.3 months and median overall survival (OS) was 52.9 months. In multivariate analyses, mucinous and clear cell carcinoma were negative prognostic factors for both PFS (p = 0.007 and p = 0.017, respectively) and OS (p = 0.002 and p = 0.013, respectively). CONCLUSIONS: In this study, poor survival outcomes were observed in patients with mucinous and clear cell carcinoma undergoing NAC. Different treatment strategies are urgently required to improve survival outcomes for this disease subset.

Autotaxin Regulates Maintenance of Ovarian Cancer Stem Cells through Lysophosphatidic Acid-Mediated Autocrine Mechanism.

Ovarian cancer shows high mortality due to development of resistance to chemotherapy and relapse. Cancer stem cells (CSCs) have been suggested to be a major contributor in developing drug resistance and relapse in ovarian cancer. In this study, we isolated CSCs through sphere culture of A2780, SKOV3, OVCAR3 epithelial ovarian cancer cells and primary ovarian cancer cells from patients. We identified heat-stable factors secreted from ovarian CSCs stimulated migration and proliferation of CSCs. Mass spectrometry and ELISA analysis revealed that lysophosphatidic acid (LPA) was significantly elevated in CSC culture media compared with non-CSC culture media. Treatment of CSCs with LPA resulted in augmented CSC characteristics such as sphere-forming ability, resistance to anticancer drugs, tumorigenic potential in xenograft transplantation, and high expression of CSC-associated genes, including OCT4, SOX2, and aldehyde dehydrogenase 1. Treatment of CSCs with LPA receptor 1-specific inhibitors or silencing of LPA receptor 1 expression abrogated the LPA-stimulated CSC properties. Autotaxin, an LPA-producing enzyme, is highly secreted from ovarian CSCs, and pharmacological inhibition or knockdown of autotaxin markedly attenuated the LPA-producing, tumorigenic, and drug resistance potentials of CSCs. Clinicopathological analysis showed a significant survival disadvantage of patients with positive staining of autotaxin. In addition, we further identified that AKT1 activity was upregulated in ovarian CSCs through an LPA-dependent mechanism and silencing of AKT1 expression led to suppression of CSC characteristics. These results suggest that autotaxin-LPA-LPA receptor 1-AKT1 signaling axis is critical for maintaining CSC characteristics through an autocrine loop and provide a novel therapeutic target for ovarian CSCs.

Laparoscopically assisted suprapubic surgery for adnexal tumors under epidural anesthesia.

OBJECTIVE: To evaluate the feasibility and safety of laparoscopically assisted surgery for benign ovarian tumors via a single suprapubic incision under epidural anesthesia. METHODS: Forty-three patients underwent laparoscopically assisted surgery via a single suprapubic incision under epidural anesthesia. Types of surgery were classified as follows: type I - suprapubic incision surgery without laparoscopic support, type II - suprapubic incision surgery with laparoscopic support but without CO2 inflation; and type III - suprapubic incision surgery with laparoscopic support and CO2 inflation. RESULTS: Type I, II, and III procedures were performed on 16, 21, and six patients, respectively. Most patients (n = 35) were discharged on postoperative day 1 or 2. No surgical complication was encountered. Types of surgery exhibited different surgical characteristics. Type I was adopted for larger diameter tumors than types II or III (p = .016), whereas type III had a longer operative time (p = .024) than types I and II. Other characteristics, such as age, body mass index, and length of hospital stay, did not differ significantly among surgical types. CONCLUSION: Laparoscopically assisted surgery for adnexal tumors via a single suprapubic incision under epidural anesthesia is feasible and safe, and should be viewed as an alternative approach to conventional minimally invasive surgery.

Maximum Standardized Uptake Value of Pelvic Lymph Nodes in [18F]-Fluorodeoxyglucose Positron Emission Tomography Is a Prognostic Factor for Para-Aortic Lymph Node Recurrence in Pelvic Node-Positive Cervical Cancer Treated With Definitive Chemoradiotherapy.

