IVF in women aged 43 years and older: a 20-year experience.

RESEARCH QUESTION: What are the reproductive outcomes of women aged 43 years and older undergoing IVF and intracytoplasmic sperm injection (ICSI) treatment using their own eggs. DESIGN: Retrospective study of 833 woman aged 43 years or older undergoing their first IVF and ICSI cycle using autologous oocytes at a tertiary referral hospital between January 1995 and December 2019. Live birth rate (LBR) after 24 weeks' gestation was the primary outcome. RESULTS: Ninety-five out of 833 (11.4%) had a positive HCG, whereas 59 (62.1% per positive HCG) had a miscarriage before 12 weeks' gestation and 36 (4.3%) live births were achieved. Analysis by age showed that the number of cumulus-oocyte complexes retrieved was significantly different between the four age groups: 43 years (5 [3-9]); 44 years (5 [2-7]); 45 years (3 [2-8)]); ≥45 years (2.5 [2-6]); P < 0.01; the number of metaphase II oocytes, however, was similar. Positive HCG rates remained low: 43 years (78/580 [13.4%]); 44 years (14/192 [7.3%]); 45 years (1/39 [2.6%]; and ≥46 years (2/22 [9.1%]); P = 0.03, as did LBR: 43 years (28 [4.8%]); 44 (7 [3.6%]); 45 years (0 [0%]); and ≥46 years (1 [4.5%]); P = 0.5. Multivariate regression analysis revealed that only number of metaphase II was significantly associated with LBR, when age was considered as a continuous (OR 1.08, 96% CI 1.004 to 1.16) or categorical variable (OR 1.08, 95% CI 1.005 to 1.16). CONCLUSION: The chances of achieving a live birth in patients aged 43 years and older undergoing IVF/ICSI with their own gametes are low, even in cases of patients with a relatively 'normal' ovarian reserve for their age.

Live births following fertility preservation using in-vitro maturation of ovarian tissue oocytes.

STUDY QUESTION: Can oocytes extracted from excised ovarian tissue and matured in vitro be a useful adjunct for urgent fertility preservation (FP)? SUMMARY ANSWER: Ovarian tissue oocyte in-vitro maturation (OTO-IVM) in combination with ovarian tissue cryopreservation (OTC) is a valuable adjunct technique for FP. WHAT IS KNOWN ALREADY: Despite the impressive progress in the field, options for FP for cancer patients are still limited and, depending on the technique, clinical outcome data are still scarce. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study conducted at a university hospital-affiliated fertility clinic between January 2012 and May 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included 77 patients who underwent unilateral oophorectomy for OTC. Cumulus-oocyte complexes (COCs) obtained during ovarian tissue processing were matured in vitro for 28-42 h. Oocytes reaching metaphase II stage were vitrified or inseminated for embryo vitrification. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 1220 COCs were collected. The mean oocyte maturation rate was 39% ± 23% (SD). There were 64 patients who had vitrification of oocytes (6.7 ± 6.3 oocytes per patient). There were 13 patients who had ICSI of mature oocytes after IVM, with 2.0 ± 2.0 embryos vitrified per patient. Twelve patients have returned to the clinic with a desire for pregnancy. For seven of these, OTO-IVM material was thawed. Two patients had OTO-IVM oocytes warmed, with survival rates of 86% and 60%. After ICSI, six oocytes were fertilised in total, generating three good quality embryos for transfer, leading to a healthy live birth for one patient. In five patients, for whom a mean of 2.0 ± 0.8 (SD) embryos had been vitrified, seven embryos were warmed in total: one embryo did not survive the warming process; two tested genetically unsuitable for transfer; and four were transferred in separate cycles to three different patients, resulting in two healthy babies. In this small series, the live birth rate per patient after OTO-IVM, ICSI and embryo transfer was 43%. LIMITATIONS, REASONS FOR CAUTION: The retrospective study design and the limited sample size should be considered when interpreting results. WIDER IMPLICATIONS OF THE FINDINGS: The results of the study illustrate the added value of OTO-IVM in combination with OTC. We report the first live birth following the use of this appended technique combined with oocyte vitrification. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. M.D.V. reports honoraria for lectures in the last 2 years from MSD and Ferring, outside the submitted work, as well as grant support from MSD. The other authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Is ovarian response associated with adverse perinatal outcomes in GnRH antagonist IVF/ICSI cycles?

