Comparison of fetal and neonatal sonographic measurements of ventricular size in second- and third-trimester fetuses with or without ventriculomegaly: cross-sectional three-dimensional ultrasound study.

OBJECTIVES: To assess, in a population comprising normal fetuses and fetuses with primary or post-hemorrhagic ventriculomegaly, the reproducibility of measurement of neonatal ultrasound indices in the fetus and to compare the performance of various cut-offs of these parameters to diagnose ventriculomegaly and classify its severity. METHODS: This was a retrospective cross-sectional study including 182 singleton fetuses assessed by transvaginal neurosonography. The sample populations included 116 normal fetuses and 66 fetuses with primary (n = 56) or post-hemorrhagic (n = 10) ventriculomegaly. In all cases, the atrial width (AW) was measured according to standard protocols and the findings were compared with four sonographic indices developed in the neonate: the anterior horn width (AHW), the ventricular index (VI), the thalamo-occipital distance (TOD) and the fronto-occipital horn ratio (FOHR). Reproducibility of measurements was assessed using the intraclass correlation coefficient (ICC) and diagnostic accuracy of the neonatal indices was assessed against AW using areas under the receiver-operating-characteristics curves (AUC). RESULTS: The intra- and interoperator reproducibility of measurement of AW and the neonatal measurements was excellent, with ICCs > 0.99 for all measures. The association in the fetus of all four variables developed in the neonate with the degree of ventriculomegaly as defined by the AW was strong for severe ventriculomegaly (AW > 15.0 mm; all AUC > 0.95), whereas the separation of cases with mild ventriculomegaly (AW, 10.0-15.0 mm) from those with normal AW (< 10.0 mm) was less effective. CONCLUSIONS: When applied in the fetus, all four indices of ventriculomegaly developed in neonates (AHW, VI, TOD, FOHR) were associated strongly with fetal AW when the AW measurement indicated severe fetal ventriculomegaly. However, for mild ventriculomegaly, the association was weaker, probably due to the fact that, in the fetus, mild ventriculomegaly is not caused by obstruction of the ventricular system. Considering the similar performance of the four neonatal variables and the technical issues involved in determination of TOD and FOHR in the fetus, use of VI and AHW is preferred. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Iatrogenic late preterm birth: when is it recommended? A Delphi survey promoted by the Italian Society of Perinatal Medicine.

BACKGROUND: The rate of iatrogenic Late Preterm (LP) Birth varies in different settings. This is due to the lack of strong evidence/guidelines on the management of the different maternal, fetal and placental complications affecting pregnancy in the LP window. Steroid prophylaxis is also under discussion. AIM: To build recommendations about the management of main medical complications (pregestational diabetes, placenta previa, preeclampsia, cholestasis, p-PROM, intrauterine growth restriction -IUGR-) occurring in the LP period to reduce clinical heterogeneity. METHODS: A group of Italian Perinatal experts were identified by Scientific Societies. A Delphi consensus methodology was used to reach agreement on different clinical sceneries. Two rounds of consultation by using a purpose built on-line survey and a third open panel discussion were performed. RESULTS: The panel of 50 experts reached agreement for the vast majority of clinical sceneries (Placenta Previa, Preeclampsia, Diabetes, Cholestasis). Overall, there was agreement to be conservative at 34 weeks and in favor of delivery at 36 weeks. The management of p-PROM and mostly of IUGR were characterized by a minor degree of consensus. Corticosteroids were found necessary at the 34th week and unnecessary at the 36th week. CONCLUSIONS: Besides providing some guidance on clinical indications for LP iatrogenic delivery, these results represent a stimulus for designing future trials investigating the grey areas in this field.

A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma.

We explored in a phase I/II clinical trial the combination of valproic acid (VPA), a clinically available histone deacetylase inhibitor, with standard chemoimmunotherapy in patients with advanced melanoma, to evaluate its clinical activity, to correlate the clinical response with the biological activity of VPA and to assess toxicity. Patients were treated initially with VPA alone for 6 weeks. The inhibition of the target in non-tumour peripheral blood cells (taken as a potential surrogate marker) was measured periodically, and valproate dosing adjusted with the attempt to reach a measurable inhibition. After the treatment with valproate alone, dacarbazine plus interferon-alpha was started in combination with valproate. Twenty-nine eligible patients started taking valproate and 18 received chemoimmunotherapy and are assessable for response. We observed one complete response, two partial remissions and three disease stabilisations lasting longer than 24 weeks. With the higher valproate dosages needed to reach a measurable inhibition of the target, we observed an increase of side effects in those patients who received chemoimmunotherapy. The combination of VPA and chemoimmunotherapy did not produce results overtly superior to standard therapy in patients with advanced melanoma and toxicity was not negligible, casting some doubts on the clinical use of VPA in this setting (at least in the administration schedule adopted).

Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors.

Valproic acid (VPA, 2-propylpentanoic acid) is an established drug in the long-term therapy of epilepsy. Recently, VPA was demonstrated to inhibit histone deacetylases (HDACs) class I enzyme at therapeutically relevant concentrations, thereby, mimicking the prototypical histone deacetylase inhibitors, tricostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA). In the present study, we investigated the cellular effects of VPA, TSA and SAHA on four human melanoma cell lines (WM115, WM266, A375, SK-Mel28) with particular reference to the modulation of regulators of apoptosis, including Bcl-2, BclXL, Mcl-1, Apaf-1, BclXs, NOXA, TRAIL-R1, TRAIL-R2, caspase 8, and survivin). Firstly, we found that VPA induced apoptosis in two of the four human melanoma cell lines, while both TSA and SAHA exhibited an antiproliferative and apoptotic effects in all four cell lines, a different expression of Bcl-2 and BclX(L/S) occurred. On the other hand, SAHA and VPA modulated differently pro- and anti-apoptotic factors. In particular, the treatment with VPA enhanced the level of expression of survivin only in VPA-resistant cell lines, whereas down-regulation of survivin was induced by VPA and SAHA in VPA-sensitive cells. In the latter, since activation of caspase 8 was documented, a receptor-mediated apoptosis was suggested. Taken together, our results suggest that HDAC inhibitors may represent a promising therapeutic strategy to treat melanoma.