Outcomes and the effect of PGT-M in women with hormone-related hereditary tumor syndrome.

Purpose: To review the outcome of PGT-M in hormone-related hereditary tumor syndrome and evaluate the effect of ovarian induction on tumor growth in those patients. Methods: Medical records of PGT-M were retrospectively analyzed in patients with hormone-related heritage tumors in our reproductive center. A total of eleven women with hereditary breast and ovarian cancer (HBOC) (including BRCA1/2 mutation carriers), and Lynch syndrome (including MMR gene mutation carriers) were included. Thirteen IVF/PGT-M cycles were performed. Eleven for PGT-M and two for fertility preservation. The ovulation protocol, numbers of oocytes retrieved and two pronuclei (2PN) zygotes, PGT-M results, and clinical outcomes were analyzed. Tumor progression was also estimated by comparing transvaginal ultrasound (TVS), MR, CT, or colonoscopy according to the follow-up requirements of different tumors. Results: Eleven IVF/PGT-M cycles were performed with an antagonist protocol; Two cycles were performed with a mild stimulation protocol. The total dose of gonadotropin (Gn) was 1827 IU per patient (range from 1200 to 2625 IU). The median number of oocytes retrieved was 13 (range from 4 to 30), and the median number of 2PN zygotes was 8 (range from 2 to 16). A total of 32 embryos underwent PGT-M, and 9 (28.1%) embryos were suitable for transfer. Six transfer cycles were performed, and 5 cycles got clinical pregnancy (83%) with five newborns (83%). The follow-up examinations conducted 10-18 months after PGT-M/delivery revealed no new lesions or tumor progression. Conclusion: PGT-M results can provide important information for improving the consultation of hormone-related heritage tumor patients regarding their fertility preservation and reproductive options. Ovarian induction for women with hormone-related hereditary tumor syndrome is not associated with tumor progression.

Aggressive angiomyxoma of female pelvis and perineum: Retrospective study of 17 cases.

OBJECTIVE: Aggressive angiomyxoma is an uncommon mesenchymal neoplasm characterized by a high recurrence rate, usually observed in the lower genital tract of women during their reproductive age. STUDY DESIGN: Seventeen cases of aggressive angiomyxoma confirmed by pathology from January 2007 to December 2021 in Beijing Chao-yang Hospital were included. We collected clinical data and summarized the clinical and immunohistochemical features. RESULTS: All seventeen included patients were females, aged between 23 and 57 years (mean, 37.7 years; median, 42 years). Fourteen patients were newly diagnosed and three were recurrent. The tumors were located in vulva (58.8 %), vagina (23.5 %), buttock (11.8 %), and cervix (5.9 %). The tumors size were 2 to 15 cm in greatest dimension (mean 8 ± 4.4 cm, median 6 cm). Follow-up data was available for nine patients, which ranged from 25 to 124 months (mean, 82 months; median, 80 months). At the end of follow-up, no other recurrence or metastasis was reported. Immunohistochemical analysis showed immunoreactive for estrogen (10/11) and progesterone (8/11) receptor, desmin (6/8), smooth muscle actin (4/10), and vimentin (4/4), S-100 (1/8) and CD34 (1/7). The Ki67 level was less than 5 % in five cases. CONCLUSIONS: AAM is a hormone-sensitive, distinct rare mesenchymal neoplasm with high incidence of local recurrence. Surgery is the preferred treatment, with complete resection being an essential prerequisite for minimizing the risk of recurrence.

Associations of novel serum lipid index with epithelial ovarian cancer chemoresistance and prognosis.

