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Ovarian cancer - Top 30 Publications

Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study.

Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment-related morbidity. The aim of this study was to assess the outcomes of pediatric patients with MOGCT.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: Recommendations on incorporating patient-reported outcomes in clinical trials in epithelial ovarian cancer.

Despite the support for including patient-reported outcomes (PROs) and health-related quality of life in clinical trials, there have been deficiencies in how these have been assessed and reported in epithelial ovarian cancer (EOC) clinical trials. To redress this, the 5th Ovarian Cancer Consensus Conference, included a plenary session entitled 'How to include PROs in clinical trials'. The perspective is a summary of the recommendations made by the Gynecologic Cancer InterGroup unanimously agreed on the importance of PROs and PRO end-points in EOC clinical trials. They recognised that effort must be made to ensure the integrity of collection of PRO data and to avoid missing data. PRO end-points should be based on the PRO hypotheses, be context specific and reflect the patient population and the objectives of treatment (e.g. first line, maintenance therapy, early or late relapse). The PRO end-points inform the choice of PRO measures used in the trial and how the results are analysed and reported. There was agreement that progression-free survival should be supported by PROs among patients with late relapse (platinum sensitive) and that progression-free survival alone was not sufficient as the primary end-point of clinical trials in patients with platinum resistant/refractory EOC and PROs should be included as either the primary/co-primary end-point in this subset of patients. Novel approaches to measure the benefit of palliative chemotherapy such as time until definitive deterioration of Health-Related Quality of Life were recommended. There was consensus to endorse the ISOQOL and CONSORT-PRO guidelines on the inclusion and reporting of PRO endpoints in protocols and that all future EOC Gynecologic Cancer InterGroup trials should adhere to these.

Relationship between HER2 and JAK/STAT-SOCS3 signaling pathway and clinicopathological features and prognosis of ovarian cancer.

The study aims to explore the relationship between expressions of HER2 and JAK/STAT3-SOCS3 signaling pathway and clinicopathological features and prognosis of ovarian cancer (OC).

Blood type, ABO genetic variants, and ovarian cancer survival.

Blood type A and the A1 allele have been associated with increased ovarian cancer risk. With only two small studies published to date, evidence for an association between ABO blood type and ovarian cancer survival is limited.

A Resident's Perspective of Ovarian Cancer.

Identifying, understanding, and curing disease is a lifelong endeavor for any medical practitioner. Equally as important is to be cognizant of the impact a disease has on the individual suffering from it, as well as on their family. Ovarian cancer is the leading cause of death from gynecologic malignancies. Symptoms are vague, and the disease is generally at an advanced stage at diagnosis. Efforts have been made to develop methods to identify ovarian cancer at earlier stages, thus improving overall mortality. Transvaginal ultrasound (TVUS), with and without laboratory tests, can be used to screen for ovarian cancer. For over thirty years, the University of Kentucky Markey Cancer Center Ovarian Cancer Screening Program has been studying the efficacy of TVUS for detecting early stage ovarian cancer. After 285,000+ TVUS examinations provided to over 45,000 women, the program has demonstrated that regular TVUS examinations can detect ovarian cancer at early stages, and that survival is increased in those women whose ovarian cancer was detected with screening and who undergo standard treatment. These results demonstrate the utility of TVUS as an efficacious method of ovarian cancer screening.

Is There a Role for Ovarian Cancer Screening in High-Risk Women?

Cancer of the ovary, fallopian tube, and peritoneum: a population-based comparison of the prognostic factors and outcomes.

The objective was to compare the prognostic factors and outcomes among primary ovarian cancer (OC), fallopian tube cancer (FC), and peritoneal cancer (PC) patients in a population-based setting.

Imaging diagnostics of breast metastases from extramammary tumors.

