Claudia Sergiampietri

Micro-RNAs and ovarian cancer: the state of art and perspectives of clinical research

Abstract Dysregulation of microRNA (mi-RNA) expression plays a major role in the development and progression of most human malignancies. Members of the miR-200 family, miR-182, miR-214 and miR-221 are frequently up-regulated, whereas miR-100, let-7i, miR-199a, miR-125b, mir-145 and miR-335 are often down-regulated in ovarian cancer compared with normal ovarian tissue. Most mi-RNA signatures are overlapping in different tumor histotypes but some mi-RNAs seem to be histotype specific. For instance, the endometrioid type shares with the serous and clear cell types the up-regulation of miR-200 family members, but also presents over-expression of miR-21, miR-202 and miR-205. Clear cell carcinoma has a significantly higher expression of miR-30a and miR-30a*, whereas mucinous histotype has elevated levels of miR-192/194. In vitro and in vivo investigations have shown that several mi-RNAs can modulate the sensitivity of ovarian cancer to platinum and taxane, and clinical studies have suggested that mi-RNA profiling may predict the outcome of patients with this malignancy. Some mi-RNAs could be used as biomarkers to identify patients that might benefit from the addition of molecularly targeted agents (i.e. anti-angiogenic agents, MET inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors) to standard chemotherapy. Moreover, mi-RNAs could represent potential targets for the development of novel therapies.

Antiangiogenic agents in gynecological cancer: State of art and perspectives of clinical research.

Vascular endothelial growth factor [VEGF] pathway, which plays a key role in angiogenesis, may be blocked by either extracellular interference with VEGF itself (bevacizumab [BEV] or aflibercept), or intracytoplasmic inhibition of VEGF receptor (pazopanib, nintedanib, cediranid, sunitinib and sorafenib). An alternative approach is represented by trebananib, a fusion protein that prevents the interaction of angiopoietin [Ang]-1 and Ang-2 with Tie2 receptor on vascular endothelium. The combination of antiangiogenic agents, especially BEV, and chemotherapy is a rational therapeutic option for primary or recurrent ovarian carcinoma. However, it will be difficult to accept that it represents the new standard treatment, until biological characterization of ovarian carcinoma has not identified subsets of tumors with different responsiveness to BEV. Anti-angiogenesis is an interesting target also for recurrent cervical or endometrial cancer, but nowadays the use of anti-angiogenic agents in these malignancies should be reserved to patients enrolled in clinical trials.

Alternatives to risk-reducing surgery for ovarian cancer

BRCA1 and BRCA2 mutation carriers have an 18%-60% and 11%-27% lifetime risk of developing ovarian carcinoma, respectively. Prophylactic bilateral salpingo-oophorectomy reduces the risk of this malignancy by up to 96%. Gynecological screening programs with periodical trans-vaginal ultrasound and serum CA125 assay have been widely used in women at hereditary high risk of ovarian carcinoma, but clinical results have been conflicting. These surveillance protocols have often fallen short of expectations because of the advanced stage of ovarian carcinoma in the identified screened women. Several investigations have been addressed to the detection of additional tumor markers able to generate more reliable screening tools. The combined serum assay of leptin, prolactin, osteopontin, CA125, macrophage inhibiting factor and insulin-like growth factor-II appears to have a significant better diagnostic reliability compared with serum CA125 alone in discriminating healthy individuals from ovarian carcinoma patients, and therefore, it could have a role in the screening of women at high risk for this malignancy. As far as chemoprevention is concerned, oral contraceptives significantly reduce the ovarian carcinoma risk also in BRCA mutation carriers, whereas the efficacy of fenretinide is still under investigation.

Squamous cell carcinoma of the vagina: natural history, treatment modalities and prognostic factors

Squamous cell carcinoma of the vagina accounts for less than 2% of all gynecologic malignancies. Surgery has a role in selected cases only. The standard treatment is radiotherapy, external beam radiation and/or brachytherapy, depending on the extent, thickness, location and morphology of the lesion. The role of chemotherapy is still under evaluation. Radiotherapy obtained 5-year overall survival rates ranged from 35% to 78%, with severe late complication rates of 9.4-23.1%. Tumor stage is the strongest prognostic factor. Tumor size >4cm, tumor location outside the upper third of the vagina, and old age at presentation are additional predictors of poor survival in most papers, whereas the prognostic value of histological grade, prior hysterectomy, and hemoglobin levels is controversial. High-risk HPV DNA and low MIB-1 index are associated with better clinical outcome. Because of the rarity of this tumor, future multicenter studies would be strongly warranted.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option

Abstract The limited efficacy of endocrine therapy and chemotherapy has stimulated several researches aimed to detect novel molecularly target therapies for advanced, persistent or recurrent endometrial cancer. Prior attempts to block vascular endothelial growth factor (VEGF) with sunitinib, sorafenib and thalidomide have obtained disappointing results. Bevacizumab has shown a promising activity in a phase II study. The percentages of patients with progression-free survival ≥6 months were similar for endometrioid (35%) and serous carcinoma (36%), but the number of cases was too small to assess the relevance of histological type for response to bevacizumab. In a phase II study, aflibercept was administered every 2 weeks to women with recurrent or persistent disease after chemotherapy. Forty-one percent of the patients were progression-free at 6 months, but 32% of the women had been removed from study because of toxicity. The detection of activating mutations of Fibroblast Growth Factor Receptor (FGFR)-2 in primary endometrial carcinoma has generated a new avenue for the development of molecularly target agents. Dovitinib, a tyrosine kinase inhibitor targeting both VEGF receptor (VEGFR) and FGFRs, is under clinical investigation in different malignancies including endometrial cancer.

