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Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a \"freeze-all\" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p<0.01) and progesterone levels at ovulation triggering (p = 0.01) were the only two variables that significantly predicted top quality blastocyst formation rate after adjusting for relevant factors including female age, BMI, basal AMH and total dose of FSH used for COS. More specifically, progesterone levels at induction showed an inverse relation with top quality blastocyst formation (correlation coefficient B = -1.08, 95% CI -1.9 to -0.02) and ROC curve analysis identified P level >1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p<0.01). Our study is the first to investigate the top quality blastocyst formation rate in relation to progesterone levels in IVF/ICSI cycles, showing that increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are observed. This observation extends the results of two recent studies focused on day-3 embryos and deserves further research.

PurposeTo evaluate obstetric outcome in women with endometriosis who conceive naturally and receive standard obstetric care in Italy.MethodsCases were consecutive women with endometriosis managed in eleven Italian referral centers. Controls were women in whom endometriosis was excluded. All women filled in a questionnaire addressing previous natural pregnancies. Marginal logistic regression models were fitted to evaluate the impact of endometriosis on obstetric outcome. A post hoc analysis was performed within the endometriosis group comparing women with severe adenomyosis versus women with absent or mild adenomyosis.ResultsThree hundred and fifty-five pregnancies in endometriosis group and 741 pregnancies in control group were included. Women with endometriosis had a higher risk of preterm delivery < 34 weeks (6.4% vs 2.8%, OR 2.42, 95% CI 1.22–4.82), preterm delivery < 37 weeks (17.8% vs 9.7%, OR 1.98, 95% CI 1.23–3.19), and neonatal admission to Intensive Care Unit (14.1% vs 7.0%, OR 2.04, 95% CI 1.23–3.36). At post hoc analysis, women with endometriosis and severe adenomyosis had an increased risk of placenta previa (23.1% vs 1.8%, OR 16.68, 95% CI 3.49–79.71), cesarean delivery (84.6% vs 38.9%, OR 8.03, 95% CI 1.69–38.25) and preterm delivery < 34 weeks (23.1% vs 5.7%, OR 5.52, 95% CI 1.38–22.09).ConclusionWomen with endometriosis who conceive naturally have increased risk of preterm delivery and neonatal admission to intensive care unit. When severe adenomyosis is coexistent with endometriosis, women may be at increased risk of placenta previa and cesarean delivery.Trial registrationClinical trial registration number: NCT03354793.

Objective: The aim of this study is to evaluate the long-term outcome of granulosa cell tumour (GCT) of the ovary in a large series of patients treated in MITO centres (Multicentre Italian Trials in Ovarian Cancer) and to define prognostic parameters for relapse and survival. Methods: A retrospective multi-institutional review of patients with GCTs of the ovary treated or referred to MITO centres was conducted. Surgical outcome, intraoperative and pathological findings and follow-up data were analysed. Kaplan–Meier and Cox proportional hazards analyses were used to determine the predictors for survival and recurrence. Results: A total of 97 patients with primary GCT of the ovary were identified. The median follow-up period was 88 months (range 6–498). Of these, 33 patients had at least one episode of disease recurrence, with a median time to recurrence of 53 months (range 9–332). Also, 47% of recurrences occurred after 5 years from initial diagnosis. At multivariate analysis, age and stage were independent poor prognostic indicators for survival; surgical treatment outside MITO centres and incomplete surgical staging retained significant predictive value for recurrence in both univariate and multivariate analyses. Conclusions: This study confirms the generally favourable prognosis of GCTs of the ovary, with 5-year overall survival approaching 97%. Nevertheless, prognosis after 20 years was significantly poorer, with 20-year survival rate of 66.8% and a global mortality of 30–35. These findings support the need for lifelong follow-up even in early-stage GCT.