Breast metastases of solid extramammary tumors are very rare in comparison to primary malignancies of the breast and account for only 0.33-6.3% of all malignant neoplasms of the breast. The most common primary tumors are malignant melanoma, distant sarcomas, lung cancer, ovarian cancer, renal cell cancer and thyroid cancer in decreasing order of frequency. This review article summarizes the clinical features and the different imaging findings of breast metastases from different extramammary solid tumors. Breast metastases are often incidental findings in computed tomography (CT) or positron emission tomography CT (PET-CT) imaging. Mammography shows two different imaging patterns, namely focal lesions and diffuse architectural distortion with skin thickening. Breast metastases presenting as focal masses usually occur as solitary and more rarely as multiple round lesions with a smooth edge boundary. Associated calcifications are rare findings. Diffuse architectural distortion with skin thickening is more common in breast metastases from most gastric tumors, ovarian cancer and rhabdomyosarcoma. Using ultrasound most lesions are hypoechoic, oval or round with smooth boundaries and posterior acoustic enhancement. The magnetic resonance imaging (MRI) criteria of breast metastases show an inconstant signal behavior that cannot be safely classified as benign or malignant. In summary, in patients with known malignancies the presence of breast metastases should be considered even with imposing clinically and radiologically benign findings.

Expressions of OCT4, Notch1 and DLL4 and their clinical implications in epithelial ovarian cancer.

To investigate the correlations among OCT4, Notch1 and DLL4 and their association with the clinicopathological features of patients with epithelial ovarian cancer (EOC).

Dasatinib + Gefitinib, a non platinum-based combination with enhanced growth inhibitory, anti-migratory and anti-invasive potency against human ovarian cancer cells.

Ovarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin. Their expression is increased in advanced ovarian cancers and is correlated with poor prognosis. Despite a clear potential in inhibiting these proteins in ovarian cancer, as a single agent or in combination with a carboplatin treatment, we need to target kinases in tandem because of their capacity to trigger compensatory pathways that synergize to promote drug resistance.

Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms.

Sex cord-stromal tumors (SCSTs) are the second most frequent category of testicular neoplasms, accounting for approximately 2-5% of cases. Both genetic and epigenetic factors account for the differences in frequency and histologic composition between testicular and ovarian SCSTs. For example, large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia occur in the testis but have not been described in the ovary. In this article, we discuss recently described diagnostic entities as well as inconsistencies in nomenclature used in the recent World Health Organization classifications of SCSTs in the testis and ovary. We also thoroughly review the topic of neoplasms composed of both germ cells and sex cord derivatives with an emphasis on controversial aspects. These include "dissecting gonadoblastoma" and testicular mixed germ cell-sex cord stromal tumor (MGC-SCST). The former is a recently described variant of gonadoblastoma that sometimes is an immediate precursor of germinoma in the dysgenetic gonads of patients with a disorder of sex development. Although the relationship of "dissecting gonadoblastoma" to the previously described undifferentiated gonadal tissue is complex and not entirely resolved, we believe that it is preferable to continue to use the term undifferentiated gonadal tissue for those cases that are not neoplastic and are considered to be the precursor of classical gonadoblastoma. Although the existence of testicular MGC-SCST has been challenged, the most recent evidence supports its existence; however, testicular MGC-SCST differs significantly from ovarian examples due to both genetic and epigenetic factors.

The value of red cell distribution width in patients with ovarian cancer.

The red cell distribution width (RDW) has attracted attention in the diagnosis of malignant tumors. In this study, we analyzed the correlation between the RDW and ovarian cancer by observing changes in the RDW in patients with ovarian cancer.

Tea consumption and the risk of ovarian cancer: A meta-analysis of epidemiological studies.