OBJECTIVES: This study aimed to identify prognostic factors for para-aortic lymph node (PALN) recurrence and their effect on survival outcomes in patients with pelvic node-positive squamous cell carcinoma (SCC) of the cervix treated with definitive concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Of the 116 patients with biopsy-proven SCC of the uterine cervix who underwent primary CCRT from 2007 to 2012, 48 patients with pelvic LN metastasis detected by [F]-fluorodeoxyglucose positron emission tomography (FDG PET) were retrospectively analyzed. Patients with evidence of para-aortic lymphadenopathy were excluded. The whole pelvis was the standard irradiation field for all patients. The associations of age, stage, serum SCC antigen (SCC-Ag) level, maximum standardized uptake value (SUVmax), hemoglobin level, overall treatment time, adjuvant chemotherapy, and pelvic LN status with PALN recurrence and survival outcomes were evaluated. RESULTS: At a median follow-up of 34.0 months (range, 8-73 months), 10 (20.8%) patients had developed PALN recurrences. The relationship between pelvic LN FDG uptake and PALN recurrence was evaluated by the cutoff value (SUVmax = 3.85) determined by receiver operating characteristic curve analysis. The independent risk factors for PALN recurrence were FDG-avid pelvic LN (SUVPLN) greater than 3.85 (hazard ratio, 13.12; P = 0.025) and posttreatment SCC-Ag level greater than 2.0 (ng/mL) (hazard ratio, 20.69; P = 0.019). Patients with an SUVPLN greater than 3.85 were found to have significantly worse 5-year distant metastasis-free (51.0% vs 79.0%, P = 0.016) and progression-free survival (38.7% vs 67.3%, P = 0.011) than those with an SUVPLN less than or equal to 3.85. CONCLUSIONS: SUVPLN is a statistically significant prognostic factor of PALN recurrence and survival after definitive CCRT for pelvic node-positive SCC of the uterine cervix.

Diffusion-weighted magnetic resonance imaging in the differentiation of endometriomas from hemorrhagic cysts in the ovary.

BACKGROUND: The classic magnetic resonance imaging (MRI) feature of endometriomas is the shading sign, which is characterized by T2-shortening in ovarian cystic lesions that are hyperintense on T1-weighted images. The shading sign is infrequently observed in hemorrhagic ovarian cysts. PURPOSE: To investigate the value of MRI with diffusion-weighted imaging (DWI) for distinguishing endometriomas from hemorrhagic cysts in the ovary. MATERIAL AND METHODS: This retrospective study included 91 patients with 98 ovarian endometriomas and 21 hemorrhagic ovarian cysts that were confirmed pathologically, who had undergone MRI with DWI. Two radiologists compared MRI features, including size, bilaterality, multilocularity, the shading sign, the ovarian lesion/muscle signal intensity ratio at T2-weighted images, and T2 dark spots, between endometriomas and hemorrhagic cysts. We also compared the mean ADC value between endometriomas and hemorrhagic cysts, and determined the optimal cutoff ADC value for differentiating endometriomas from hemorrhagic cysts. RESULTS: The size and mean ADC values were significantly different between endometriomas and hemorrhagic cysts. The mean ADC values of endometriomas and hemorrhagic cysts were 1.06 ± 0.38 × 10 (-3) mm(2)/s and 0.73 ± 0.29 × 10(-3) mm(2)/s, respectively (P < 0.002). The optimal cutoff ADC value for differentiating endometriomas from hemorrhagic cysts was 0.849 × 10(-3) mm(2)/s (sensitivity, 77.6%; specificity, 76.2%). CONCLUSION: The addition of DWI could help in differentiating endometriomas from hemorrhagic cysts in the ovary, when conventional MRI is challenging.

DDX4 (DEAD box polypeptide 4) colocalizes with cancer stem cell marker CD133 in ovarian cancers.

DDX4 (DEAD box polypeptide 4), characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), is an RNA helicase which is implicated in various cellular processes involving the alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. DDX4 is known to be a germ cell-specific protein and is used as a sorting marker of germline stem cells for the production of oocytes. A recent report about DDX4 in ovarian cancer showed that DDX4 is overexpressed in epithelial ovarian cancer and disrupts a DNA damage-induced G2 checkpoint. We investigated the relationship between DDX4 and ovarian cancer stem cells by analyzing the expression patterns of DDX4 and the cancer stem cell marker CD133 in ovarian cancers via tissue microarray. Both DDX4 and CD133 were significantly increased in ovarian cancer compared to benign tumors, and showed similar patterns of expression. In addition, DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. Furthermore, almost all CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4, suggesting a strong possibility that DDX4 plays an important role in cancer stem cells, and/or can be used as an ovarian cancer stem cell marker.