Purpose Gestational trophoblastic neoplasia (GTN) is a rare and aggressive tumour that is usually sensitive to chemotherapy. The usefulness of conventional imaging modalities in evaluating treatment response is limited, mainly due to the difficulty in differentiating between residual tumour tissue and necrosis. The aim of the present study was to evaluate the role of FDG PET or PET/CT in primary staging and in monitoring treatment efficacy. The effect of FDG PET and combined PET/CT on the management of patients with GTN was also evaluated comparing the differences between standard treatments based on conventional imaging and alternative treatments based on PET. Methods This retrospective study included 41 patients with GTN referred to San Raffaele Hospital between 2002 and 2010. All patients were studied by either PET or PET/CT in addition to conventional imaging. Of the 41 patients, 38 were evaluated for primary staging of GTN and 3 patients for chemotherapy resistance after first-line chemotherapy performed in other Institutions. To validate the PET data, PET and PET/CT findings were compared with those from conventional imaging, including transvaginal ultrasonography (TV-US) in those with uterine disease, CT and chest plain radiography in those with lung disease and whole-body CT in those with systemic metastases. Conventional imaging was considered positive for the presence of uterine disease and/or metastases when abnormal findings relating to GTN were reported. PET and PET/CT were considered concordant with conventional imaging when metabolic active disease was detected at the sites corresponding to the pathological findings on conventional imaging. In addition, in 12 of the 41 patients showing extrauterine disease, FDG PET/CT was repeated to monitor treatment efficacy, in 8 after normalization of beta human chorionic gonadotropin (βHCG) and in 4 with βHCG resistance. In some patients, PET or PET/CT findings led to an alternative nonconventional treatment, and this was considered a change in patient management for the study analysis. Results When compared to TV-US, chest radiography and CT for staging, PET showed a concordance in 91 %, 84 % and 81 % of patients, respectively. In 8 of the 41 patients with extrauterine disease during staging, PET/CT showed a complete response to therapy after βHCG normalization. PET and PET/CT identified the sites of persistent disease in all seven high-risk patients with βHCG resistance, of whom four underwent second-line chemotherapy, two surgical removal of resistant disease instead of additional chemotherapy, and one surgical removal of resistant disease and second-line chemotherapy with subsequent negative βHCG. Conclusion In staging, PET cannot replace conventional imaging and does not show any information in addition to that shown by conventional imaging. The additional value of PET/CT in GTN with respect to conventional imaging is found in patients with high-risk disease. PET can identify the sites of primary and/or metastatic disease in patients with persistent high levels of βHCG after first-line chemotherapy and may be of additional value in patient management for guiding alternative treatment.

Background An increased incidence of imprint-associated disorders has been reported in babies born from assisted reproductive technology (ART). However, previous studies supporting an association between ART and an altered DNA methylation status of the conceived babies have been often conducted on a limited number of methylation sites and without correction for critical potential confounders. Moreover, all the previous studies focused on the identification of methylation changes shared among subjects while an evaluation of stochastic differences has never been conducted. This study aims to evaluate the effect of ART and other common behavioral or environmental factors associated with pregnancy on stochastic epigenetic variability using a multivariate approach. Results DNA methylation levels of cord blood from 23 in vitro and 41 naturally conceived children were analyzed using the Infinium HumanMethylation450 BeadChips. After multiple testing correction, no statistically significant difference emerged in the number of cord blood stochastic epigenetic variations or in the methylation levels between in vitro- and in vivo-conceived babies. Conversely, four multiple factor analysis dimensions summarizing common phenotypic, behavioral, or environmental factors (cord blood cell composition, pre or post conception supplementation of folates, birth percentiles, gestational age, cesarean section, pre-gestational mother’s weight, parents’ BMI and obesity status, presence of adverse pregnancy outcomes, mother’s smoking status, and season of birth) were significantly associated with stochastic epigenetic variability. The stochastic epigenetic variation analysis allowed the identification of a rare imprinting defect in the locus GNAS in one of the babies belonging to the control population, which would not have emerged using a classical case-control association analysis. Conclusions We confirmed the effect of several common behavioral or environmental factors on the epigenome of newborns and described for the first time an epigenetic effect related to season of birth. Children born after ART did not appear to have an increased risk of genome-wide changes in DNA methylation either at specific loci or randomly scattered throughout the genome. The inability to identify differences between cases and controls suggests that the number of stochastic epigenetic variations potentially induced by ART was not greater than that naturally produced in response to maternal behavior or other common environmental factors.