A large number of epidemiological studies have provided conflicting results about the relationship between tea consumption and ovarian cancer. This study aimed to clarify the association between tea consumption and ovarian cancer. A literature search of the MEDICINE, Scopus, PubMed, and Web of Science databases was performed in April 2016. A total of 18 (11 case-control and 7 cohort) studies, representing data for 701,857 female subjects including 8,683 ovarian cancer cases, were included in the meta-analysis. A random-effects meta-analysis was used to compute the pooled relative risks (RR), meta regression, and publication bias, and heterogeneity analyses were performed for the included trials. We found that tea consumption had a significant protective effect against ovarian cancer (relative risk [RR] = 0.86; 95% confidence interval [CI]: 0.76, 0.96). The relationship was confirmed particularly after adjusting for family history of cancer (RR = 0.85; 95% CI: 0.72, 0.97), menopause status (RR = 0.85; 95% CI: 0.72, 0.98), education (RR = 0.82; 95% CI: 0.68, 0.96), BMI (RR = 0.85; 95% CI: 0.70, 1.00) , smoking (RR = 0.83; 95% CI: 0.72, 0.93) and Jadad score of 3 (RR = 0.76; 95% CI: 0.56, 0.95) and 5 (RR = 0.74; 95% CI: 0.59, 0.89). The Begg's and Egger's tests (all P > 0.01) showed no evidence of publication bias. In conclusion, our meta-analysis showed an inverse association between tea consumption and ovarian cancer risk. High quality cohort-clinical trials should be conducted on different tea types and their relationship with ovarian cancer.

The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcemic type.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodeling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodeling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumor samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis and neuron-like differentiation. EZH2 inhibitors suppressed tumor growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease.

Correlation of preoperative ROMA scores with clinical stage in epithelial ovarian cancer patients.

The significance of the Risk of Ovarian Malignancy Algorithm (ROMA) in differentiating benign and malignant ovarian lesions has been evidenced. In our clinical work, we found that advanced ovarian cancer were accompanied commonly with high ROMA scores. Thus, this study aimed to clarify the performance of ROMA in different disease stage of epithelial ovarian cancer (EOC) prior to surgery.

A brief review of the management of platinum-resistant-platinum-refractory ovarian cancer.

Ovarian cancer, which ranks fifth in cancer deaths among women, is the most lethal gynecologic malignancy. Epithelial ovarian cancer (EOC) is the most common histologic type, with the 5-year survival for all stages estimated at 45.6%. This rate increases to more than 70% in the minority of patients who are diagnosed at an early stage, but declines to 35% in the vast majority of patients diagnosed at advanced stage. Recurrent EOC is incurable. Platinum sensitivity (or lack thereof) is a major determinant of prognosis. The current standard treatment is primary surgery followed by platinum-based chemotherapy. In recurrent platinum-resistant/platinum-refractory EOC, sequential single-agent salvage chemotherapy is superior to multiagent chemotherapy. Multiagent regimens increase toxicity without clear benefit; however, no preferred sequence of single agents is recommended. The impact of targeted therapies and immunotherapies on progression-free survival and overall survival, which remains dismal, is under active investigation. Currently, clinical trials offer the best hope for the development of a new treatment paradigm in this recalcitrant disease.

Characterization of FOXO1, 3 and 4 transcription factors in ovaries of fetal, prepubertal and adult rhesus macaques.

The phosphoinositide 3-kinase/AKT signaling pathway negatively regulates follicle activation via the forkhead box O (FOXO) transcription factor in rodents. FOXO3 knockout mice exhibit global activation of primordial follicles leading to early depletion of ovarian follicles and subsequent infertility. Whether a similar mechanism for follicle activation exists in the primate ovary is unclear. In the current study, protein localization of FOXO1, 3 and 4 as well as their upstream regulator, AKT/p-AKT, were examined in rhesus macaque ovaries of 3 developmental stages: fetal, prepubertal and adult. FOXO1 protein is expressed in granulosa cells of fetal, prepubertal and adult ovaries. FOXO3 is distributed sparsely in the mitotically active germ cells, but its expression decreases following follicle formation in the macaque fetal ovary. In addition, FOXO3 is seldom with inter-animal variation in the prepubertal ovary and is absent in the adult ovary. FOXO4 is nondetectable in fetal ovaries, although it is expressed in some theca cells of antral follicles and some stromal cells in prepubertal and adult ovaries. Our results suggest that the regulation and/or function of FOXO3 in the primate primordial follicle may differ than that of the rodent. Nevertheless, AKT/p-AKT is expressed in macaque primordial oocytes, suggesting that similar upstream events, but different downstream effects may regulate primordial follicle activation in nonhuman primates compared to rodents. Elucidation of the mechanism responsible for follicle activation in primates will be crucial for understanding primary ovarian insufficiency, improving female fertility, and applying techniques for in vitro maturation of follicles for fertility preservation in cancer survivors.