Purpose: To evaluate the relationship between novel serum lipid index and chemoresistance as well as prognosis of epithelial ovarian cancer (EOC). Patients and methods: Patients' serum lipid profiles of 249 cases diagnosed with epithelial ovarian cancer, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) as well as their ratios, the novel indicators HDL-C/TC and HDL-C/LDL-C, and clinicopathologic characteristics were retrospectively collected and calculated from January 2016 to January 2020 and correlation between serum lipid index and clinicopathological features such as chemoresistance as well as prognosis were evaluated. Results: 249 patients pathologically diagnosed EOC who underwent cytoreductive surgery were included in our cohort. The mean age of these patients was 55.20 ± 11.07 years. Binary logistic regression analyses indicated Federation International of Gynecology and Obstetrics (FIGO(stage and HDL-C/TC ratio had significant association with chemoresistance. Univariate analyses demonstrated pathological type, chemoresistance, FIGO stage, neoadjuvant chemotherapy, maintenance treatment, HDL-C/LDL-C ratio, HDL-C/TC ratio were related to Progression-Free Survival (PFS) and Overall Survival (OS) (P<0. 05). Particularly, multivariate analyses indicated that HDL-C/LDL-C ratio was independent protective factors for both PFS and OS. Conclusion: The complex serum lipid index HDL-C/TC ratio has a significant correlation with chemoresistance. HDL-C/LDL-C ratio is closely related to the clinicopathological characteristics and prognosis of patients with EOC and is an independent protective factor indicating better outcome.

Establishment of an optimized CTC detection model consisting of EpCAM, MUC1 and WT1 in epithelial ovarian cancer and its correlation with clinical characteristics.

Objective: Emerging studies have demonstrated the promising clinical value of circulating tumor cells (CTCs) for diagnosis, disease assessment, treatment monitoring and prognosis in epithelial ovarian cancer. However, the clinical application of CTC remains restricted due to diverse detection techniques with variable sensitivity and specificity and a lack of common standards. Methods: We enrolled 160 patients with epithelial ovarian cancer as the experimental group, and 90 patients including 50 patients with benign ovarian tumor and 40 healthy females as the control group. We enriched CTCs with immunomagnetic beads targeting two epithelial cell surface antigens (EpCAM and MUC1), and used multiple reverse transcription-polymerase chain reaction (RT-PCR) detecting three markers (EpCAM, MUC1 and WT1) for quantification. And then we used a binary logistic regression analysis and focused on EpCAM, MUC1 and WT1 to establish an optimized CTC detection model. Results: The sensitivity and specificity of the optimized model is 79.4% and 92.2%, respectively. The specificity of the CTC detection model is significantly higher than CA125 (92.2% vs. 82.2%, P=0.044), and the detection rate of CTCs was higher than the positive rate of CA125 (74.5% vs. 58.2%, P=0.069) in early-stage patients (stage I and II). The detection rate of CTCs was significantly higher in patients with ascitic volume ≥500 mL, suboptimal cytoreductive surgery and elevated serum CA125 level after 2 courses of chemotherapy (P<0.05). The detection rate of CTCEpCAM + and CTCMUC1+ was significantly higher in chemo-resistant patients (26.3% vs. 11.9%; 26.4% vs. 13.4%, P<0.05). The median progression-free survival time for CTCMUC1+ patients trended to be longer than CTCMUC1- patients, and overall survival was shorter in CTCMUC1+ patients (P=0.043). Conclusions: Our study presents an optimized detection model for CTCs, which consists of the expression levels of three markers (EpCAM, MUC1 and WT1). In comparison with CA125, our model has high specificity and demonstrates better diagnostic values, especially for early-stage ovarian cancer. Detection of CTCEpCAM+ and CTCMUC1+ had predictive value for chemotherapy resistance, and the detection of CTCMUC1+ suggested poor prognosis.

Abnormal Elevation of Anti-Mullerian Hormone and Androgen Levels Presenting as Granulosa Cell Tumor.