RESEARCH QUESTION: Is there an association between ovarian response and perinatal outcomes? DESIGN: A retrospective, single-centre cohort study including all women undergoing their first ovarian stimulation cycle in a gonadotrophin releasing hormone antagonist protocol, with a fresh embryo transfer that resulted in a singleton live birth from January 2009 to December 2015. Patients were categorized into four groups according to the number of oocytes retrieved: one to three (category 1), four to nine (category 2), 10-15 (category 3), or over 15 oocytes (category 4). RESULTS: The overall number of patients analysed was 964. No relevant statistical difference was found among neonatal outcomes across the four ovarian response categories. Neonatal weight (in grams) was comparable between all groups (3222 ± 607 versus 3254 ± 537 versus 3235 ± 575 versus 3200 ± 622; P = 0.85, in categories 1, 2, 3 and 4, respectively). No statistically significant differences were found among the ovarian response categories for birth weight z-scores (taking into account neonatal sex and delivery term). The incidence of pre-term birth and low birth weight was comparable across the different ovarian response groups (P = 0.127 and P = 0.19, respectively). Finally, the occurrence of adverse obstetric outcomes did not differ among the ovarian response categories. Multivariate regression analysis revealed that the number of oocytes was not associated with neonatal birth weight. CONCLUSIONS: No association was found between ovarian response and adverse perinatal outcomes in antagonist IVF and intracytoplasmic sperm injection cycles. Future, larger scale and prospectively designed investigations are needed to validate these results.

Severe hemoperitoneum due to endometriosis in a non-pregnant woman under dienogest therapy: a case report.

Endometriosis is a chronic, estrogen-dependent, inflammatory disease that mainly affects women of reproductive age and is defined by the presence of endometrial glands and stroma at ectopic sites. Spontaneous hemoperitoneum due to bleeding of pelvic endometriotic foci represents a very rare and severe complication of endometriosis, although most cases described in literature regard pregnant women. We hereby present a case of a severe hemoperitoneum in a non-pregnant, 42 years old woman, under dienogest therapy for deep endometriosis. This life-threatening condition was promptly managed by performing an exploratory laparoscopy where the source of bleeding was found and hemostasis successfully achieved.Bleeding from pelvic endometriotic foci ought to be considered in the differential diagnosis of gynecological causes of acute abdomen and hemoperitoneum, even under medical therapy.

Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer.

Breast cancer is the most common malignancy in women worldwide, and ovarian cancer is the most lethal gynecological malignancy. Women carrying a BRCA1/2 mutation have a very high lifetime risk of developing breast and ovarian cancer. The only effective risk-reducing strategy in BRCA-mutated women is a prophylactic surgery with bilateral mastectomy and bilateral salpingo-oophorectomy. However, many women are reluctant to undergo these prophylactic surgeries due to a consequent mutilated body perception, unfulfilled family planning, and precocious menopause. In these patients, an effective screening strategy is available only for breast cancer, but it only consists in close radiological exams with a significant burden for the health system and a significant distress to the patients. No biomarkers have been shown to effectively detect breast and ovarian cancer at an early stage. MicroRNAs (miRNAs) are key regulatory molecules operating in a post-transcriptional regulation of gene expression. Aberrant expression of miRNAs has been documented in several pathological conditions, including solid tumors, suggesting their involvement in tumorigenesis. miRNAs can be detected in blood and urine and could be used as biomarkers in solid tumors. Encouraging results are emerging in gynecological malignancy as well, and suggest a different pattern of expression of miRNAs in biological fluids of breast and ovarian cancer patients as compared to healthy control. Aim of this study is to highlight the role of the urinary miRNAs which are specifically associated with cancer and to investigate their role in early diagnosis and in determining the prognosis in breast and ovarian cancer.

Posttranslational nitration of tyrosine residues modulates glutamate transmission and contributes to N-methyl-D-aspartate-mediated thermal hyperalgesia.

