EEG-informed fMRI analysis during a hand grip task: estimating the relationship between EEG rhythms and the BOLD signal.

In the last decade, an increasing interest has arisen in investigating the relationship between the electrophysiological and hemodynamic measurements of brain activity, such as EEG and (BOLD) fMRI. In particular, changes in BOLD have been shown to be associated with changes in the spectral profile of neural activity, rather than with absolute power. Concurrently, recent findings showed that different EEG rhythms are independently related to changes in the BOLD signal: therefore, it would be also important to distinguish between the contributions of the different EEG rhythms to BOLD fluctuations when modeling the relationship between the two signals. Here we propose a method to perform EEG-informed fMRI analysis where the changes in the spectral profile are modeled, and, at the same time, the distinction between rhythms is preserved. We compared our model with two other frequency-dependent regressors modeling using simultaneous EEG-fMRI data from healthy subjects performing a motor task. Our results showed that the proposed method better captures the correlations between BOLD signal and EEG rhythms modulations, identifying task-related, well localized activated volumes. Furthermore, we showed that including among the regressors also EEG rhythms not primarily involved in the task enhances the performance of the analysis, even when only correlations with BOLD signal and specific EEG rhythms are explore

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015

Outcome clinico delle pazienti con carcinoma della cervice uterina in stadio FIGO Ib2-IIb: analisi delle recidive e terapia adiuvante

Il carcinoma della cervice uterina è la seconda neoplasia per incidenza nel sesso femminile dopo quello della mammella ed è anche la seconda causa di morte per decesso correlato a neoplasia,specialmente nei paesi in via di sviluppo. La disponibilità dei test di screening citologici ha contribuito a ridurre drasticamente l’incidenza del carcinoma cervicale invasivo specie nei paesi industrializzati mentre, nei paesi in via di sviluppo dove non esistono programmi di prevenzione primaria, il carcinoma cervicale è una patologia comune con alto tasso di mortalità. La sopravvivenza a 5 anni secondo i dati FIGO dell’ Annual Report (2006) n. 26, è del 97.5% per le pazienti in stadio Ia1, 94.8% per lo stadio Ia2, 89.1% nello stadio Ib1, 75.7% per lo stadio Ib2, 73.4% per lo stadio IIa, 65.8% per lo stadio IIb, 39.7% per lo stadio IIIa, 41.5% per lo stadio IIIb, 22.0% per lo stadio IVa, e 9.3% per il IVb. Lo stadio clinico, il diametro tumorale, lo stato linfonodale, l’infiltrazione dei parametri e/o la positività dei margini e lo stato degli spazi vascolari sono le più importanti variabili prognostiche per questa neoplasia. L’isterectomia radicale con linfadenectomia e/o il trattamento radiante esclusivo hanno contribuito a migliorare l’outcome clinico nei tumori in stadio iniziale,ottenendo percentuali di sopravvivenza a 5 anni dell’ 80-90%, mentre la radioterapia rappresenta il trattamento di scelta nella malattia avanzata. Sino al 1999, la radioterapia esclusiva era il trattamento di scelta nelle pazienti con malattia localmente avanzata. In seguito ai risultati di 5 studi randomizzati, due meta-analisi hanno concluso che il trattamento standard è la chemio-radioterapia concomitante a base di platino. Recentemente la chemioterapia neoadiuvante (NACT) seguita da isterectomia radicale ha ottenuto risultati soddisfacenti nel management del carcinoma cervicale in stadio Ib2-IIb. Studi clinici randomizzati dimostrano che questo trattamento integrato riduce significativamente il rischio di morte in queste pazienti rispetto al solo trattamento radioterapico. Di contro ci sono pochi dati in letteratura sull’efficacia di una terapia adiuvante in questo tipo di pazienti. Lo scopo di questa tesi è stato quello di valutare la sopravvivenza libera da malattia e la sopravvivenza globale nelle pazienti con carcinoma cervicale localmente avanzato (stadio FIGO Ib2-IIb) trattate con NACT a base di platino seguita da isterectomia radicale e di correlare l’outcome clinico con la risposta patologica ed il trattamento post-operatorio

Menstrual function and childbearing potential after fertility-sparing surgery and platinum-based chemotherapy for malignant ovarian germ cell tumours

Malignant ovarian germ cell tumours (MOGCT) account for 5% of all ovarian malignancies. Their elevated chemosensitivity, the frequent unilaterality and the young age of patients have strongly supported the conservative surgery as the standard approach, often followed by adjuvant platinum-based chemotherapy. The risk for recurrence is not affected by the performance of conservative versus radical surgery. During chemotherapy 50% of patients become amenorrhoeic but more than 95% of them resume normal menses after treatment completion. Literature has reported several healthy babies born after fertility-sparing surgery with or without chemotherapy for MOGCT. The incidence of miscarriages is in the normal range, whereas malformation rate is slightly higher compared to general population, without any difference between chemotherapy-treated and -untreated patients. Therefore, young women with MOGCT must be reassured of their excellent chances of survival and fertility preservation following conservative surgery and adjuvant platinum-based chemotherapy

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 investigatio

Novel insights on the malignant transformation of endometriosis into ovarian carcinoma