We report a rare subtype of adult cystic granulosa cell tumor (AGCT) characterized by elevated anti-Mullerian hormone and hyperandrogenism. A 35-year-old woman with primary infertility, hyperandrogenism, and irregular menses who was previously diagnosed with polycystic ovarian syndrome was diagnosed with AGCT based on histopathological examination and FOXL2 genetic test after laparoscopy. Due to fertility aspirations, she underwent controlled ovarian stimulation followed by embryo cryopreservation before salpingo-oophorectomy, and two embryos were frozen-thawed and transferred after surgery. A healthy female infant was delivered at 40 weeks' gestation. Cystic granulosa cell tumors should be considered a differential diagnosis in patients with persistent ovarian cysts and hyperandrogenism. Younger patients with AGCT with fertility goals should consider active assisted reproduction measures to preserve fertility before treatment for AGCT.

Evaluating the benefits of neoadjuvant chemotherapy for advanced epithelial ovarian cancer: a retrospective study.

OBJECTIVE: To compare the chemoresistance and survival in patients with stage IIIC or IV epithelial ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) or primary debulking surgery (PDS). The clinical characteristics of patients who benefited from NACT were further evaluated. METHODS: We retrospectively analyzed 220 patients who underwent NACT followed by IDS or PDS from January 2002 to December 2016. Differences in clinicopathological features, chemoresistance and prognosis were analyzed. RESULTS: The incidence rate for optimal cytoreduction and chemoresistance in the NACT group was relatively higher than PDS group. No differences were observed in progression free survival or overall survival. Patients without macroscopic RD in NACT group (NACT-R0) had a similar prognosis compared to those in PDS group who had RD<1 cm, and a relatively better prognosis compared to the PDS group that had RD ≥ 1 cm. The survival curve showed that patients in NACT-R0 group that were chemosensitive seemed to have a better prognosis compared to patients in PDS group that had RD. CONCLUSION: Patients without RD after PDS had the best prognosis, whereas patients with RD after NACT followed by IDS had the worst. However, even if patients achieved no RD, their prognosis varied depending on chemosensitivity. Survival was better in patients who were chemosensitive compared to thosewho underwent PDS but had RD. Hence evaluating the chemosensitivity and feasibility of complete cytoreduction in advance is crucial.

Correction: The hMLH1 -93G>A Polymorphism and Risk of Ovarian Cancer in the Chinese Population.

[This corrects the article DOI: 10.1371/journal.pone.0135822.].

Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription.

Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT are still under investigation. In this study, we identified a previously unrecognized role of HSP90 in cooperating with signal transducer and activator of transcription 3 (STAT3) to regulate TWIST1 transcription in cancer cells. The HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin suppressed TWIST1 mRNA expression and promoter activity in epithelial ovarian cancer, renal clear cell cancer, and nasopharyngeal cancer cell lines. The interactions between HSP90 and transcription factors were visualized in cancer cell lines and tumor tissues using proximity ligation assays. Our findings reveal that HSP90 promotes the binding of STAT3 to the TWIST1 promoter, leading to the transcription of TWIST1. The inhibition of HSP90 downregulates STAT3 activity and TWIST1 transcription, thereby suppressing EMT and potentially inhibiting tumor progression, metastasis, and chemoresistance in different types of cancers. SIGNIFICANCE STATEMENT: Our study provides new evidence that HSP90 promotes EMT through enhancing TWIST1 transcription, which can be suppressed by HSP90 inhibitors. The HSP90 inhibitor inhibits EMT, thus potentially slowing down tumor growth, invasion, dissemination, metastasis, and drug resistance. These findings will hopefully pave the way for new therapeutic opportunities to target EMT and metastasis using HSP90 inhibitors.

Feasibility and outcome of primary laparoscopic cytoreductive surgery for advanced epithelial ovarian cancer: a comparison to laparotomic surgery in retrospective cohorts.