Premenopausal Hysterectomy and Risk of Ovarian Cancer in African-American Women.

Although the inverse association between hysterectomy and epithelial ovarian cancer (EOC) was considered well established, investigators in recent studies including women diagnosed after 2000 have observed modest increases in risk. Most studies have been conducted in white women with little representation of African-American women. We examined the relationship between premenopausal hysterectomy and EOC in African-American women and explored whether hormone therapy (HT) modified this association in 614 cases and 743 controls enrolled in the African American Cancer Epidemiology Study (2010-2015). Premenopausal hysterectomy was inversely associated with the odds of EOC (odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.56, 1.01). Qualitative interaction by estrogen-only HT was present; among never users of estrogen-only HT, premenopausal hysterectomy was associated with a significantly decreased odds of EOC (OR = 0.65, 95% CI: 0.46, 0.92), whereas among users of estrogen-only HT, a positive association was observed (OR = 1.71, 95% CI: 0.76, 3.84). In a population of African-American women diagnosed after 2000, our overall results are consistent with the inverse association observed in the era before 2000, yet the effect modification by HT suggests that HT use among women who have had hysterectomies may negate the protective effects of hysterectomy on EOC, creating the appearance of a null or slightly increased risk.

Prediction of therapy response in ovarian cancer: Where are we now?

Therapy resistance is a major challenge in the management of ovarian cancer (OC). Advances in detection and new technology validation have led to the emergence of biomarkers that can predict responses to available therapies. It is important to identify predictive biomarkers to select resistant and sensitive patients in order to reduce important toxicities, to reduce costs and to increase survival. The discovery of predictive and prognostic biomarkers for monitoring therapy is a developing field and provides promising perspectives in the era of personalized medicine. This review article will discuss the biology of OC with a focus on targetable pathways; current therapies; mechanisms of resistance; predictive biomarkers for chemotherapy, antiangiogenic and DNA-targeted therapies, and optimal cytoreductive surgery; and the emergence of liquid biopsy using recent studies from the Medline database and ClinicalTrials.gov.

Confounder factors masking a Leydig-cell ovarian tumor in a post-menopausal woman treated for androgen-positive receptor breast cancer.

Post-menopause hyperandrogenism is a condition that needs careful evaluation. Aromatase inhibitors (AI), which are important in the management of positive estrogen breast cancer, and chronic kidney disease (CKD) can puzzle the evaluation of this condition. A postmenopause female with type-2 diabetes and advanced CKD was attended due to progressive virilization, which has started after the introduction of an AI for breast cancer 5 years earlier. Clinical and radiological investigation has confirmed a pure Leydig cell tumor as source of hyperandrogenism. Re-evaluation of the breast tumor immunohistochemistry has shown positive androgen receptor expression and negative expression for estrogen, progesterone and HER-2 receptors. Even though an ovarian tumor was the source of androgen excess, we discuss that AI could exert a slight contribution to patient's virilization by reducing estradiol counterbalance. Also, although the onset of hyperandrogenic symptoms was unclear, we could not exclude that the ovarian tumor had produced enough androgens to play a role in breast tumor progression. This case report supports the literature regarding the possible association between Leydig cell tumor and androgen-receptor-positive breast cancer development. Finally, progressive hyperandrogenic symptoms in postmenopause, even under AI therapy or the presence of advanced CKD, impose a more detailed investigation.

Synergistic effect of graphene oxide coated nanotised apigenin with paclitaxel (GO-NA/PTX): A ROS dependent mitochondrial mediated apoptosis in ovarian cancer.