Activation of the N-methyl-D-aspartate receptor (NMDAR) is fundamental in the development of hyperalgesia. Overactivation of this receptor releases superoxide and nitric oxide that, in turn, forms peroxynitrite (PN). All of these events have been linked to neurotoxicity. The receptors and enzymes involved in the handling of glutamate pathway--specifically NMDARs, glutamate transporter, and glutamine synthase (GS)--have key tyrosine residues which are targets of the nitration process causing subsequent function modification. Our results demonstrate that the thermal hyperalgesia induced by intrathecal administration of NMDA is associated with spinal nitration of GluN1 and GluN2B receptor subunits, GS, that normally convert glutamate into nontoxic glutamine, and glutamate transporter GLT1. Intrathecal injection of PN decomposition catalyst FeTM-4-PyP(5+) prevents nitration and overall inhibits NMDA-mediated thermal hyperalgesia. Our study supports the hypothesis that nitration of key proteins involved in the regulation of glutamate transmission is a crucial pathway used by PN to mediate the development and maintenance of NMDA-mediated thermal hyperalgesia. The broader implication of our findings reinforces the notion that free radicals may contribute to various forms of pain events and the importance of the development of new pharmacological tool that can modulate the glutamate transmission without blocking its actions directly.

Update on Male Infertility.

Infertility, defined as the failure to conceive after one year of regular intercourse without the use of contraception, in women less than 35 years of age remains a unique medical condition, as it involves a couple rather than a single individual [...].

Androgens and Anti-Müllerian Hormone in Infertile Patients.

To investigate whether there is an association between androgens and ovarian reserve, expressed through anti-Mullerian hormone. This is a retrospective cross-sectional analysis of all consecutive women attending a tertiary fertility center, who presented with regular menstrual cycles. Patients had their AMH values measured with the same AMH assay (Immunotech (IOT) Beckmann Coulter assay), the same day in which androgens sampling was performed. Women with PCOS or other forms of androgen excess or untreated endocrine or metabolic disorders were excluded. A total of 942 women were included. Significant correlation was observed between total testosterone/free androgens index (FAI)/DHEAS and AMH (Spearman's r = 0.20/0.14/0.13, P value < 0.001, P value < 0.001, and P value < 0.001, respectively). After multiple linear regression analysis adjusting for confounders (age, BMI, cause of infertility, day of the menstrual cycle when the blood sample was performed), the regression slope in all participants for total testosterone predicting logAMH was 0.20 (P value < 0.001). Similarly, FAI was significantly associated with logAMH (regression coefficient = 0.04, P value = 0.04). In contrast, DHEAS was not significantly associated with logAMH. There was a significant, but weak relation between testosterone and AMH, while no significant association was observed between DHEAS and AMH. Future research is needed to elucidate whether testosterone supplementation may have any effect on ovarian function.

Non-compaction cardiomyopathy in pregnancy: a case report of spongy myocardium in both mother and foetus and systematic review of literature.

PURPOSE: Cardiovascular disease is the main nonobstetric cause of maternal death during pregnancy and is present in 0.5-4% of pregnancies in the western world. While hypertensive disorders remain the most frequent events, occurring in 6-8% of all pregnancies, cardiomyopathies are rare but encompass high complication rates. The aim of this systematic review is to report all data available up to date regarding pregnancies in patients with left ventricular noncompaction (LVNC) cardiomyopathy. METHODS: PubMed, Medline, Cochrane, Scopus and Embase were searched, up to January 2019, using combinations of these terms: left ventricular noncompaction, hypertrabeculation cardiomyopathy, spongy myocardium, spongiform cardiomyopathy and delivery, gestation, pregnancy, cesarean section (CS). After careful selection, 22 articles, reporting a total of 30 cases, including our own were included in the review. RESULTS: Fifteen out of 26 women (58%) were diagnosed with LVNC before pregnancy. Around 56% of women presented with symptoms during pregnancy while 44% were asymptomatic. Heart failure is by far the most common symptom occurring in almost half the cases. Uncommon clinical presentations included a heart attack, a stroke, and pulmonary hypertension. Timing of delivery was reported preterm in 58% of cases and at term in 42%. Eleven women gave birth through vaginal delivery, while 15 (58%) underwent a CS. Our reported case is the first case of a pregnancy where both mother and fetus are affected by LVNC and the fetus is diagnosed prenatally. CONCLUSIONS: LVNC is not a contraindication for pregnancy, but clearly increases the risk of preterm birth and the rate of cesarean section. On the other hand, pregnancy in a LVNC patient exposes her to increased risk of clinical deterioration. Further studies are needed to better characterize the management of pregnancies in women with cardiomyopathies.

Update on the management of poor ovarian response in IVF: the shift from Bologna criteria to the Poseidon concept.