OBJECTIVES: To assess the feasibility and outcome of primary laparoscopic cytoreductive surgery on advanced epithelial ovarian cancer in comparison with conventional open surgery. MATERIALS AND METHODS: Patients undergoing primary laparoscopic cytoreductive surgery (LCS) from March 2007 to December 2016 were matched to controls treated with laparotomic cytoreduction during the same period. Procedural data and outcomes were analyzed. RESULTS: The LCS group (n = 64) and laparotomic group (n = 68) had similar age, BMI, stages, histologic type and grading. The LCS group exhibited significantly less operating time (P < 0.001), less intraoperative blood loss (P < 0.001), and shorter time to recover postoperatively (P = 0.002). No statistical difference was observed for the number of pelvic and para-aortic lymph nodes dissected (P = 0.326 and P = 0.151). Significant difference was observed in satisfaction of the cytoreduction (95.3% vs. 76.5%, P = 0.008). No significant difference were observed either in intra-operative or in post-operative complications between the two groups (P = 0.250). Three patients in the LCS group experienced intra-operative complications (4.7%) and were all treated laparoscopically. The conversion rate was 3.1%. No significant differences were observed in the progression-free survival and overall survival between the two groups during the medium follow-up of 18 months (P = 0.236 and P = 0.216). The 2-year and 3-year progression-free survival was 67.9%, 55.5% in LCS group and 53.8%, 33.3% respectively in the control group. The 2-year and 3-year overall survival was 95.8%, 88.7% respectively in the LCS group and 89.0%, 83.7% in the control group. CONCLUSIONS: Primary laparoscopic cytoreductive surgery in some strictly selected advanced stages of EOC patients was feasible and safe, resulting in oncologic outcomes not inferior to those in open surgery.

The hMLH1 -93G>A Polymorphism and Risk of Ovarian Cancer in the Chinese Population.

BACKGROUND: As a mismatch repair (MMR) gene, hMLH1 plays an important role in the maintenance of chromosomal integrity. Several studies have investigated the associations of hMLH1 -93G>A (rs1800734) and Ile219Val (rs1799977) in diverse tumor types with discordant results, but their roles in ovarian cancer in the Chinese population remains to be elucidated. METHODS: In a case-control analysis, we assessed the association between these two polymorphisms and ovarian cancer risk in 421 ovarian cancer patients and 689 control subjects in the Chinese population using logistic regression. RESULTS: We found that the variant hMLH1 genotypes (-93AA and AG) are associated with risk of ovarian cancer (adjusted odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.42-2.89) compared with the -93GG genotype. The A allele increases the risk of ovarian cancer in a dose-dependent manner (P<10-4). Functional test showed that -93A allele increased hMLH1 promoter transcriptional activity and the luciferase activity. However, no significant difference was found in the genotype frequencies at the Ile219Val site between the cases and controls. CONCLUSIONS: These findings indicate that the -93G>A polymorphism in hMLH1 may affect ovarian cancer susceptibility in the Chinese population.

[Study on mesh-augmented vaginal reconstructive surgery in treatment of pelvic organ prolapse].

OBJECTIVE: To evaluate clinical outcome and complications of mesh-augmented vaginal reconstructive surgery in treatment of pelvic organ prolapse. METHODS: From Feb 2007 to Jan 2009, mesh-augmented vaginal reconstructive surgery were performed on 66 women with pelvic organ prolapse stage III-IV. Pre and postoperative symptoms, pelvic organ prolapse quantitation (POP-Q) stage and pelvic floor distress inventory-short form 20 (PFDI-20) measurements were studied to assess anatomic and quality-of-life outcome. Operative complications were also analyzed. RESULTS: Totally 65 patients underwent successful surgeries. The rate of follow-up was 97% (63/65) with a median follow-up of 17.2 months. Subjective cure rate and objective cure rate were both 97% (61/63) at 6 and 12 months after surgeries, 51 women completed PFDI-20 measurements and scores were 102 ± 50 before surgery, 16 ± 21 at 6 months and 15 ± 20 at 12 months. It reached statistical difference when scores were compared before and after surgeries (P < 0.05). Among 66 patients, 2 patients underwent organ injuries, 2 had recurrent prolapse, 4 had mesh-related complications and 1 had severe de novo stress urinary incontinence. Six patients underwent second surgery. CONCLUSIONS: Mesh-augmented vaginal reconstructive surgery in treatment of pelvic organ prolapsed brought satisfied clinical outcome. The incidence of mesh-related complications was low and secondary operative interventions were effective.