Ovarian cancer is most lethal among all gynecologic malignancies. Paclitaxel (PTX) is well used chemotherapeutic regimen for cancer control; however its undesired toxicity has been always a matter of concern for clinicians. Here we used the graphene oxide coated nanotised apigenin (GO-NA) as chemo sensitizing agent to enhance the efficacy of paclitaxel to overcome the limitations of chemotherapy. GO and GO-Apigenin was prepared by modified Hummers method and the nanoparticles were characterized by dynamic light scattering and transmission electron microscopy Human ovarian adenocarcinomas (SKOV-3) cells was treated by DMSO, Group I (Control)-McCoy's 5A Medium, Group II-Paclitaxel (5nM) alone, Group III- Nanotised Apigenin (GO-NA-10μM) Group IV- Paclitaxel (5nM) + GO-NA (10μM). Cell viability and IC-50 value were determined by MTT assay, synergism by Compusyn software, ROS by DCFH-DA assay, SOD activity by commercially available kit and MMP were examined by JC-1 and mitotracker/DAPI staining, cell cycle by flow cytometry, mRNA and protein level of apoptotic molecules caspase-3, Bax, and Bcl-2 were detected by Real Time-PCR and Western blot respectively. Results showed that GO-NA-PTX dramatically enhanced the anti-proliferative effect in synergistic manner as compare to GO-NA and PTX alone. GO-NA-PTX significantly suppressed the SOD activity, promotes the ROS accumulation, mitochondrial depolarization, DNA integrity and cell cycle arrest collectively accord the apoptotic cell death. In addition, results of immunocytochemistry, RT-PCR and western blot also supported the apoptosis by up-regulating the bax, caspase3 and down-regulation of Bcl2. Conclusively, our data showed the GO-NA-PTX may be a promising method for ovarian cancer chemotherapy.

Targeted Therapy of Ovarian Cancer with Angiogenesis Inhibitors.

Specific blocking of interactions between ligands and receptors along the angiogenic pathways represent an effective approach for enhancing the efficacy as well as reducing adverse effects of chemotherapy. Over the past decade, there was a rapid progression in the application of this therapeutic strategy in cancer treatment. Anti-angiogenic therapy is the most promising targeted therapy for ovarian cancer. The addition of bevacizumab to conventional chemotherapy, either in the first-line setting or at disease relapse, may improve overall survival (OS) of ovarian cancer patients, at least in a subset of patients with poor prognosis. In this article, we summarize published data on the major agents used for anti-angiogenic therapy in ovarian cancers. We will review the molecular mechanisms, results of clinical trial of existing agents and describe the development of new agents. The limitations and side effects of angiogenesis inhibitor are also discussed.

MiR-1202 functions as a tumor suppressor in glioma cells by targeting Rab1A.

Aberrant expression of microRNAs correlates with the development and progression of human cancers by targeting downstream proteins. MiR-1202 is downregulated in ovarian cancer and clear cell papillary renal cell carcinoma; however, its role in glioma remains unknown. The purpose of this study was to determine the expression and the role of miR-1202 and to elucidate its regulatory mechanism in glioma. We used quantitative real-time polymerase chain reaction to measure miR-1202 expression in both glioma tissues and cell lines. The findings showed that the miR-1202 expression decreased dramatically in clinical glioma tissues and cell lines, and miR-1202 expression was inversely correlated with the expression of Rab1A. Using bioinformatics and luciferase reporter assays, we identified Rab1A as a novel and direct target of miR-1202. In vitro, overexpression of miR-1202 inhibited glioma cell proliferation and induced endoplasmic reticulum stress and apoptosis through targeting Rab1A, whereas suppression of miR-1202 promoted cell proliferation and inhibited endoplasmic reticulum stress and apoptosis. Similarly, silencing Rab1A with small interfering RNA also suppressed glioma cell growth and induced endoplasmic reticulum stress and apoptosis. Taken together, our data indicate that miR-1202 suppresses proliferation and induces endoplasmic reticulum stress and apoptosis through targeting and inhibiting Rab1A in glioma cells. These results suggest miR-1202 as a potential therapeutic target for the treatment of glioma patients.

