Sexual functioning in women with functional hypothalamic amenorrhea: exploring the relevance of an underlying polycystic ovary syndrome (PCOS)-phenotype.

PURPOSE: To study sexual function and distress in women with functional hypothalamic amenorrhea (FHA) compared to women with FHA and an underlying polycystic ovary syndrome (PCOS)-phenotype, considering also their psychometric variables. As a secondary aim, we explored the relationship between sexual functioning and hormonal milieu in these women. METHODS: This is a retrospective cross-sectional study conducted on 36 women with typical FHA and 43 women with FHA + PCOS-phenotype. The following validated psychometric questionnaires were administered: Female Sexual Functional Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Body Attitude Test (BAT), Bulimia Investigation Test (BITE), State Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Multidimensional Perfectionism Scale (MPS). Available hormones to formulate FHA diagnosis in the standard routine were considered. RESULTS: Women with typical FHA reported a significantly lower FSFI total score than women with FHA + PCOS-phenotype (95% CI for median 16-21.3 vs. 21.1-24.1, p = 0.002), whereas the FSDS-R score was similar in the two groups (95% CI for median 6-16 vs. 6-16.3). No statistically significant differences were evident in body attitude, state and trait anxiety, depression, bulimic risk, and perfectionism between the two groups, confirming the two FHA groups were superimposable from a psychometric perspective. State anxiety correlated negatively with the FSFI total score in both typical FHA (rho: - 0.33, p = 0.05) and FHA + PCOS-phenotype (rho: - 0.40, p = 0.009). In the entire study population, a positive correlation was found between luteinizing hormone, androstenedione, and 17ß-estradiol and the total FSFI score (rho: 0.28, p = 0.01; rho: 0.27, p = 0.01, rho: 0.27, p = 0.01, respectively). CONCLUSION: Women with FHA showed a very high rate of sexual symptoms as part of their condition, but those with a typical diagnosis displayed a more severe sexual impairment as compared with the FHA + PCOS-phenotype, in spite of a similar psychometric profile. Sexual distress was equally present in both groups (approximately 4 out of 10 women). Further studies should be designed to investigate the potential role of sex hormones, mainly LH-driven androstenedione, in influencing women's sexual functioning.

Single-cell DNA-seq depicts clonal evolution of multiple driver alterations in osimertinib-resistant patients.

BACKGROUND: The development of targeted agents, such as osimertinib for EGFR-mutated non-small-cell lung cancer (NSCLC), has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinib-resistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whether those alterations and the activating EGFR mutations occur within a single cancer cell or in distinct cell populations is largely debated. PATIENTS AND METHODS: Tumor sequencing was used to identify the acquired resistance mechanisms to osimertinib in the MATCH-R trial (NCT0251782). We implemented single-cell next-generation sequencing to investigate tumor heterogeneity on patient's frozen tissues in which multiple alterations have been identified. Patient-derived models, cell lines, and patient-derived xenografts were exposed to specific inhibitors to investigate combination treatment strategies. RESULTS: Among the 45 patients included in MATCH-R who progressed on osimertinib, 9 developed a second targetable alteration (n = 2 FGFR3-TACC3, n = 1 KIF5B-RET, n = 1 STRN-ALK fusions; n = 2 BRAFV600E, n = 1 KRASG12V, n = 1 KRASG12R, n = 1 KRASG12D mutations). Single-cell analysis revealed that the two driver alterations coexist within one single cancer cell in the four patients whose frozen samples were fully contributive. A high degree of heterogeneity within samples and sequential acquisitions of molecular events were highlighted. A combination treatment concomitantly targeting the two driver alterations was required on the corresponding patient-derived models to restore cell sensitivity, which was consistent with clinical data showing efficacy of brigatinib in the patient with ALK fusion after progression to osimertinib and crizotinib administered sequentially. CONCLUSIONS: Distinct molecular driver alterations at osimertinib resistance coexist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.

The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer.

BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology. PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes. RESULTS: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%). CONCLUSIONS: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.

Third-trimester ultrasound for antenatal diagnosis of placenta accreta spectrum in women with placenta previa: results from the ADoPAD study.