Despite the considerate progress to which assisted reproduction technology (ART) has been subject since 1978, some issues remain unresolved. Notably, the clinical management of patients with a poor ovarian response is still a challenge in everyday practice, frustrating to both the patient and the fertility expert. Poor ovarian responders (PORs) embody 9-24% of patients undergoing ovarian stimulation, meaning that up to one in four patients conceals a poor reproductive prognosis. The last decade has witnessed the attempts of the medical community to standardize diagnosis of POR with the developing of the Bologna Criteria and the subsequent evolution of the low prognosis patient elaborated in the POSEIDON classification. The aim of this article is to summarize all evidence concerning etiology and management of poor ovarian response, including the most recent advances and future prospects in this regard.

Low Testosterone and Semen Parameters in Male Partners of Infertile Couples Undergoing IVF with a Total Sperm Count Greater than 5 Million.

Low serum testosterone is found in approximately 15% of subfertile men. Although testosterone is essential in spermatogenesis, it is unclear whether low testosterone levels may have a negative impact on the semen parameters of men belonging to infertile couples with a total sperm count greater than 5 million. Furthermore, it is debatable whether the initial evaluation of the subfertile male should include an endocrine assessment. This was a retrospective, single-center cohort study conducted at a tertiary fertility clinic. Male partners of infertile couples undergoing in vitro fertilization (IVF), with a total sperm count greater than 5 million, were included. All men provided morning blood samples, and none had been on exogenous testosterone or other relevant medications. Low total testosterone (TT) was defined as <264 ng/dL. Free T was calculated using TT and sex hormone-binding globulin (SHBG) levels (nmol/L) by a constant albumin concentration of 43 g/L. In total, 853 patients were included: 116 had low TT (<264 ng/dL) and 737 had normal TT (≥264 ng/dL). Semen volume, sperm cell count, progressive (A + B) motility and morphology (≥4% strict Kruger) were lower in the low TT group but not significantly different between low and normal TT groups (3.2 ± 1.79 vs. 3.23 ± 1.64, p = 0.87; 76.82 ± 83.18 vs. 67.55 ± 57.70, p = 0.7; 54.89 ± 19.45 vs. 56.25 ± 19.03, p = 0.6; 5.77 ± 3.23 vs. 6.89 ± 3.94, p = 0.23). The percentage of patients with below-reference sperm volume (<1.5 mL), cell count (<15 × 106/mL), motility (A + B) (<32%) and morphology (<4%) was higher in the low TT group but not statistically different compared to the normal TT group. Multivariable regression analysis revealed that low TT and free T levels had no significant effect on the aforementioned semen parameters (coefficient: 3.94, 0.88, 1.37, 0.39; p = 0.53, 0.8, 0.3, 0.2; coefficient: 0.001, 0.06, 0.007, 0.0002; p = 0.73, 0.52, 0.85, 0.98). Despite our robust methodological approach, the presence of biases related to retrospective design cannot be excluded. Our findings highlighted the lack of association between low TT levels and semen parameter alterations in male partners of infertile couples undergoing IVF, with a total sperm count greater than 5 million. However, it is important to emphasize that more patients in the low TT group had subnormal semen parameters, albeit the difference was not statistically significant. Larger, prospective studies are warranted in order to validate these findings, as well as to investigate the existence of a TT threshold below which semen parameters might be negatively affected.

Heterogeneity Among Poor Ovarian Responders According to Bologna Criteria Results in Diverging Cumulative Live Birth Rates.

Research Question: Does reproductive outcome differ among the various subgroups of poor ovarian responders according to the Bologna criteria? Design: This was a retrospective, cohort study including poor ovarian responders according to Bologna criteria, undergoing an ICSI cycle from January 2011 until December 2017. Patients were divided into four groups: (1) age ≥ 40 years and abnormal ovarian response test, (2) age ≥ 40 years, abnormal ovarian reserve test and one previous poor response to stimulation, (3) age ≥ 40 years and one previous poor response, (4) abnormal ovarian reserve test and one previous poor response. Result(s): Overall, 846 cycles in 706 Bologna poor ovarian responders were included: 310 cycles in group 1, 169 in group 2, 52 in group 3, and 315 in group 4. There were significant differences in age, antral follicle count, antimüllerian hormone, cycle cancellation rates, and number of retrieved oocytes between the four groups. Live birth and cumulative live birth rate differed significantly between groups and were highest in Group 4 [Live birth rate: 7.4% (1) vs. 4.1% (2) vs. 5.8% (3) vs. 13.4% (4), p = 0.001 and Cumulative live birth rate: 8.3% (1) vs. 4.1 % (2) vs. 9.6% (3) vs. 16.8% (4) p < 0.001]. The multivariate GEE analysis revealed that the number of MIIs and the Bologna criteria pattern were the variables which were significantly associated with cumulative live birth rate. Conclusion(s): Poor ovarian responders represent a heterogeneous population. The young subpopulation has a better clinical prognosis in terms of fresh and cumulative live birth rate.