Significant simultaneous changes in serum CA19-9 and CA125 due to prolonged torsion of mature cystic teratoma of the ovary.

Mature cystic teratoma is a common benign neoplasm of the ovary. Complications occur in approximately 20% of cases. Clinical manifestations, laboratory findings, and imaging studies can assist in making a diagnosis of ovarian torsion of mature cystic teratoma. Furthermore, serum tumor markers may be helpful for diagnosing mature cystic teratoma and its torsion and, thus, can lead to early surgical intervention. A 56-year-old woman presented with a huge pelvic mass and pelvic pain. Serum CA19-9, CA125, and carcinoembryonic antigen levels were abnormally elevated at >700 U/ml, 282.5 U/ml, and 3.94 U/ml, respectively. The tumor was surrounded by extensive adhesions and showed inflammatory changes. The serum levels of these markers returned to normal levels after surgery.

BBT-877, a Novel Autotaxin Inhibitor, Abrogates Drug Resistance in Epithelial Ovarian Cancer Stem Cells.

BACKGROUND/AIM: Cancer stem cells (CSCs) contribute significantly to the poor prognosis of patients with epithelial ovarian cancer (EOC) due to their roles in drug resistance and tumor metastasis. Autotaxin (ATX) plays a pivotal role in the maintenance of the CSC-like properties of EOC tumors. BBT-877 is a novel ATX inhibitor used in clinical treatment of idiopathic pulmonary fibrosis. However, the effects of BBT-877 on drug resistance and metastasis in ovarian CSCs remain unknown. In this study, we aimed to investigate the effects of BBT-877 on drug resistance and intraperitoneal metastasis of EOC. MATERIALS AND METHODS: Spheroid-forming CSCs, which were isolated from two EOC cell lines, A2780 and SKOV3, were investigated by cell viability, western blot, PCR, Spheroid-forming assay, and in vivo experiments. RESULTS: Spheroid-forming CSCs exhibited increased CSC-like properties and paclitaxel (PTX) resistance. BBT-877 treatment inhibited the viability of spheroid-forming CSCs more potently than that of adherent ovarian cancer cell lines. Combinatorial treatment with BBT-877 and PTX significantly attenuated the viability of spheroid-forming CSCs. In a SKOV3 cells-derived intraperitoneal metastasis model, BBT-877 treatment reduced the number of metastatic tumor nodes, while combinatorial treatment with BBT-877 and PTX more potently attenuated the formation of metastatic nodes and accumulation of ascitic fluid. CONCLUSION: These results suggest that BBT-877 can be combined with conventional anticancer drugs for the treatment of patients with recurrent or drug-resistant EOC.

Comparison of survival outcome of open, total laparoscopic, and laparoscopy-assisted radical vaginal hysterectomy for stage IB2 cervical cancer patients: A multicenter retrospective study.

The aim of this study was to compare survival outcomes of 3 different radical hysterectomy (RH) types, namely total abdominal radical hysterectomy (TARH), total laparoscopic radical hysterectomy (TLRH), and laparoscopy-assisted radical vaginal hysterectomy (LARVH), in patients with FIGO stage IB2 cervical cancer. We retrospectively identified a cohort of patients who underwent RH for cervical cancer between 2010 and 2017. Patients with stage IB2 cervical cancer were included and were classified into TARH, TLRH, and LARVH treatment groups. Survival outcomes were estimated by the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were fit to estimate the independent association of RH technique with outcome. 194 patients were included in this study: 79 patients in the TARH group, 55 in the TLRH group, and 60 in the LARVH group. No significant differences were found in clinicopathological characteristics between the 3 RH groups. On comparing survival outcomes with TARH, both TLRH and LARVH showed no significant difference in terms of 5-year overall survival (TARH vs TLRH, P = .121 and TARH vs LARVH, P = .436). Conversely, compared to the TARH group, 5-year progression-free survival (PFS) was significantly worse in the TLRH group (P = .034) but not in the LARVH group (P = .288). Multivariate analysis showed that TLRH surgical approach (hazard ratio, 3.232; 95% confidence interval, 1.238-8.438; P = .017) was an independent prognostic factor for PFS in patients with IB2 cervical cancer. Our study suggests that in patients with FIGO stage IB2 cervical cancer, among the minimally invasive RH approaches, TLRH and LARVH, only TLRH approach was associated with worse PFS when compared with the TARH approach.