OBJECTIVE: To evaluate the performance of third-trimester ultrasound for the diagnosis of clinically significant placenta accreta spectrum disorder (PAS) in women with low-lying placenta or placenta previa. METHODS: This was a prospective multicenter study of pregnant women aged ≥ 18 years who were diagnosed with low-lying placenta (< 20 mm from the internal cervical os) or placenta previa (covering the internal cervical os) on ultrasound at ≥ 26 + 0 weeks' gestation, between October 2014 and January 2019. Ultrasound suspicion of PAS was raised in the presence of at least one of these signs on grayscale ultrasound: (1) obliteration of the hypoechogenic space between the uterus and the placenta; (2) interruption of the hyperechogenic interface between the uterine serosa and the bladder wall; (3) abnormal placental lacunae. Histopathological examinations were performed according to a predefined protocol, with pathologists blinded to the ultrasound findings. To assess the ability of ultrasound to detect clinically significant PAS, a composite outcome comprising the need for active management at delivery and histopathological confirmation of PAS was considered the reference standard. PAS was considered to be clinically significant if, in addition to histological confirmation, at least one of these procedures was carried out after delivery: use of hemostatic intrauterine balloon, compressive uterine suture, peripartum hysterectomy, uterine/hypogastric artery ligation or uterine artery embolization. The diagnostic performance of each ultrasound sign for clinically significant PAS was evaluated in all women and in the subgroup who had at least one previous Cesarean section and anterior placenta. Post-test probability was assessed using Fagan nomograms. RESULTS: A total of 568 women underwent transabdominal and transvaginal ultrasound examinations during the study period. Of these, 95 delivered in local hospitals, and placental pathology according to the study protocol was therefore not available. Among the 473 women for whom placental pathology was available, clinically significant PAS was diagnosed in 99 (21%), comprising 36 cases of placenta accreta, 19 of placenta increta and 44 of placenta percreta. The median gestational age at the time of ultrasound assessment was 31.4 (interquartile range, 28.6-34.4) weeks. A normal hypoechogenic space between the uterus and the placenta reduced the post-test probability of clinically significant PAS from 21% to 5% in women with low-lying placenta or placenta previa in the third trimester of pregnancy and from 62% to 9% in the subgroup with previous Cesarean section and anterior placenta. The absence of placental lacunae reduced the post-test probability of clinically significant PAS from 21% to 9% in women with low-lying placenta or placenta previa in the third trimester of pregnancy and from 62% to 36% in the subgroup with previous Cesarean section and anterior placenta. When abnormal placental lacunae were seen on ultrasound, the post-test probability of clinically significant PAS increased from 21% to 59% in the whole cohort and from 62% to 78% in the subgroup with previous Cesarean section and anterior placenta. An interrupted hyperechogenic interface between the uterine serosa and bladder wall increased the post-test probability for clinically significant PAS from 21% to 85% in women with low-lying placenta or placenta previa and from 62% to 88% in the subgroup with previous Cesarean section and anterior placenta. When all three sonographic markers were present, the post-test probability for clinically significant PAS increased from 21% to 89% in the whole cohort and from 62% to 92% in the subgroup with previous Cesarean section and anterior placenta. CONCLUSIONS: Grayscale ultrasound has good diagnostic performance to identify pregnancies at low risk of PAS in a high-risk population of women with low-lying placenta or placenta previa. Ultrasound may be safely used to guide management decisions and concentrate resources on patients with higher risk of clinically significant PAS. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Antibiotic-exposed patients with non-small-cell lung cancer preserve efficacy outcomes following first-line chemo-immunotherapy.

BACKGROUND: Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes to chemo-immunotherapy combinations is still unknown. PATIENTS AND METHODS: In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions. RESULTS: Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 [95% confidence interval (CI): 0.91-2.22]; P = 0.1207} and PFS [HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552], compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS [HR = 1.29 (95% CI: 0.91-1.84); P = 0.149] and PFS [HR = 1.20 (95% CI: 0.89-1.63); P = 0.222] when evaluated as time-varying covariate in multivariable analysis. CONCLUSIONS: In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed.

Serial cervical-length measurements after first episode of threatened preterm labor improve prediction of spontaneous delivery prior to 37 weeks' gestation.