Management of morbidity associated with pancreatic resection during cytoreductive surgery for epithelial ovarian cancer: A systematic review.

INTRODUCTION: In ovarian cancer (OC), survival benefit in case of complete cytoreduction with absence of residual tumor has been clearly demonstrated; however, it often requires extensive surgery. Particularly, pancreatic resection during cytoreduction, may severely impact perioperative morbidity and mortality. OBJECTIVES: The aim of this systematic review is to evaluate complication rates and related optimal management of ovarian cancer patients undergoing pancreatic resection as part of cytoreductive surgery. METHODS: Literature was searched for relevant records reporting distal pancreatectomy for advanced ovarian cancer. All cohorts were rated for quality. We focused our analysis on complications related to pancreatic surgical procedures evaluating the following outcomes: pancreatic fistula (PF), abdominal abscess, pancreatitis, iatrogenic diabetes, hemorrhage from splenic vessels and pancreatic-surgery-related mortality. RESULTS: The most frequent complication reported was PF. Similar rates of PF were reported after hand-sewn (20%) or stapled closure (24%). Continued drainage is the standard treatment, and often, the leak can be managed conservatively and does not require re-intervention. Abdominal abscess is the second most frequent complication and generally follows a non-adequately drained PF and often required re-laparotomy. Pancreatitis is a rare event that could be treated conservatively; however, death can occur in case of necrotic evolution. Cases of post-operative hemorrhage due to splenic vessel bleeding have been described and represent an emergency. CONCLUSIONS: Knowledge of pancreatic surgery and management of possible complications ought to be present in the oncologic-gynecologic armamentarium. All patients should be referred to specialized, dedicated, tertiary centers in order to reduce, promptly recognize and optimally manage complications.

Etirinotecan pegol in women with recurrent platinum-resistant or refractory ovarian cancer.

Introduction: A PEGylated form of irinotecan, a topoisomerase I inhibitor, is now available in commerce; its safety and efficacy have been tested in platinum resistant/refractory ovarian cancer (PROC) patients. This novel agent is known as Etirinotecan Pegol (EP). EP, like irinotecan, exerts its action through its principal metabolite SN-38. Areas covered: This drug evaluation article focuses on the most recent investigations and clinical progress regarding EP, a long-acting polymer conjugate of irinotecan for the treatment of PROC. Expert opinion: EP provides prolonged and continuous exposure of SN-38 in tumors, when compared to its parent drug irinotecan. Results from phase II studies are comparable in terms of efficacy to other agents of proven use in PROC. A limitation of the use of EP is the schedule-dependent toxicities (mainly diarrhea and dehydration). In the future, EP could be investigated in association with other agents, even in attempts to restore sensitivity to other treatments. PROC remains a very difficult setting and EP might be a valid agent for patients with good performance status that have exhausted therapeutic options. In such a setting, participation in clinical trials is strongly encouraged.

Parp inhibitors as maintenance treatment in platinum sensitive recurrent ovarian cancer: An updated meta-analysis of randomized clinical trials according to BRCA mutational status.