[Study of the therapeutic effects of costimulatory molecules B7-1 and interleukin 12 modified tumor cells vaccines on ovarian epithelial carcinoma through induction of anti-cancer immunity of the body].

OBJECTIVE: To study the biological characters of tumor cell vaccines modified by interleukin 12 (IL-12) and co-stimulatory molecule B(7 - 1) and their combination therapeutic effect on rat ovarian cancer animal model. METHODS: Retroviral vector pLmB(7 - 1)SN, which expressed murine B(7 - 1) was constructed. An epithelial ovarian cancer cell line NuTu-19 was infected with pLmIL-12SN and/or pLmB(7 - 1)SN by lipofectin-mediated gene transfer system. Cell lines that could highly express either or both of these cytokines were named NuTu-19/IL-12, NuTu-19/B(7 - 1) or NuTu-19/IL-12-B(7 - 1), according to the results of enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM). NuTu-19/Neo, the cell line that was transfected by vector pLXSN was used as a control. Various types of cytokine-modified tumor cells were injected subcutaneously into syngeneic rats Fischer 344 and their tumorigenecities were recorded. After being immunized twice by various types of mitomycin C treated gene modified tumor cells, the survival time of the intraperitoneal disseminating ovarian cancer animal model was observed, and the anti-tumor mechanisms of different gene modified tumor cell lines were discussed. RESULTS: The reconstruction of pLmB(7 - 1)SN was successful. Stable IL-12 and B(7 - 1) expression in cell lines NuTu-19/B(7 - 1), NuTu-19/IL-12 and NuTu-19/IL-12-B(7 - 1) were confirmed by ELISA and FCM. Tumorigenecities of various gene modified tumor cells decreased in syngeneic rats. The splenic lymphocytes proliferation indices (PI) in B(7 - 1) group (NuTu-19/B(7 - 1) immunized group) and IL-12 group (NuTu-19/IL-12 immunized group) were 2.4 and 4.6 (the letter P < 0.05 compared with that in control group), while PI in B(7 - 1) and IL-12 combination group (NuTu-19/IL-12-B(7 - 1) immunized group) increase to 10.2, being of significantly difference compared with those in control or B(7 - 1) or IL - 12 group (P < 0.01). More significant cytotoxic effects of cytotoxic lymphocytes (CTLs) on syngeneic tumor cells could be observed in B(7 - 1) group (15.0%) or IL-12 group (31.5%) (P < 0.05 or P < 0.01, compared with 2.6% in control group), while coexpression of IL-12 and B(7 - 1) was of great importance in enhancing CTL activity (52.4%), compared with that in control or B(7 - 1) or IL-12 group (P < 0.05, respectively). The life spans of ovarian cancer-bearing rats immunized by IL-12 (59.8 d) or B(7 - 1) (56.2 d) tumor cell vaccines were a little longer than that in control group (53.4 d), but no significant differences existed (P > 0.05), whereas in the animal models who had received IL-12 and B(7 - 1) co-immunization, prolonged survival time was showed which had statistical significance compared with that in control group (66.0 d, P < 0.05). CONCLUSION: B(7 - 1) and IL-12 modified tumor cell vaccines can induce anti-tumor immunity through stimulating lymphocytes proliferation and inducing recognition and cytotoxic effects of CTLs on tumor cells. An obvious synergistic effect exists when the two cytokines are combined. Combined immunogenic therapy with IL-12 and B(7 - 1) should prove to be a promising therapeutic strategy in ovarian cancer.