OBJECTIVE: To assess whether repeat cervical-length (CL) measurement in women discharged from hospital after their first episode of threatened preterm labor can predict their risk of spontaneous preterm birth. METHODS: This was a secondary analysis of a randomized controlled trial of maintenance tocolysis, in which CL was measured on transvaginal ultrasound at the time of hospital discharge and after 2, 4, 8 and 12 weeks, in women who remained undelivered after their first episode of threatened preterm labor. After univariate analysis, multivariate logistic regression analysis was used to assess whether CL < 10 mm at the time of hospital discharge or at any follow-up evaluation could predict spontaneous delivery prior to 37 weeks of gestation. RESULTS: Of 226 women discharged after a diagnosis of threatened preterm labor, 57 (25.2%) delivered spontaneously prior to 37 weeks' gestation. The risk of spontaneous preterm birth was higher among women with CL < 10 mm at hospital discharge compared to those with CL ≥ 10 mm (adjusted odds ratio (aOR), 3.3; 95% CI, 1.2-9.2). Moreover, spontaneous preterm delivery was more common when CL < 10 mm was detected up to 2 weeks (aOR, 2.9; 95% CI, 1.1-7.3) or up to 4 weeks (aOR, 7.3; 95% CI, 2.3-22.8) post discharge, as compared with when CL was persistently ≥ 10 mm. The association was not significant when considering CL measurements at 8 weeks, and there was insufficient information to assess the effect of measurements obtained at 12 weeks. CONCLUSIONS: Women who remain undelivered after their first episode of threatened preterm labor continue to be at high risk of spontaneous preterm birth if their CL is below 10 mm at the time of hospital discharge or at any follow-up visit up to 4 weeks later. CL measurement could be included in the antenatal care of these women in order to stratify their risk of preterm birth, rationalize resource utilization and help clinicians improve pregnancy outcome. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis.

OBJECTIVE: To report mode of delivery and immediate neonatal outcome in women infected with COVID-19. DESIGN: Retrospective study. SETTING: Twelve hospitals in northern Italy. PARTICIPANTS: Pregnant women with COVID-19-confirmed infection who delivered. EXPOSURE: COVID 19 infection in pregnancy. METHODS: SARS-CoV-2-infected women who were admitted and delivered from 1 to 20 March 2020 were eligible. Data were collected from the clinical records using a standardised questionnaire on maternal general characteristics, any medical or obstetric co-morbidity, course of pregnancy, clinical signs and symptoms, treatment of COVID 19 infection, mode of delivery, neonatal data and breastfeeding. MAIN OUTCOME AND MEASURES: Data on mode of delivery and neonatal outcome. RESULTS: In all, 42 women with COVID-19 delivered at the participating centres; 24 (57.1%, 95% CI 41.0-72.3) delivered vaginally. An elective caesarean section was performed in 18/42 (42.9%, 95% CI 27.7-59.0) cases: in eight cases the indication was unrelated to COVID-19 infection. Pneumonia was diagnosed in 19/42 (45.2%, 95% CI 29.8-61.3) cases: of these, 7/19 (36.8%, 95% CI 16.3-61.6) required oxygen support and 4/19 (21.1%, 95% CI 6.1-45.6) were admitted to a critical care unit. Two women with COVID-19 breastfed without a mask because infection was diagnosed in the postpartum period: their newborns tested positive for SARS-Cov-2 infection. In one case, a newborn had a positive test after a vaginal operative delivery. CONCLUSIONS: Although postpartum infection cannot be excluded with 100% certainty, these findings suggest that vaginal delivery is associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn. TWEETABLE ABSTRACT: This study suggests that vaginal delivery may be associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn.

Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer.