OBJECTIVE: This meta-analysis investigated the effectiveness of PARP inhibitors (PARPis) as maintenance treatment in platinum sensitive recurrent ovarian cancer (ROC), stratifying results based on BRCA mutational status into five different categories: whole population, germ-line BRCA mutated patients, somatic BRCA mutated patients, HRD patients and wild type population. METHODS: PubMed, Medline, Scopus, EMBASE and clinicaltrials.gov, as well as meeting proceedings were searched for eligible studies that described RCTs testing the efficacy of PARPis as maintenance treatment in platinum sensitive ROC. Data were extracted independently and analysed using RevMan statistical software version 5.3. Primary end-point was progression free survival (PFS). RESULTS: The analysis confirmed the positive effect of PARPis in patients with platinum sensitive ROC in case of germinal or somatic BRCA mutations. Specifically, HR for PFS was 0.26, 95% CI 0.21-0.31, p < 0.00001 for the mutation of BRCA gene and 0.24, 95%, CI 0.12-0.48, p < 0.0001 for the somatic alteration. In addition, in the HRD population, studies that analysed the efficacy of PARPis  reported a PFS improvement with HR 0.34, 95% CI 0.26-0.43, p < 0.00001. Finally, our analysis confirms the role of these drugs in prolonging PFS in the whole population with HR 0.36, 95% CI 0.32-0.42, p < 0.00001, although to a lesser extent, with a significant improvement even in wild type cancers with HR 0.49, 95%, CI 0.41-0.59, p < 0.00001). CONCLUSIONS: PARPis are effective regardless of BRCA mutational status. Future investigations are necessary to explore the use of different PARPis as monotherapy, comparing them among each other in terms of efficacy and toxicity, and exploring their potential re-use.

Rucaparib: An emerging parp inhibitor for treatment of recurrent ovarian cancer.

Recently, Poly-ADP-Ribose Polymerase (PARP) inhibitors are one of the most intensively studied group of antiblastic agents for the management of recurrent ovarian cancer. Among this family, Olaparib was the first to be approved by European Medicines Agency as maintenance therapy post-response to platinum-based chemotherapy for recurrent ovarian cancer in women with deleterious BRCA1/2 mutation. Following that, the Food and Drug Administration (FDA) approved Olaparib monotherapy as fourth or later line of treatment in advanced ovarian cancer with deleterious germ-line BRCA1/2 mutation. On March 2017, Niraparib, was approved as maintenance treatment of patients with recurrent epithelial ovarian, who are in complete or partial response to platinum-based chemotherapy, independently of BRCA mutation. Rucaparib inhibits PARP-1, 2 and 3, PARP-4, -12, -15 and -16, as well as tankyrase 1 and 2. On December 2016, it was granted accelerated approval by the FDA, based on data from two multicenter, single arm, phase II trials that evaluated the efficacy of Rucaparib in patients with deleterious, germline and/or somatic BRCA mutation-associated, advanced OC, who have been treated with two or more lines of chemotherapy. The maximum tolerated dose reported was 600 mg twice a day administered orally. Phase III studies are currently ongoing to further validate the efficacy of Rucaparib in the treatment setting and explore its usefulness in a maintenance setting as well. The focus of our review is to report the most recent investigations and clinical progress regarding Rucaparib for treatment of recurrent ovarian cancer.

Fertility preservation in ovarian tumours.

A considerable number of patients with a cancer diagnosis are of childbearing age and have not satisfied their desire for a family. Despite ovarian cancer (OC) usually occurring in older patients, 3%-14% are diagnosed at a fertile age with the overall 5-year survival rate being 91.2% in women ≤44 years of age when it is found at 1A-B stage. In this scenario, testing the safety and the efficacy of fertility sparing strategies in OC patients is very important overall in terms of quality of life. Unfortunately, the lack of randomised trials to validate conservative approaches does not guarantee the safety of fertility preservation strategies. However, evidence-based data from descriptive series suggest that in selected cases, the preservation of the uterus and at least one part of the ovary does not lead to a high risk of relapse. This conservative surgery helps to maintain organ function, giving patients of childbearing age the possibility to preserve their fertility. We hereby analysed the main evidence from the international literature on this topic in order to highlight the selected criteria for conservative management of OC patients, including healthy BRCA mutations carriers.

Bartholin gland cancer.

INTRODUCTION: Bartholin gland carcinoma is an extremely rare condition. Because of its, phase III trials have not been carried out, there exists no unanimous consensus on treatment and guidelines are missing. METHODS: All studies reporting cases of Bartholin cancer were collected and screened for the evaluations. Baseline characteristics of studies were extracted and were queried in a database. RESULTS: A total number of 133 manuscripts collected were available for the review process, representing a total number of 275 reported cases. The histological type of Bartholin gland cancer was specified in 90.4% cases: 30.7% cases were squamous cell carcinoma, 29.6% adenoid cystic carcinoma, 25% adenocarcinomas. At multivariate analysis adenocarcinoma histotype and positive lymph node were statistical correlated with worse prognosis. CONCLUSION: Bartholin gland cancer remains a challenge for gynecologic oncologists. To better understand and treat this disease, centralization to referral centers and design of multi institutional trials is crucial.

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents.