Continuous Administration of Anti-VEGFA Antibody Upregulates PAI-1 Secretion from Ovarian Cancer Cells via miR-143-3p Downregulation.

Although bevacizumab (BEV) plays a key role in ovarian cancer treatment, BEV resistance is often observed in clinical settings. This study aimed to identify the genes responsible for BEV resistance. C57BL/6 mice inoculated with ID-8 murine ovarian cancer cells were treated with anti-VEGFA antibody or IgG (control) twice weekly for 4 weeks. The mice were sacrificed, then, RNA was extracted from the disseminated tumors. qRT-PCR assays were performed to identify angiogenesis-related genes and miRNAs that were altered by anti-VEGFA treatment. SERPINE1/PAI-1 was found to be upregulated during BEV treatment. Therefore, we focused on miRNAs to elucidate the mechanism underlying the upregulation of PAI-1 during BEV treatment. Kaplan-Meier plotter analysis revealed that higher expression levels of SERPINE1/PAI-1 were associated with poor prognoses among BEV-treated patients, suggesting that SERPINE1/PAI may be involved in the acquisition of BEV resistance. miRNA microarray analysis followed by in silico and functional assays revealed that miR-143-3p targeted SERPINE1 and negatively regulated PAI-1 expression. The transfection of miR-143-3p suppressed PAI-1 secretion from ovarian cancer cells and inhibited in vitro angiogenesis in HUVECs. Next, miR-143-3p-overexpressing ES2 cells were intraperitoneally injected into BALB/c nude mice. ES2-miR-143-3p cells downregulated PAI-1 production, attenuated angiogenesis, and significantly inhibited intraperitoneal tumor growth following treatment with anti-VEGFA antibody. Continuous anti-VEGFA treatment downregulated miR-143-3p expression, which upregulated PAI-1 and activated an alternative angiogenic pathway in ovarian cancer. In conclusion, the substitution of this miRNA during BEV treatment may help overcome BEV resistance, and this may be used as a novel treatment strategy in clinical settings. IMPLICATIONS: Continuous administration of VEGFA antibody upregulates SERPINE1/PAI-1 expression via the downregulation of miR-143-3p, which contributes to acquiring bevacizumab resistance in ovarian cancer.

Obstetrical outcomes of labor with and without analgesia in Robson classification groups 1 and 2a: a single-center retrospective study.

PURPOSE: This study aimed to elucidate the effects of neuraxial analgesia on labor in women classified based on the Robson classification system. METHODS: We retrospectively reviewed the clinical data of singleton cephalic nulliparous deliveries in labor at term between January 2018 and December 2021 and compared obstetrical outcomes between deliveries with and without neuraxial analgesia in women of Robson group 1 (spontaneous labor) and group 2a (induced labor). Statistical analyses were performed using the Wilcoxon ranked-sum test, Fisher's exact test, and logistic regression model. Statistical significance was set at p < 0.05. RESULTS: We identified 2726 deliveries during the period, of which 387 deliveries (215 with analgesia and 172 without analgesia) were in Robson group 1 and 502 deliveries (258 with analgesia and 244 without analgesia) in Robson 2a. In Robson group 1 pregnancies, the cesarean section (CS) rate was higher in those who received analgesia (15%) than in those who did not (3%) (p = 0.0001). Multivariate analysis revealed that labor with analgesia was a significant risk factor for CS (p < 0.0001). Similarly, in Robson group 2a pregnancies, we observed a higher CS rate in those with analgesia than in those without analgesia (18 vs. 11%, p = 0.042). CONCLUSION: A higher CS rate was observed in deliveries with analgesia than in those without analgesia both in the Robson group 1 and group 2a pregnancies.

Safety and efficacy of Ninjin'yoeito along with iron supplementation therapy for preoperative anemia, fatigue, and anxiety in patients with gynecological disease: an open-label, single-center, randomized phase-II trial.