Ovarian response to controlled ovarian stimulation in women with different polycystic ovary syndrome phenotypes

Abstract Controlled ovarian stimulation (COH) in PCOS is a challenge for fertility expert both ovarian hyperstimulation syndrome (OHSS) and oocytes immaturity are the two major complication. Ovarian response to COH vary widely among POCS patients and while some patients are more likely to show resistance to COH, other experienced an exaggerated response. The aim of our study is to investigate a possible correlation between PCOS phenotypes and the variety of ovarian response to COH and ART outcomes in patients with different PCOS phenotypes. We retrospectively analyzed a total of 71 cycles performed in 44 PCOS infertile patients attending ART at Centre of Infertility and Assisted Reproduction of Pisa University between January 2013 and January 2016. Patientsundergoing IVF with GnRH-antagonist protocol and 150–225 UI/days of recombinant FSH; triggering was carried out using 250 mg of recombinant hCG or a GnRH analogous on the basis of the risk to OHSS. We observed that Phenotype B had a tendency to have a greater doses of gonadotropins used respect to all phenotypes. Phenotype A group showed a greater serum estrogen levels compared to all phenotypes groups, a greater number of follicles of diameter between 8–12 mm found by ultrasound on the day of triggering and a greater mean number of freeze embryo. Additionally serum AMH and antral follicles count (AFC) follow the same trend in the different phenotypes ad they were significantly higher in phenotype A and in phenotype D. In conclusion this study shows that the features of PCOS phenotypes reflect the variety of ovarian response to COH as well as the risks to develop OHSS. Serum AMH and AFC are related to the degree of ovulatory dysfunction making these ‘added values’ in identifying the different PCOS phenotypes. Phenotype A seems to be the phenotype with the higher risk to develop OHSS and the use of GnRH as a trigger seems to improve oocyte quality. To classify PCOS phenotype at diagnosis might help clinicians to identify patients at greater risk of OHSS, customize therapy and subsequently plan the trigger agent.

Fertility outcome of breast cancer and Hodgkin’s lymphoma female survivors: a growing clinical challenge for gynecologists and oncologists

Abstract The issue of taking into consideration future fertility in young women with breast cancer and Hodgkin’s lymphoma [HL] will become more and more common and represent a growing clinical challenge for gynecologists and oncologists. The present paper will review literature data on the attempts of preventing chemotherapy-induced ovarian damage in these women and on their fertility outcome. Gonadotropin-releasing hormone [Gn-RH] agonists have been widely investigated as agents able to prevent ovarian failure in animal models and in humans. The majority of the studies on women with breast cancer and HL have shown a protective effect of Gn-RH agonists. A recent meta-analysis of five randomized trials, including 528 premenopausal breast cancer patients, revealed that relative risk [RR] of developing premature ovarian failure within one year was 0.40 (95% confidence interval [CI] = 0.21–0.75) for the women who received Gn-RH agonists with chemotherapy compared to those who received chemotherapy alone. However, the concurrent administration of Gn-RH agonists during chemotherapy appeared to have no effect on spontaneous pregnancy rates. Limited information are available about pregnancies in breast cancer and HL survivors, but the current literature appears to show no apparent increase in pregnancy complications, spontaneous abortions, or congenital abnormalities compared to general obstetric population.

PCOS and pregnancy: a review of available therapies to improve the outcome of pregnancy in women with polycystic ovary syndrome

ABSTRACT Introduction: Polycystic ovary syndrome (PCOS) is a common cause of female infertility affecting multiple aspects of a women’s health. Areas covered: The aim of this review is to summarize the existing evidence on the treatment of PCOS patients and to examine the actual available therapies to overcome the problem of infertility and improve the outcome of pregnancy. We analyse different treatment strategies such as lifestyle modification, bariatric surgery, insulin sensitizing agents, inositol, clomiphene citrate (CC), aromatase inhibitors, gonadotrophins, laparoscopic ovarian drilling, and assisted reproductive techniques (ART). Expert commentary: Lifestyle modification is the best initial management for obese PCOS patients seeking pregnancy and insulin sensitizing agents seem to have an important role in treating insulin resistance. Up to now, CC maintains a central role in the induction of ovulation and it has been confirmed as the first-line treatment; the use of gonadotrophins is considered the second-line in CC resistant patients; laparoscopic ovarian drilling is an alternative to gonadotrophins in patients who need laparoscopy for another reason. However, in anovulatory patients, ART represents the only possible alternative to obtain pregnancy. Larger and well-designed studies are needed to clarify the best way to improve the outcome of pregnancy in PCOS women.