Combination effect of poly (ADP-ribose) polymerase inhibitor and DNA demethylating agents for treatment of epithelial ovarian cancer.

OBJECTIVE: Poly (ADP)-ribose polymerase inhibitors (PARPi) are effective clinical agents for treatment of epithelial ovarian cancer (EOC) harboring BRCA mutations as well as those without BRCA mutations. In this study, we evaluate the efficacy of combined PARPi and DNA methyltransferase inhibitor (DNMTi) in EOCs. METHODS: Expression levels of DNMT1 and PARP1 proteins in EOC cells were assessed using western blot analysis and immunohistochemistry. To evaluate the effects of co-treatment of PARPi (olaparib) and DNMTi (5-azacitidine, 5-AZA), we performed cell proliferation, apoptosis, and wound-healing assays in EOC cells. In addition, we performed in vivo experiments using both cell-line and patient-derived xenograft (PDX) models of EOC. RESULTS: The combination of olaparib and 5-AZA significantly inhibited cell proliferation and migration and induced apoptosis compared with olaparib or 5-AZA alone in EOC cell lines including A2780, HeyA8, A2780-CP20, and HeyA8-MDR. Moreover, in vivo experiments with this combination showed significantly decreased weight and nodule numbers of tumors in cell-line xenograft models with A2780 cells and a PDX model compared with control, olaparib, and 5-AZA groups. As a potential mechanism, the expression of intracellular reactive oxygen species (ROS) and its related proteins, including p-ERK, NRF2, p-p38, HO-1, and γH2AX, was affected in EOC cells. CONCLUSIONS: Co-treatment with PARPi and DNMTi had a significant anti-tumor effect in EOC cells. This combination might be a potential therapeutic strategy for EOCs.

Prognostic Significance of HER3 Expression in Patients with Cervical Cancer.

HER3 has been recognized to have an oncogenic role in various types of cancer. However, its prognostic significance has not been elucidated in cervical cancer. The aim of this study was to investigate the prognostic significance of HER3 expression in cervical cancer using immunohistochemistry (IHC). HER3 immunohistochemical staining was performed on the tumor tissue samples of 336 cervical cancer patients. The association between the clinicopathological characteristics and patient survival analysis was assessed according to HER3 expression. HER3 IHC staining was positive in 31.0% (104/336) of the cervical cancer patients. A higher proportion of adeno-/adenosquamous carcinoma was observed in the HER3-positive group (34.6%) than in the HER3-negative group (18.8%). In survival analysis, HER3 expression was significantly associated with poorer disease-free survival (DFS) and overall survival (OS) (p < 0.001 and p = 0.002, respectively). Multivariate analysis also indicated that HER3 expression was an independent prognostic factor for DFS (hazard ratio (HR) = 2.58, 95% confidence interval (CI) 1.42−4.67, p = 0.002) and OS (HR = 3.21, 95% CI, 1.26−8.14, p = 0.014). HER3 protein expression was a poor prognostic factor of survival in patients with cervical cancer. This finding could help to provide individualized management for these patients.

Role of reactive thrombocytosis after primary cytoreductive surgery in advanced ovarian cancer.

We investigated the incidence of reactive thrombocytosis after maximal cytoreductive surgery in advanced epithelial ovarian cancer (EOC) and its role in patient survival. We retrospectively reviewed the electronic medical records of patients who underwent primary cytoreductive surgery for advanced EOC from 1 January 2012 to 31 December 2017. We analyzed the serum platelet counts at various time points from before surgery, during the peri-operative period, and after each cycle of adjuvant chemotherapy. A total of 474 patients were eligible for the analysis. Among them, 401 patients (84.6%) had FIGO stage III disease status. The most common histology type was serous adenocarcinoma (405 patients, 85.4%). Seventy-nine patients (22.6%) received splenectomy, and optimal cytoreduction was achieved in 326 patients (68.8%). A week after surgery, thrombocytosis was observed in 165 patients (34.8%) in the entire cohort. Higher platelet counts were observed in patients with splenectomy compared with patients without splenectomy. In particular, thrombocytosis on the fifth cycle of adjuvant chemotherapy showed the most significant effects on overall survival in multivariate analysis. In a logistic regression model, splenectomy was significantly attributed to thrombocytosis on the fifth cycle of chemotherapy. Reactive thrombocytosis after primary cytoreductive surgery is associated with poor survival in advanced EOC, particularly when thrombocytosis is observed during adjuvant chemotherapy.