Lung cancer represents the leading cause of cancer-related deaths worldwide. Despite great advances in its management with the recent emergence of molecular targeted therapies for non-small-cell lung cancer (NSCLC), relapse of the metastatic disease always occurs within approximately one year. Epidermal growth factor receptor (EGFR) mutant tumours are the prime example of oncogene addiction and clonal evolution in oncology, regarding the emergence of resistance to first- and second-generation EGFR inhibitors. Multiple studies have revealed that the EGFR-T790M gatekeeper mutation is the main cause of tumour escape. Recently, irreversible pyrimidine-based EGFR inhibitors especially designed for this particular setting have shown robust clinical activity. However, similar to first- and second-generation inhibitors, the development of a diversified set of resistance mechanisms in response to these new compounds is an emerging issue. To date, clinical management of this growing number of patients has not been clearly established, even if anecdotal responses to subsequent molecularly guided therapies have been observed. By exhaustively reviewing and classifying all the preclinical and clinical data published on resistance to third-generation EGFR inhibitors in NSCLC, this work reveals the heterogeneity of the mechanisms that a tumour can develop to evade therapeutic pressure. Strategies currently being tested in clinical trials are discussed in light of these findings.

Clinical and metabolic outcomes in pregnant women at risk for gestational diabetes mellitus supplemented with myo-inositol: a secondary analysis from 3 RCTs.

BACKGROUND: Gestational diabetes mellitus is defined as carbohydrate intolerance that begins or is first recognized during pregnancy. Insulin sensitizing substances such as myo-inositol have been considered for the prevention of gestational diabetes mellitus and related complications. OBJECTIVE: Because previous studies failed to show a clear reduction of gestational diabetes mellitus complications, the aim of this study was to evaluate clinical and metabolic outcomes in women who are at risk for gestational diabetes mellitus supplemented with myo-inositol since the first trimester. STUDY DESIGN: A secondary analysis of databases from 3 randomized, controlled trials (595 women enrolled) in which women who were at risk for gestational diabetes mellitus (a parent with type 2 diabetes mellitus, obese, or overweight) were supplemented with myo-inositol (4 g/d) throughout pregnancy. Main measures were the rate of adverse clinical outcomes: macrosomia (birthweight, ≥4000 g), large-for-gestational-age babies (fetal growth, ≥90 percentile), fetal growth restriction (fetal growth, ≤3 percentile), preterm birth (delivery before week 37 since the last menstruation), gestational hypertension, and gestational diabetes mellitus. RESULTS: A significant reduction was observed for preterm birth (10/291 [3.4%] vs 23/304 [7.6%]; P=.03), macrosomia (6/291 [2.1%] vs 16/304 [5.3%]; P=.04), Large-for-gestational-age babies (14/291 [4.8%] vs 27/304 [8.9%]; P=.04) with only a trend to significance for gestational hypertension (4/291 [1.4%] vs 12/304 [3.9%]; P=.07). Gestational diabetes mellitus diagnosis was also decreased when compared with the control group (32/291 [11.0%] vs 77/304 [25.3%]; P<.001). At univariate logistic regression analysis, myo-inositol treatment reduced the risk for preterm birth (odds ratio, 0.44; 95% confidence interval, 0.20-0.93), macrosomia (odds ratio, 0.38; 95% confidence interval, 0.14-0.98), and gestational diabetes mellitus diagnosis (odds ratio, 0.36; 95% confidence interval, 0.23-0.57). CONCLUSION: Myo-inositol treatment in early pregnancy is associated with a reduction in the rate of gestational diabetes mellitus and in the risk of preterm birth and macrosomia in women who are at risk for gestational diabetes mellitus.

A prospective examination of circulating tumor cell profiles in non-small-cell lung cancer molecular subgroups.

BACKGROUND: We report the first study examining the clinical, numerical and biological properties of circulating tumor cells according to molecular subtypes of non-small-cell lung cancer. PATIENTS AND METHODS: 125 patients with treatment-naïve stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype, and survival were assessed. RESULTS: 51/125 patients (40.8%) were total CTC+ and 26/125 (20.8%) were vim CTC+ at baseline. Multivariate analysis showed patients with ≥5 total CTCs had significantly reduced OS (HR 0.55, 95% CI 0.33-0.92, P = 0.022) but not PFS (HR 0.68, 95% CI 0.42-1.1, P = 0.118) compared to patients with <5 total CTCs. No OS difference was evident between vim+ CTC and vim-negative CTC patients overall (HR 1.24, 95% CI 0.67-2.28, P = 0.494), but after subdivision according to NSCLC driver mutation, we found an increase of vim+ CTCs in the EGFR-mutated subgroup (N = 21/94 patients; mean 1.24 vs 1.22 vim+ CTCs, P = 0.013), a reduction of total CTCs in the ALK-rearranged subgroup (N = 13/90 patients; mean 1.69 vs 5.82 total CTCs, P = 0.029), and a total absence of vim+ CTCs in KRAS-mutated adenocarcinomas (N = 19/78 patients; mean 0 vs 1.4 vim+ CTCs, P = 0.006). CONCLUSIONS: We validate that the baseline presence of ≥5 total CTCs in advanced NSCLC confers a poor prognosis. CTCs from EGFR-mutant NSCLC express epithelial-mesenchymal transition characteristics, not seen in CTCs from patients with KRAS-mutant adenocarcinoma.