Introduction/BackgroundChemotherapy-Induced Nausea (CIN) is a distressing side effect for patients undergoing chemotherapy, which deeply affects their quality of life and everyday activities. Several treatment-related and patient-related factors may be involved in the expression of CIN. This study aims to identify predictive factors for nausea after the first chemotherapy infusion in a sample of women with gynecological cancer.MethodologyOne hundred and sixty-five patients (mean age=58.23, SD=13.19) treated for gynecological cancer at the San Raffaele Hospital completed the MASCC Antiemesis Tool (MAT) in order to register the presence of acute (within 24 hours) and delayed (24–72 hours) nausea after the first chemotherapy infusion. Socio-demographic and clinical characteristics that could represent risk factors for nausea were collected with an ad hoc questionnaire designed by the research team. Logistic regression analyses were performed for predicting acute or delayed CIN; significance level was set at 0.05.ResultsSixty-three (38.7%) patients experienced acute nausea after their first chemotherapy infusion; 46% (n=75) of the sample experienced delayed nausea. Neoadjuvant (vs. adjuvant) chemotherapy represents a protective factor for delayed CIN (OR=0.350; p=0.033). Hyperemesis gravidarum and anticipatory nausea both represent risk factors for delayed nausea (OR=2.307, p=0.026; OR=4.316; p=0.004, respectively). No significant association was found with acute nausea.ConclusionDespite advancements in antiemetic therapy, results show that CIN still represents a common chemotherapy side-effect for women with gynecological cancer. Specific patient-related and treatment-related characteristics seem to influence the onset of delayed nausea after the first chemotherapy infusion. The knowledge of risk factors for CIN could help identify patients who are more vulnerable to this symptom and implement specific psychological and medical interventions in order to promote a better adjustment to the disease and its treatment.DisclosureNothing to disclose.

Abstract A network of endometriosis experts from 16 Italian academic departments and teaching hospitals distributed all over the country made a critical appraisal of the available evidence and definition of 10 suggestions regarding measures to be de-implemented. Strong suggestions were made only when high-quality evidence was available. The aim was to select 10 low-value medical interventions, characterized by an unfavorable balance between potential benefits, potential harms, and costs, which should be discouraged in women with endometriosis. The following suggestions were agreed by all experts: do not suggest laparoscopy to detect and treat superficial peritoneal endometriosis in infertile women without pelvic pain symptoms; do not recommend controlled ovarian stimulation and IUI in infertile women with endometriosis at any stage; do not remove small ovarian endometriomas (diameter <4 cm) with the sole objective of improving the likelihood of conception in infertile patients scheduled for IVF; do not remove uncomplicated deep endometriotic lesions in asymptomatic women, and also in symptomatic women not seeking conception when medical treatment is effective and well tolerated; do not systematically request second-level diagnostic investigations in women with known or suspected non-subocclusive colorectal endometriosis or with symptoms responding to medical treatment; do not recommend repeated follow-up serum CA-125 (or other currently available biomarkers) measurements in women successfully using medical treatments for uncomplicated endometriosis in the absence of suspicious ovarian cysts; do not leave women undergoing surgery for ovarian endometriomas and not seeking immediate conception without post-operative long-term treatment with estrogen–progestins or progestins; do not perform laparoscopy in adolescent women (<20 years) with moderate–severe dysmenorrhea and clinically suspected early endometriosis without prior attempting to relieve symptoms with estrogen–progestins or progestins; do not prescribe drugs that cannot be used for prolonged periods of time because of safety or cost issues as first-line medical treatment, unless estrogen–progestins or progestins have been proven ineffective, not tolerated, or contraindicated; do not use robotic-assisted laparoscopic surgery for endometriosis outside research settings. Our proposal is to better address medical and surgical approaches to endometriosis de-implementing low-value interventions, with the aim to prevent unnecessary morbidity, limit psychological distress, and reduce the burden of treatment avoiding medical overuse and allowing a more equitable distribution of healthcare resources.