Clinical experience of uterine smooth muscle tumor of uncertain malignant potential in two gynecological centers: Oncological and obstetrical aspects.

OBJECTIVES: To evaluate the clinical characteristics and obstetrical and oncological outcomes of patients with uterine smooth muscle tumors of uncertain malignant potential (STUMP) and analyze the risk factors for recurrence. STUDY DESIGN: A retrospective cohort study was performed at two gynecological centers using data collected between January 2008 and August 2018. All the patients enrolled were diagnosed with STUMP and had been followed up for at least 6 months. The patients' characteristics, treatment methods, recurrence rate, and subsequent pregnancy outcomes were evaluated. RESULTS: The mean age of the 62 patients was 36.1 ±â€¯9.1 years (median 35, range 20-55 years) and mean follow-up duration was 36.3 ±â€¯26.8 months (29.5, 6-130). All the patients were of premenopausal status. Fourteen patients (22.6 %) were initially treated by hysterectomy and 48 (77.4 %) by myomectomy. During the study period, three patients (4.8 %) experienced recurrence. However, there was no statistical difference between myomectomy and hysterectomy in terms of the rate of recurrence of STUMP or sarcoma, and all patients survived even after recurrence. Multivariate analysis revealed that a history of previous myomectomy was the sole independent risk factor for recurrence (odds ratio = 51.071; 95 % confidence interval = 2.743-950.726; p = 0.008). Subsequent pregnancies were successful in 10 of 19 women (52.6 %) who tried to conceive. Two of them had ongoing pregnancies at the time of last follow-up; the remaining eight women experienced a total of 14 subsequent pregnancies. CONCLUSIONS: The recurrence rate of STUMP was similar between hysterectomy and myomectomy. Therefore, fertility sparing myomectomy can be considered in women diagnosed with STUMP with close monitoring.

Feasibility of Single-Port Access (SPA) Laparoscopy for Large Ovarian Tumor Suspected to Be Borderline Ovarian Tumor.

OBJECTIVES: To compare the surgical, pathological and oncological outcomes of single-port access (SPA) laparoscopy against laparotomy for large ovarian tumor (>15 cm) suspected to be a borderline ovarian tumor (BOT) on preoperative imaging. METHODS: A retrospective review of the patients who underwent SPA laparoscopy (SPA Group) or laparotomy (Laparotomy Group) for suspected BOT was performed. Surgical outcomes, including the rates of iatrogenic spillage of tumor contents, and oncological outcomes, such as recurrence-free survival (RFS) and overall survival (OS), were compared between the two groups. Correlation between intraoperative frozen section analysis and permanent pathology results was also assessed. RESULTS: A total of 178 patients underwent surgical treatment for suspected large BOT. Among them, 105 patients with a mean tumor diameter of 20.9 ± 6.5 cm underwent SPA laparoscopy, and the other 73 patients, with a mean tumor diameter 20.2 ± 5.9 cm, underwent laparotomy. The mean operation time did not differ between the two groups (99.1 ± 41.9 min for SPA Group vs. 107.3 ± 35.7 min for Laparotomy Group, p = 0.085). There was no difference in the occurrence of iatrogenic spillage of tumor contents between the groups either (11.4% in the SPA Group vs. 6.8% in the Laparotomy Group, p = 0.381). However, the postoperative complication rates were significantly higher in the Laparotomy Group compared with SPA Group (16.4% vs. 5.7%, p = 0.025). The surgical approach was not associated with the misdiagnosis rates of frozen section analysis (19% in the SPA Group vs. 26% in the Laparotomy Group, p = 0.484). The most common histologic type of the tumors was mucinous in both groups. CONCLUSION: SPA laparoscopy is feasible, safe, and not inferior to laparotomy for surgical treatment of large ovarian tumors that suspected to be BOT on preoperative imaging.

Prognostic Significance of Tumor Regression Rate during Concurrent Chemoradiotherapy in Locally Advanced Cervix Cancer: Analysis by Radiation Phase and Histologic Type.

This study aimed to evaluate the prognostic significance of tumor regression rate according to radiation phase and histologic subtype in patients with locally advanced cervical cancer (LACC) treated with chemoradiation. We retrospectively reviewed the medical records of 398 patients with FIGO stage IIB-IVA cervical cancer treated with concurrent chemoradiotherapy (CCRT) between 2001 and 2019. Tumor response was assessed using serial magnetic resonance imaging (MRI) at three time points: pre-treatment, post-external beam radiotherapy (EBRT), and post-intracavitary radiotherapy (ICR). Tumor regression pattern according to histologic subtype and radiation phase (EBRT and ICR) was evaluated. Overall survival (OS) and progression-free survival (PFS) were the primary outcomes. Of 398 patients, 44 patients had adenocarcinoma/adenosquamous carcinoma (AC/ASC) and 354 patients had squamous cell carcinoma (SCC). AC/ASC was associated with significantly worse PFS and OS than SCC (p < 0.001). AC/ASC had a relatively poorer regression rate in response to EBRT than SCC (p < 0.001), whereas there was no significant difference in overall tumor regression rate after completion of RT (EBRT and ICR) between the two histologic subtypes. Multivariable analysis demonstrated AC/ASC histology to be an independent prognostic factor of decreased PFS and OS. Moreover, tumor regression rate after completion of EBRT (post-EBRT tumor regression rate (EBRTregression ≤ 26%) and proportion of tumor regression during EBRT to overall tumor regression (EBRTproportion ≤ 40%) were independent predictors of poor survival in patients with LACC. Tumor regression pattern of LACC in response to CCRT differs according to histologic subtype. AC/ASC histology and poor tumor response to EBRT are independent prognostic factors for worse survival in patients with LACC. Further studies are needed to develop a CCRT protocol that is specialized for patients with AC/ASC.

Changes in Ulnar Variance after a Triangular Fibrocartilage Complex Tear.

Purpose The relationship between triangular fibrocartilage complex (TFCC) tear and ulnar impaction syndrome has not been fully understood. We hypothesized that a TFCC tear could change the ulnar variance, which may be the cause of ulnar impaction syndrome. Patients and Methods A total of 72 patients who underwent TFCC foveal repair between January 2011 and June 2016 were included in this retrospective study. Among them, 44 patients diagnosed with TFCC foveal tear with distal radioulnar joint instability and no ulnar impaction syndrome underwent TFCC foveal repair only (group A) and 28 patients diagnosed with TFCC foveal tear with ulnar impaction syndrome underwent TFCC foveal repair and ulnar shortening osteotomy simultaneously (group B). We measured their ulnar variances in preoperative, postoperative, and last follow-up plain radiography. We also compared them with the ulnar variance of the contralateral (uninjured) wrist. Postoperative clinical outcomes, such as range of motions of the wrist, the visual analog scale (VAS) for pain, grip strength, and Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, were assessed. Results Ulnar variance increased after TFCC tears compared with that on the uninjured side in both groups (group A: 0.98 vs. 0.52 mm, p = 0.013; group B: 2.71 vs. 2.13 mm, p = 0.001). Once the TFCC was repaired, ulnar variance decreased (group A: 0.98 to 0.01 mm, p < 0.01; group B: 2.71 to 0.64 mm, p < 0.01). However, it was increased on the last follow-up radiograph (group A: 0.01 to 0.81 mm, p < 0.01; group B: 0.64 to 1.05 mm, p = 0.004). There were no significant improvement of range of motion, except for pronation-supination motion ( p = 0.04). Mean grip strength increased from 56.8 to 70.8% of the contralateral unaffected hand at the last assessment ( p = 0.01). Mean VAS for pain decreased from 7.4 ± 2.5 preoperatively to 2.7 ± 2 postoperatively ( p = 0.001). The QuickDASH score significantly improved from 45 to 9 ( p = 0.001). Conclusion Ulnar variance may be changed after a TFCC tear. In our study, it decreased after TFCC foveal repair. However, as time went on, the ulnar variance increased again, which could be one of the causes of ulnar impaction syndrome and ulnar-sided wrist pain. Level of Evidence This is a therapeutic Level IV study.

A comparison of surgical outcomes between robot and laparoscopy-assisted adenomyomectomy.

We aimed to investigate the feasibility of robotic adenomyomectomy and compared surgical outcomes between laparoscopic and robotic approaches for adenomyomectomy.We retrospectively reviewed the data of women who were diagnosed with adenomyosis and underwent adenomyomectomy through a minimally invasive approach between January 2014 and March 2018 at the CHA Gangnam Medical Center, Seoul, Republic of Korea. Patient demographics and operation-related outcomes were compared between the robotic and laparoscopic surgery groups.We evaluated 43 women who underwent adenomyomectomy through a minimally invasive approach (21 underwent a laparoscopic and 22 underwent a robotic adenomyomectomy). All 22 women who had originally been scheduled to undergo robotic adenomyomectomy could successfully undergo the robotic surgery without requiring conversion to laparotomy and/or serious complications. No statistically significant differences in patient demographics were observed between the robotic and the laparoscopic surgery groups. No significant intergroup difference was observed in the operative time, estimated blood loss, weight of the resected nodule, and length of hospitalization (160.0 vs 212.5 min, P = .106; 500.0 vs 300.0 mL, P = .309; 60.0 vs 70.0 g, P = .932; and 5.0 vs 6.0 days, P = .277). No serious perioperative complications were observed in either group.Robotic adenomyomectomy is feasible for women with adenomyosis. Surgical outcomes of robotic adenomyomectomy were comparable to those of a laparoscopic approach. There was, however, no superiority of robotic adenomyomectomy in terms of surgical outcomes. Further multicenter prospective studies using standardized surgical procedures are needed to confirm the conclusion of this study.

Global gene expression analysis of cell-free RNA in amniotic fluid from women destined to develop preeclampsia.

Preeclampsia (PE) is a disorder specific to pregnancy characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. There is no definite treatment for PE except delivery of the placenta. The purpose of this study was to elucidate the biological pathways involved in the development of PE and to discover a novel biomarker for PE by performing global gene expression analysis of amniotic fluid cell-free RNA.The participants were recruited from the Department of Obstetrics and Gynecology of CHA Gangnam Medical Center (Seoul, Korea) between March 2014 and February 2015. Eight samples were collected from 8 subjects at second trimester who were later diagnosed with PE. From the amniotic fluid samples, cell-free RNA extraction was performed and gene expression was analyzed using the GeneChip PrimeView Array. Transcriptome data previously analyzed by our group from 9 euploid mid-trimester amniotic fluid samples were used as the control for comparative analysis. Functional analysis of the probe sets was performed using the online Database for Annotation, Visualization, and Integrated Discovery (DAVID) toolkit 6.7.We identified 1841 differentially expressed genes (DEGs) between the PE group and the control. Of these, 1557 genes were upregulated in the PE group, while 284 genes were upregulated in the control. The functional annotation of DEGs identified specific enriched functions such as "transport," "signal transduction," and "stress response." Functional annotation clustering with enriched genes in the PE group revealed that translation-related genes, cell-cell adhesion genes, and immune-related genes were enriched. KEGG pathway analysis showed that several biological pathways, including the ribosome pathway and various immune pathways, were dysregulated. Several genes, including RPS29, IGF-2, and UBC, were significantly upregulated in PE, up to tenfold.This study provides the first genome-wide expression analysis of amniotic fluid cell-free RNA in PE. The results showed that gene expression involving the ribosome pathway and immunologic pathways are dysregulated in PE. Our results will aid in understanding the underlying pathogenesis of PE.