An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model.

BACKGROUND: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics. AIM: We developed and characterized a robust, consistent, and reproducible mouse model of severe exacerbation of chronic allergic asthma. METHODS: Chronic allergic airway inflammation was induced following a house dust mite (HDM) sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled fluticasone propionate (FP), systemic corticosteroids (Pred), or anti-IL-5. Mice were killed at different time points after infection: Cellular accumulation and cytokines levels in the airways, PenH as a measure of airway hyper-responsiveness (AHR), and lung histology and viral replication were assessed. RESULTS: Infection with low-dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri-vascular, peri-bronchial, and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14 h after virus exposure by a marked innate, but no Th2 and Th1 response subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic, and T cells into the lung lumen, parenchyma, and draining lymph nodes in HDM-sensitized mice. Anti-IL-5 treatment attenuated eosinophils and prevented the X31-induced exacerbation. CONCLUSIONS: Together, these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote the development of novel therapeutics.

Adipose tissue displays trophic properties on normal lung cellular components without promoting cancer cells growth.

Surgical removal is the mainstay for early lung cancer treatment and persistent air leaks represent one of the most common clinical complications after lung surgery. Adipose tissue transplantation has been proposed as a new strategy for regenerative therapy after breast cancer surgery; however its efficacy and safety of lung tissue healing after lung resections are unknown. The purpose of this study was to test the biological activity of adipose tissue to facilitate lung tissue healing and evaluate its effect on cancer cells growth, thus providing insight for a possible clinical application. Different in vitro cellular models were used to prove the potential biologic effect of autologous fat tissue (AFT) in repairing injured lung tissue, and in vivo xenograft models were used to evaluate tumor promoting potential of AFT on putative residual cancer cells. Treatment of both embryonic (WI-38) and adult lung fibroblasts and of normal bronchial epithelial cells (HBEC-KT) with AFT samples, harvested from subcutaneous tissue layer of 20 patients undergoing pulmonary metastasectomy, improved wound healing and cell proliferation indicating a trophic effect on both mesenchymal and epithelial cell types. Conversely AFT-conditioned medium was unable to stimulate in vitro proliferation of a lung adenocarcinoma reporter cellular system (A549). Moreover, co-injection of AFT and A549 cells in nude mice did not promote engraftment and progression of A549 cells. These preclinical findings provide preliminary evidence on the potential efficacy of AFT to accelerate lung tissue repair without undesired tumor promoting effects on putative residual cancer cells.

[The role of oral probiotic for bacterial vaginosis in pregnant women. A pilot study]. / Studio pilota sul ruolo dei probiotici nel trattamento della vaginosi batterica in gravidanza.

AIM: The aim of this study was to compare the effects of a dietary supplementation with oral probiotic, and the treatment with vaginal clindamycin in pregnant women with bacterial vaginosis. METHODS: Fourty pregnant women, with a diagnosis of bacterial vaginosis according to the Amsel criteria, were enrolled between the 10th and the 34th week of gestation. The patients were randomized in two groups. Patients in the group A were treated with probiotic orally (VSL3® Ferring), 2 tablets a day for 5 days, followed by 1 tablet daily for 10 days. Patients in group B were treated with vaginal clindamycin 100 mg daily for 15 days. After 5-10 days from the end of the treatment the patients returned for the follow-up. RESULTS: After treatment the vaginal discharge was completely absent in group A, and reduced in group B. The itching occurred only in 10% of patients in each of the two groups. The improvement of constipation occurs only in the group A (P=0.002). Vaginal swabs resulted negative in both groups in particular for Gardnerella V. CONCLUSION: The oral treatment with VSL#3® is effective in the treatment of VB in pregnant women as a topical treatment with clindamycin. In particular for the resolution of leukorrhea, itching and in particular in the bacterial vaginosis caused by Gardnerella V.