Introduction/BackgroundIn high grade serous ovarian cancer(HGSOC),the association between tumor-infiltrating lymphocytes(TILs)and survival suggests a role for T cell immune surveillance. Despite this, initial attempts with PD1 checkpoint blockade and adoptive T-cell therapy(ACT) had limited efficacy. This highlights the need to characterize the phenotype of TILs and to find new potential tumor-associated antigens.Wilms tumor-1(WT-1)expression showed a prognostic significance in HGSOC, making it an interesting target.To identify molecules potentially relevant for HGSOC immunotherapy, we evaluated the expression of WT-1 and the pattern of inhibitory receptors(IRs)in TILs.MethodologyPeripheral blood(PB), tumor and ascites were retrieved from HGSOC patients admitted for primary surgery.WT-1 expression and immune infiltrate were characterized on 34 specimens by immunohistochemistry (IHC) for lineage markers and inhibitory molecules.T cells isolated from tumor, ascites and PB of 14 patients were also characterized by flow cytometry for the expression of lineage and memory markers (CD3, CD4, CD8, CD45RA, CD62L, CD95),inhibitory molecules (PD1, CTLA-4, LAG-3, TIGIT, TIM-3, 2B4, GITR, KLRG1, CD39, CD160)and the activation marker CD137.ResultsWT1 was almost uniformly expressed,with 76% of cases showing high WT1 expression in the majority of tumor cells. 6% of cases were immune desert; all other cases displayed a wide range of immune cell density, dominated by T lymphocytes and macrophages. Intratumoral T cells(ITTCs), mainly CD8, were present in 88.2% of samples. PD-1, LAG-3 and TIM-3 were expressed by 61.9%, 61.7% and 61.7% of ITTCs. PD-L1 was expressed by neoplastic cells and immune cells in 40% and 82.3% of samples.Flow cytometry confirmed the expression of several IRs.Compared with PB and ascites,TILs were enriched in effector memory lymphocytes and in cells coexpressing PD-1, CD39 and CD137.ConclusionWT-1 is a potential target for ACT in HGSOC,which is infiltrated by antigen-experienced T lymphocytes displaying features of activation and partial exhaustion.DisclosureNothing to disclose.

Human papillomavirus (HPV) testing is more sensitive and has higher negative predictive value (NPV) than the Pap test for the detection of cervical intraepithelial neoplasia (CIN) in patients with atypical squamous cells of undetermined significance (ASCUS) cytology, but has low specificity, leading to high referral rates to second-level triage. Our goal was to identify the prognostic significance of HPV viral load figures. We evaluated whether a correlation between viral load, expressed as relative light units/cutoff (RLU/CO), and the severity of cervical lesions existed in 614 ASCUS cases. Hybrid Capture 2 (HC2®) RLU/CO values, categorised into five classes, were correlated to clinical outcomes and statistically analysed. A significant correlation ( p  < 0.0001) was observed between increasing RLU values and the prevalence of high-grade CIN (CIN2/CIN3). The mean RLU values for negative, low-grade and high-grade lesions were 68.1, 172.5 and 1,020.0 RLU/CO, respectively ( p  < 0.0001). CIN2/CIN3 ranged from 4% for 0 < RLU/CO values ≤ 1, to 5% for 1 < RLU/CO values ≤ 10, to 9% for 10 < RLU/CO values ≤ 100, to 23% for 100 < RLU/CO values ≤ 1,000 and to 48% when RLU/CO values were >1,000 ( p  < 0.05). The HPV viral load in ASCUS cases significantly correlates with the severity of cervical cancer precursors. These data may have prognostic value, as they significantly correlate with the probability of a CIN2+ .

Purpose In this study we hypothesized that the mRNA vector Staufen mediates RNA relocalization during meiotic maturation, and by virtue of its interactions with endoplasmic reticulum, provides a possible mechanism by which protein synthesis is regulated. Methods We assessed the expression of staufen ( STAU ) and calreticulin ( CALR ), the latter adopted as a marker of the endoplasmic reticulum, in human oocytes at different stages of maturation: GV, metaphase MI and MII. Oocytes were subjected to polymerase chain reaction in order to investigate the expression of STAU and CALR . The corresponding protein products were identified by immunofluorescence and confocal laser scanning microscopy. Results STAU and CALR were constantly expressed and selectively localized during oocyte maturation. At the GV stage the both proteins displayed a dispersed distribution localization throughout the cytoplasm. Progressing to the MII stage, STAU tended to compartmentalize towards the cortical area of the oocyte clustering in granules of larger sizes. At the MII stage, CALR assumed a pattern reminiscent and possibly coincident with the position of the meiotic spindle. Conclusions The changing pattern of STAU distribution during meiotic maturation of human oocytes implicates a novel mechanism for the regulation of protein synthesis based on mRNA localization. Moreover, the unique disposition of CALR at the MII spindle uncovers a physical interaction with endoplasmic reticulum that may mediate cytoskeletal remodelling during oocyte maturation.