BACKGROUND: Preoperative anemia affects perioperative outcomes and often causes fatigue and psychological disorders. Therefore, anemia should be treated before a patient undergoes surgery. Ninjin'yoeito (NYT), a Japanese Kampo medicine composed of ginseng and Japanese angelica root with the other 10 herbs, is administered for anemia, fatigue and anxiety; however, there are a few reports that have prospectively examined the effects of NYT before surgery for gynecological diseases. Hence, we tended to investigate its efficacy and safety. METHODS: In this open-label randomized trial, women with gynecological diseases accompanied by preoperative anemia (defined as < 11.0 g/dL Hemoglobin [Hb]) were randomly assigned (1:1) into the iron supplementation and NYT groups. Patients of the iron supplementation group and the NYT group received 100 mg/day iron supplementation with and without NYT (7.5 g/day) for at least 10 days before surgery. The primary endpoint was improvement in Hb levels before and after treatment, and Cancer Fatigue Scale (CFS) and Visual Analogue Scale for Anxiety (VAS-A) scores between groups. Statistical analyses were performed with Wilcoxon signed rank test, Wilcoxon rank sum test, and Fisher's exact test as appropriate. RESULTS: Forty patients were enrolled of whom 30 patients were finally analyzed after allocating 15 to each group. There was no difference in the characteristics between both groups. Hb significantly increased in both groups (iron supplementation group, 9.9 ± 0.8 g/dL vs. 11.9 ± 1.6 g/dL; NYT group, 9.8 ± 1.0 g/dL vs. 12.0 ± 1.0 g/dL); the difference in the elevations in Hb between both groups was statistically insignificant (P = 0.72). Contrarily, CFS (17.9 ± 10.2 vs. 8.1 ± 5.2) and VAS-A (56 mm (50-70) vs. 23 mm (6-48)) scores were significantly decreased only in the NYT group and these changes were greater in the NYT group (∆CFS, P = 0.015; ∆VAS-A, P = 0.014). Liver dysfunction occurred in one patient of the NYT group. CONCLUSIONS: For treating preoperative anemia in women with gynecological conditions, NYT administration along with iron supplementation safely and efficiently improved the preoperative fatigue and anxiety in addition to the recovery from anemia. TRIAL REGISTRATION: jRCT1051190012 (28/April/2019, retrospectively registered).

Magnetic resonance imaging evaluation of pelvic floor structure during pregnancy.

OBJECTIVE: Among the various risk factors of pelvic floor disorders, pregnancy has been reported to affect the pelvic floor structure; however, not all these effects have been understood yet. The aim of this study is to elucidate how pregnancy affects pelvic floor structure via magnetic resonance imaging (MRI). STUDY DESIGN: We conducted a retrospective study between January 2010 and December 2019 to extract clinical records of pregnant and non-pregnant women, who underwent MRI for obstetrical diseases and ovarian benign tumors, respectively. The data on age, body mass index (BMI), complications, gravida, parity, gestational age, and obstetrical history were collected, and pubo-coccygeal line (PCL), pubo-rectal line (PRL), and M line (ML) on their MR images were measured. Statistical analyses were performed with Wilcoxon test, chi-square test, and Kruskal-Wallis test with Steel-Dwass post hoc test as appropriate. Statistical significance was set at P < 0.05. RESULTS: We analyzed the reports of 56 (pregnancy group) and 106 women (non-pregnancy group). There was no significant difference in age or BMI, while the obstetric history was significantly different between these groups. Median PCL, PRL, and ML in the pregnancy group were significantly longer than those in the non-pregnancy group (114.1 mm vs. 110.0 mm, P = 0.018; 48.6 mm vs. 41.6 mm, P < 0.0001 and 21.7 mm vs. 10.0 mm, p < 0.0001. respectively). The subgroup analysis of the effect of pregnancy and vaginal delivery (VD) history on changes in these lines revealed that pregnancy-induced PRL increase tended to recover to the reference level of "non-pregnant without VD," but ML increase did not fully recover. CONCLUSION: MRI revealed a strong effect of pregnancy on pelvic floor structure.

Exosomal CD47 Plays an Essential Role in Immune Evasion in Ovarian Cancer.