Herbal supplements in pregnancy: unexpected results from a multicentre study.

STUDY QUESTION: How common is the use of herbal supplements during pregnancy and does it adversely affect the pregnancy outcome? SUMMARY ANSWER: The use of herbal products during pregnancy is very common and daily almond oil spreading is associated with preterm birth (PTB). WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Herbal drugs are often promoted as 'natural' and 'safe' and such claims attract pregnant women. More than a quarter of Italian pregnant women consume herbs every day for at least 3 months during pregnancy. We raise an alert over the habit of daily almond oil spreading since it seems to be associated with PTB. DESIGN: A multicenter retrospective cohort study performed over a 15-month period. PARTICIPANTS AND SETTING: Seven hundred women interviewed within 3 days of childbirth, in three public hospitals in northern Italy. MAIN RESULTS AND ROLE OF CHANCE: One hundred and eighty-nine women were considered 'regular users', since they consumed herbs every day, for at least 3 months. Almond oil, chamomile and fennel were the most commonly used herbs. Both length of gestation and birthweight were affected by herb consumption. Almond oil users showed more pre-term birth (29 of 189) than non-users (51 of 511). After adjusting for multiple pregnancies, smoking, advanced age and drug intake, almond oil users maintained an increased risk to give birth <37th week (odds ratio = 2.09, 95% confidence interval: 1.08-4.08). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The association between daily spreading of almond oil and PTB only raises a hypothesis that requires confirmation in larger trials devoted to this topic. The relatively small sample size did not allow the investigation of other adverse pregnancy outcomes in herb users. GENERALIZABILITY TO OTHER POPULATIONS: The population under investigation did not significantly differ from the general population attending the same hospitals. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest exists. The study has been supported by a public grant from the University of Modena and Reggio Emilia. TRIAL REGISTRATION NUMBER: None.

Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials.

Polycystic ovary syndrome (PCOS) affects 5%-10% of women in reproductive age, and it is the most common cause of infertility due to ovarian dysfunction and menstrual irregularity. Several studies have reported that insulin resistance is common in PCOS women, regardless of the body mass index. The importance of insulin resistance in PCOS is also suggested by the fact that insulin-sensitizing compounds have been proposed as putative treatments to solve the hyperinsulinemia-induced dysfunction of ovarian response to endogenous gonadotropins. Rescuing the ovarian response to endogenous gonadotropins reduces hyperandrogenemia and re-establishes menstrual cyclicity and ovulation, increasing the chance of a spontaneous pregnancy. Among the insulin-sensitizing compounds, there is myo-inosiol (MYO). Previous studies have demonstrated that MYO is capable of restoring spontaneous ovarian activity, and consequently fertility, in most patients with PCOS. With the present review, we aim to provide an overview on the clinical outcomes of the MYO use as a treatment to improve ovarian function and metabolic and hormonal parameters in women with PCOS.

First-trimester prediction of gestational hypertension through the bioelectrical impedance analysis of the body composition.