Epidemiology of ovarian cancer: a review.

Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women in the world and the tenth most common in China. Epithelial OC is the most predominant pathologic subtype, with five major histotypes that differ in origination, pathogenesis, molecular alterations, risk factors, and prognosis. Genetic susceptibility is manifested by rare inherited mutations with high to moderate penetrance. Genome-wide association studies have additionally identified 29 common susceptibility alleles for OC, including 14 subtype-specific alleles. Several reproductive and hormonal factors may lower risk, including parity, oral contraceptive use, and lactation, while others such as older age at menopause and hormone replacement therapy confer increased risks. These associations differ by histotype, especially for mucinous OC, likely reflecting differences in etiology. Endometrioid and clear cell OC share a similar, unique pattern of associations with increased risks among women with endometriosis and decreased risks associated with tubal ligation. OC risks associated with other gynecological conditions and procedures, such as hysterectomy, pelvic inflammatory disease, and polycystic ovarian syndrome, are less clear. Other possible risk factors include environmental and lifestyle factors such as asbestos and talc powder exposures, and cigarette smoking. The epidemiology provides clues on etiology, primary prevention, early detection, and possibly even therapeutic strategies.

Judging the Fertility Protective Effect of GnRH Agonists in Chemotherapy-It Is a Matter of Perspective.

miR-762 can negatively regulate menin in ovarian cancer.

Ovarian cancer accounts for the major part of the mortality attributable to female reproductive system malignant tumors worldwide. Recently, the incidence of ovarian cancer has been increasing annually, and there remains a lack of suitable treatment methods that can significantly improve the 5-year survival rates of patients. Therefore, it is necessary to identify more effective treatments for ovarian cancer. It is established that microRNAs (miRNAs) have important roles in the diagnosis and treatment of ovarian cancer and a specific miRNA, miR-762, can promote the development of a variety of tumors. Menin is encoded by MEN1, a tumor suppressor gene, that is usually downregulated in ovarian cancer. In this study, we evaluated the expression levels of miR-762 and menin in ovarian cancer tissues and demonstrated that they were correlated. In addition, we found that miR-762 can downregulate the expression of menin through a binding site in its 3'-UTR and consequently upregulate the Wnt cell signaling pathway to promote the development of ovarian cancer. These results indicate that miR-762 is a promising potential target for the treatment of ovarian cancer.

Investigational and experimental GnRH analogs and associated neurotransmitters.

The GnRH agonistic analogs enable for desensitizing the hypothalamo-pituitary-gonadal axis in malignant and benign conditions where minimizing the production of sex hormones, or blocking ovulation is necessary. The possible indications are prostate cancer, benign prostate hyperplasia, breast cancer, endometriosis, precocious puberty, uterine leiomyomata, assisted reproduction (ART)/in vitro fertilization (IVF), PCOS, minimizing the gonadotoxic effect of chemotherapy in young women, and possibly ovarian cancer. Areas covered: The aim of the current review is to summarize, giving a critical overview, of the investigational GnRH agonists, and shortly discuss the difference between the GnRH agonists, antagonists, Kisspeptin, and Neurokinin B analogs. Expert opinion: The broad armamentarium of agonists may make it possible, in the future, to expand the indications and uses of these analogs, choosing and specifically tailoring the analog to the required effect, while minimizing side effects.

Doxorubicin-induced female reproductive toxicity: an assessment of ovarian follicular apoptosis, cyclicity and reproductive tissue histology in Wistar rats.