TAZ mediates lysophosphatidic acid-induced migration and proliferation of epithelial ovarian cancer cells.

BACKGROUND: Transcriptional co-activator with PDZ-binding motif (TAZ), a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co-activator. Lysophosphatidic acid (LPA) is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein-coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated. METHODS: In order to demonstrate the role of TAZ in LPA-stimulated tumorigenesis, the effects of LPA on TAZ expression and cell migration were determined by Western blotting and chemotaxis analyses in R182 human epithelial ovarian cancer cells. RESULTS AND CONCLUSION: Treatment of R182 cells with the LPA receptor inhibitor Ki16425 blocked LPA-induced cell migration. In addition, transfection of R182 cells with small interfering RNA specific for LPA receptor 1 resulted in abrogation of LPA-stimulated cell migration. LPA induced phosphorylation of ERK and p38 MAP kinase in R182 cells and pretreatment of cells with the MEK-ERK pathway inhibitor U0126, but not the p38 MAPK inhibitor SB202190, resulted in abrogation of LPA-induced cell migration. Pretreatment of R182 cells with U0126 attenuated LPA-induced mRNA levels of TAZ and its transcriptional target genes, such as CTGF and CYR61, without affecting phosphorylation level of YAP. These results suggest that MEK-ERK pathway plays a key role in LPA-induced cell migration and mRNA expression of TAZ in R182 cells, without affecting stability of TAZ protein. In addition, small interfering RNA-mediated silencing of TAZ expression attenuated LPA-stimulated migration of R182 cells. These results suggest that TAZ plays a key role in LPA-stimulated migration of epithelial ovarian cancer cells.

Validation of multi-gene panel next-generation sequencing for the detection of BRCA mutation in formalin-fixed, paraffin-embedded epithelial ovarian cancer tissues.

OBJECTIVE: The therapeutic effect of poly (ADP-ribose) polymerase (PARP) inhibitors in patients with epithelial ovarian cancer (EOC) with somatic BRCA mutations is consistent with that observed in patients with germline BRCA mutations, indicating the importance of detecting both germline and somatic BRCA mutations concurrently. We compared the efficacy of multi-gene panel next generation sequencing (NGS) in EOC patients' formalin-fixed, paraffin-embedded (FFPE) tissue to that of conventional Sanger sequencing in blood samples. MATERIALS AND METHODS: This study included 48 patients with EOC, and both blood Sanger sequencing and FFPE tissue NGS were conducted in all of them. Clinical and pathological data were reviewed, including age at diagnosis, histology, and stage. Blood Sanger sequencing was performed using peripheral blood leukocytes. The target regions of 90 cancer-related genes were identified using FFPE tissue. RESULTS: The median age of patients was 56.1 years, with serous carcinoma (n = 40, 83.3%) and stage III (n = 37, 77.1%) being the most common histology and International Federation of Gynecology and Obstetrics (FIGO) stage, respectively. FFPE tissue NGS identified ten pathogenic variants, including all eight pathogenic variants identified by blood Sanger sequencing and two additional pathogenic variants. Furthermore, FFPE tissue NGS identified 19 variants of uncertain significance (VUS), including all ten VUS identified by blood Sanger sequencing and nine additional VUS. CONCLUSION: The FFPE tissue multi-gene panel NGS had 100% sensitivity for detecting BRCA germline mutations and could detect additional somatic mutations. Furthermore, performing FFPE tissue multi-gene panel NGS followed by blood Sanger sequencing sequentially may help differentiate germline from somatic BRCA mutations for genetic counseling.