Ovarian cancer is largely diagnosed at advanced stages upon detection of multiple peritoneal dissemination, resulting in poor outcomes. CD47 is overexpressed in tumors, facilitates tumor immune evasion, and is located on exosomes. We aimed to investigate the role of exosomal CD47 in ovarian cancer progression. Prognostic significance of CD47 expression in ovarian cancer was examined using a public database including 1,435 patients and validated with 26 patients at our institution. CD47 expression was associated with poor progression-free survival and inversely correlated with macrophage infiltration in ovarian cancer tissues. Exosomes were collected from ovarian cancer cell lines, and CD47 expression on exosomes was confirmed via flow cytometry. Inhibition of exosome secretion with GW4869 and exosome uptake with 5-(N-ethyl-N-isopropyl)-amiloride inhibited the surface CD47 expression on ovarian cancer cells and promoted phagocytosis by macrophages. RAB27A (a key regulator of exosome release) knockdown inhibited exosome secretion and led to CD47 downregulation in ovarian cancer cells. In a xenograft mouse model, suppression of the release of tumor-derived exosomes by GW4869 or RAB27A knockdown suppressed tumor progression and enhanced M1 macrophage phagocytosis in cancer tissues. Collectively, CD47 expression was correlated with poor prognoses in patients with ovarian cancer, suggesting the importance of immune evasion. CD47 was expressed on exosomes and the inhibition of exosome secretion and/or uptake enhanced cancer cell phagocytosis by macrophages, and thus, suppressed peritoneal dissemination. This suggests the potential of a novel immune checkpoint therapeutic agent that focuses on exosomes. IMPLICATIONS: Mechanistic insight from the current study suggests that exosomal CD47 may be an advantageous therapeutic target in ovarian cancer.

[Comparison between Primary Debulking Surgery and Neo-Adjuvant Chemotherapy Followed by Interval Debulking Surgery for Patients with Stage III-IV Ovarian Cancer].

The current standard treatment for advanced ovarian cancer is primary debulking surgery(PDS). We may expect a good prognosis if complete debulking(no visible residual tumor)is possible. However, if complete surgery is not possible owing to the location of the tumor or poor performance status, neo-adjuvant chemotherapy(NAC)could be an alternative option. Interval debulking surgery(IDS)can be planned after NAC to try and achieve complete debulking surgery. We reviewed stage III and IV epithelial ovarian cancers treated at Kansai Rosai Hospital between January 2012 and January 2016. Fifty-one cases (PDS: 22 cases, NAC-IDS: 29 cases)were enrolled in our analysis. Progression-free survival(PFS), overall survival(OS), the successful complete surgery rate, and the contents and complications of the surgery were compared between the PDS and NAC-IDS groups. There was no significant difference in PFS and OS between the 2 groups(PFS: p=0.467, OS: p=0.685). Blood loss was larger in the PDS group(p=0.013). Patients in the NAC-IDS group were likely to be able to eventually achieve complete surgery(p=0.016). NAC followed by IDS is one of the effective treatment options for advanced ovarian cancers.

[A Retrospective Analysis of Systematic Lymphadenectomy for Loco-Regional(pT1)Epithelial Ovarian Cancer].

BACKGROUND: The incidence of lymph node metastasis in pT1 epithelial ovarian cancer is between 5% and 21%. Most cases with lymph node metastasis are those of serous carcinoma; it is relatively rare in mucinous carcinoma. Therefore, there is a recent trend to omit systematic lymphadenectomy in early stage mucinous carcinoma. The purpose of this study was to verify whether the omission of systematic lymphadenectomy in mucinous carcinoma is oncologically safe. METHODS: We reviewed all pT1 epithelial ovarian cancer cases that were treated in our hospital between January 2002 and December 2015. RESULTS: Fiftynine cases of pT1 epithelial ovarian cancer were included. The overall rate of lymph node metastasis was 6.8%(4 in 59). It was 6.5%(2 in 31)in clear cell carcinoma and 22.2%(2 in 9)in mucinous carcinoma. CONCLUSION: According to our study, lymph node metastasis in pT1 mucinous carcinoma has a rate of 22.2% and some affected cases were not detected by presurgery imaging studies. Therefore, we need to be careful about the omission of systematic lymphadenectomy in mucinous carcinoma.