Doxorubicin is a widely used chemotherapeutic agent for various cancers, particularly for the female breast cancer patients. Although the rate of young female cancer patients is increasing every year, conversely the lack of knowledge of adverse effects of doxorubicin on female reproductive system insisted us to assess the toxic effects of doxorubicin on the female reproductive tissue histoarchitecture, cyclicity, and mammary glands in Wistar rats. The rats were divided into two groups depending on the treatment period, i.e., 24 h and 28 d and further subdivided into three subgroups and administered with doxorubicin at 3 mg/kg bw (subgroup I), 6 mg/kg bw (subgroup II), and equal volume of normal saline (subgroup III) intraperitoneally once during the whole treatment period. We observed a significantly altered estrous cycle with a prolonged diestrous and short proestrous in higher dose group and dose-dependent significant changes in the uteri and mammary gland histoarchitecture in 28 days treated rats as compared to control. Moreover, the micronuclei and chromosomal aberration frequency were increased significantly in both treatment groups. A significant increase in follicular atresia in ovaries of the 28 days treated rats was observed. The immunohistochemical analysis of ovarian tissues showed an increased p53 and caspase 3 expression and apoptosis in primordial follicles of treated rats. The results suggest that though doxorubicin is a potential chemotherapeutic drug for many tumors, but the risk of adverse effects on the female reproductive system is there even at low doses.

An experiment control study on the ovarian reserve function after cisplatin intraperitoneal or intravenous chemotherapy in rats model.

Objective: To compare the impact on the ovarian reserve function after cisplatin intraperitoneal or intravenous chemotherapy in rats model. Methods: Thirty 8-weeks old female Sprague Dawley rats were randomly assigned to control group (group A, n=10), intraperitoneal chemotherapy group (group B, n=10) and intravenous chemotherapy group (group C, n=10). Cisplatin was diluted by normal saline (NS) into 4 mg/ml. On the first day of chemotherapy, 0.2 ml cisplatin dilution was injected into the abdomen of rats in group B, isodose cisplatin was injected into vein and 1.8 ml NS was injected into abdomen of rats in group C, 2.0 ml NS was injected into abdomen of rats in group A for control. Feed the three groups rats and test the anti-Mullerian hormone (AMH) in serum on day 0 (just before injection), day 10 and day 20 by ELISA, count the numble of follicle in bilateral ovaries on day 20. Results: (1) The levels of serum AMH in the three groups before and after chemotherapy were compared: ① comparison between groups: On day 10 and day 20, the AMH level in group B [(64.5±2.9), (68.6±3.4) ng/L] and group C [(76.1±4.9), (91.3±3.9) ng/L] was significantly lower than that in group A [(120.1±5.3), (121.7±4.6) ng/L; P<0.01], AMH level in group B was significantly also lower than that in group C (P=0.000). ② Comparison within groups: the AMH level on day 0 was significantly lower than that on day 10 and day 20 in group A (P<0.01), but there was no significant difference between day 10 and day 20 (P=0.427). The AMH level on day 0 was significantly higher than those on day 10 and day 20 in group B (P<0.01) and group C (P<0.01). There was no difference in AMH level between day 10 and day 20 (P=0.124) in group B, but the level was significant lower on day 10 than that on day 20 in group C (P=0.011). (2)Comparison of the number of follicles in ovaries of three groups 20 days after chemotherapy: the follicles number in group A (35±13) was greater than that in group B (16±9, P=0.003) and similar with group C (31±16, P=0.474) on day 20. The follicles number in group B was significantly less than that in group C (P=0.018). Conclusions: In the present study, both intravenous and intraperitoneal chemotherapy have impacts on ovarian reserve function and the latter might be more serious. The level of AMH will rise again over time after chemotherapy and rats undergo intravenous chemotherapy would recover faster. The results suggest that the ovarian reserve function need more time to recover after intraperitoneal chemotherapy. For patients with ovarian cancer who want to preserve fertility function, intravenous chemotherapy might be more appropriate.

(188)Re-Liposome Can Induce Mitochondrial Autophagy and Reverse Drug Resistance for Ovarian Cancer: From Bench Evidence to Preliminary Clinical Proof-of-Concept.

Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, (188)Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to (188)Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.