The malignant transformation of endometriosis is an uncommon event, which happens in 0.7-2.5% of the cases, and, when occurs, it usually involves the ovary. A 2 to 3-fold higher risk of ovarian endometrioid and clear cell carcinoma has been reported in women with endometriosis. Pathological studies have detected a morphological continuum of sequential steps from normal endometriotic cyst epithelium to atypical endometriosis and finally to invasive carcinoma. Ovarian endometrioid carcinoma harbors mutations of CTNNB1 in 16-53.3%, of PTEN in 14-20% and of ARID1A in 30-55% of the cases. Ovarian clear cell carcinoma harbors mutations of PIK3CA in 20-40% and of ARID1 in 15-75% of the cases. Whereas estrogen receptors and progesterone receptors are quite always absent, HNF-1b is often over-expressed in this histotype. Atypical endometriosis and endometriosis-related ovarian neoplasms share molecular alterations, such as PTEN mutations, ARID1A mutations and up-regulation of HNF-1b. Moreover, ARID1A mutations have been noted in clear cell tumors and contiguous atypical endometriosis, but not in distant endometriotic lesions. The loss of BAF250a protein expression is suggestive for the presence of ARID1A mutations, and represents an useful marker of malignant transformation of endometriosis

Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning.

Metformin exerts antitumor effects mainly through AMP-activated protein kinase [AMPK] activation and phosphatidylinositol 3-kinase [PI3K]-Akt-mammalian target of rapamycin [mTOR] inhibition. This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1]/AMPK pathway. LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies. AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell. AMPK activation inhibits mRNA translation and proliferation in cancer cells via down-regulation of PI3K/Akt/mTOR pathway. Moreover, metformin decreases the production of insulin, insulin-like growth factor, inflammatory cytokines and vascular endothelial growth factor, and therefore it exerts anti-mitotic, anti-inflammatory and anti-angiogenetic effects. Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells, and acts together with chemotherapy to block tumor growth in different cancers. Several epidemiological studies and meta-analysis have shown that metformin use is associated with decreased cancer risk and/or reduced cancer mortality for different malignancies. The present review analyzes the recent biological and clinical data suggesting a possible growth-static effect of metformin also in gynecological cancers. The large majority of available clinical data on the anti-cancer potential of metformin are based on observational studies. Therefore long-term phase II-III clinical trials are strongly warranted to further investigate metformin activity in gynecological cancers

EEG-informed fMRI analysis during a hand grip task: estimating the relationship between EEG rhythms and the BOLD signal

In the last decade, an increasing interest has arisen in investigating the relationship between the electrophysiological and hemodynamic measurements of brain activity, such as EEG and (BOLD) fMRI. In particular, changes in BOLD have been shown to be associated with changes in the spectral profile of neural activity, rather than with absolute power. Concurrently, recent findings showed that different EEG rhythms are independently related to changes in the BOLD signal: therefore, it would be also important to distinguish between the contributions of the different EEG rhythms to BOLD fluctuations when modeling the relationship between the two signals. Here we propose a method to perform EEG-informed fMRI analysis where the changes in the spectral profile are modeled, and, at the same time, the distinction between rhythms is preserved. We compared our model with two other frequency-dependent regressors modeling using simultaneous EEG-fMRI data from healthy subjects performing a motor task. Our results showed that the proposed method better captures the correlations between BOLD signal and EEG rhythms modulations, identifying task-related, well localized activated volumes. Furthermore, we showed that including among the regressors also EEG rhythms not primarily involved in the task enhances the performance of the analysis, even when only correlations with BOLD signal and specific EEG rhythms are explored

Patterns of Recurrence and Clinical Outcome of Patients with Stage IIIC to Stage IV Epithelial Ovarian Cancer in Complete Response after Primary Debulking Surgery Plus Chemotherapy or Neoadjuvant Chemotherapy Followed by Interval Debulking Surgery: An Italian Multicenter Retrospective Study

OBJECTIVE: The objective of this retrospective study was to assess the clinical outcome of patients with advanced epithelial ovarian cancer in complete response after primary debulking surgery (PDS) or neoadjuvant chemotherapy followed by interval debulking surgery (IDS]). METHODS: The authors reviewed the hospital records of 384 patients who underwent PDS (n = 322) or IDS (n = 62) and who were in complete response after primary treatment. RESULTS: Optimal (residual disease [RD] < 1 cm) and complete (no gross RD) cytoreduction rates were higher after IDS than after PDS (71.0% vs 55.9%; P = 0.001 and 51.6% vs 35.7%, respectively; P = 0.02). Tumor recurred in 73.0% of the 322 complete responders after PDS versus 87.1% of the 62 complete responders after IDS (P = 0.01). The IDS group showed a higher recurrence rate within 6 months (11.3% vs 3.1%: P = 0.01) and a trend to higher recurrence rate between 6 and 12 months (30.6% vs 19.9%). Tumor recurred in 57.4% of the 115 completely cytoreduced patients after PDS versus 87.5% of the 32 completely cytoreduced patients after IDS (P = 0.001). The IDS group showed a trend to higher recurrence rate within 6 months (6.2% vs 1.7%) and a higher recurrence rate between 6 and 12 months (37.5% vs 15.6%; P = 0.01). Two-year, 5-year, and 7-year progression-free survival were 65.8%, 40.8%, and 39.3% for completely cytoreduced patients after PDS versus 43.8%, 12.5%, and 12.5% for completely cytoreduced patients after IDS (P = 0.001); and 2-year, 5-year, and 7-year overall survival were 96.4%, 69.3%, and 50.4% for the former versus 87.1%, 41.8%, and 32.6% for the latter (P = 0.001). CONCLUSIONS: The clinical outcome of completely cytoreduced patients was significantly better for PDS group than for IDS group, and therefore, the achievement of no gross RD after surgery seemed to have a different prognostic relevance for the 2 groups