OBJECTIVE: Obesity is a risk factor for the development of gestational hypertension, with important consequences for both the mother and fetus. This prospective observational study aims to propose an early prediction model of hypertensive disorders in pregnancy among obese women, through the bioelectrical impedance analysis (BIA) at the first trimester, thus allowing early recognition of obese women that are at risk to develop gestational hypertension, in order to target preventive interventions. PATIENTS AND METHODS: Singleton obese women (BMI ≥ 30 kg/m2) between the 9th and 12th week of pregnancy were included in the study. The exclusion criteria were chronic diseases, like type 2 diabetes mellitus, hypertension, and other medical pre-existing conditions. Eligible women were followed up at 20, 28, and 36 weeks of gestation by measuring blood pressure, weight, and body composition with the use of the BIA. The diagnosis of gestational hypertension was made after the 20th week of gestation. Pregnancy and perinatal outcomes were then recorded. RESULTS: Of the 479 women included in the study, 85 (17.7%) developed gestational hypertension; the remaining 394 (82.3%) resulted to be normotensive. A higher rate of nulliparous women was found in the hypertensive group (50.6% vs. 37.6%, p = 0.02), together with a higher rate of induction of labor (55.3% vs. 40.9%, p = 0.02) and of small for gestational age (SGA) newborns (12.9% vs. 6.9%, p = 0.03). Significant differences emerged in the body composition between the two groups already from the first trimester, indeed women developing gestational hypertension showed elevated values of Total body Mass, FM, FFM, TBW (p < 0.02), and of leg's FM, FFM (p < 0.006). At the multivariate logistics regression, the risk of developing gestational hypertension resulted higher in women with elevated total body water levels in the first trimester (OR 1.10 95% CI 1.04 -1.92). CONCLUSIONS: The BIA is a rapid, easy, non-invasive, and inexpensive tool to evaluate the body composition of obese pregnant women. It represents a promising predictor of hypertensive disorders in pregnancy, which allows an early identification of the patients at risk of developing gestational hypertension, thus opening a window of opportunity for strictly monitoring and target preventive intervention.

The role of fetal autopsy and placental examination in the causes of fetal death: a retrospective study of 132 cases of stillbirths.

PURPOSE: To investigate the most plausible cause of stillbirth by evaluating clinical records and postmortem examination findings including placental analysis. METHODS: A retrospective cohort study concerning 132 stillbirths from 124 pregnancies occurred in the Mother-Infant Department of the University Hospital of Modena, Italy, from January 2000 to December 2004. Collected data were reviewed and classified according to the Gardosi ReCoDe system. RESULTS: A reasonable cause of fetal death was identified in 99/124 pregnancies (79.84%). No associated relevant factors were disclosed in 25 fetuses (20.16%) classified as unexplained stillbirths. A succeeding scrupulous analysis of the placenta and an accurate clinical record review were useful to detect other conditions in 82 cases, including 5 cases of unexplained stillbirth. The major relevant conditions associated to stillbirths were feto-placental infection especially in the early fetal gestation age, under the 24th week of gestation, and placental insufficiency occurred both in early and late gestation age fetuses and mainly associated with a IUGR (<10th customized percentile). The main frequent secondary conditions were represented by placental anomalies including cluster of avascular villi with stromal fibrosis associated to thrombosis in minor and/or major vessel(s). Through the further analysis of the placenta, we were able to reduce the unexplained stillbirth rate from 20.16 to 15%. CONCLUSION: Accurate fetal autopsy and placental examination related to meticulous clinical collecting data are requisites in the valuation of stillbirth and could play an important role in reduction of unexplained stillbirth rate.

[Identification of preterm labor: the role of the fibronectin and ultrasound cervicometry and their association]. / La identificazione del travaglio pretermine: ruolo della fibronectina e della cervicometria ecografica e loro associazione.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of the fetal fibronetcin (fFN) test and ultrasonographic cervical length measurement used alone or in combination with each other in order to further improve the identification of patients in preterm labor. METHODS: Prospective multicenter observational study on patients between 24 and 32 weeks of gestation with symptoms of preterm labor (total patients = 132). The endpoint was the delivery at 34 weeks or more. The screening methods used were: the fFN test (group 1), the cervical length measurement by transvaginal ultrasound (group 2) or a combination of both tests (group 3) according to an established protocol. The statistical analysis was performed using the χ2 test using the SPSS software. RESULTS: Group 1: positive fFN test in 25.7% of cases, incidence of preterm birth (<34 weeks) of 18%. Group 2: cervical length <25 mm in 56.2% of cases, incidence of preterm birth (<34 weeks) of 18.5%. The negative predictive value is equivalent to 99.0% for the fFN test and 95.2% for cervicometry; combined use reaches 100%, compared to 54% positive predictive value. CONCLUSION: The identification of women at high risk of preterm delivery carried out with the fFN test or with transvaginal ultrasound cervicometry is clinically valid. The study also showed that the contextual use of biochemical and biophysical tests reaches a high negative predictive value (100%), making it a very useful method to identify patients truly at risk and to further reduce the incidence of non adequate treatment.