Preventing HIV mother-to-child transmission in a vertically infected pregnant woman with multiclass drug resistance, role of bis-in-die dolutegravir and neonatal AZT prophylaxis: A case report.

A suppressive antiretroviral therapy (ART) is necessary to prevent mother-to-child transmission (MTCT) of HIV during pregnancy. During this period, it is recommended to continue an ongoing safe and suppressive regimen, but history of multiclass drug-resistance (MDR) might need tailored, uncommon approaches posing tolerability and toxicity issues. This is the case of a 33 years of age, vertically infected woman with MDR HIV infection suppressed on a darunavir/cobicistat + atazanavir regimen switched during pregnancy to lamivudine + darunavir/ritonavir + dolutegravir 50 mg bis-in-die, maintaining complete viral suppression and delivering via caesarian section and without zidovudine (AZT) intrapartum prophylaxis a healthy HIV-negative newborn who received AZT post-exposure prophylaxis and showed regular growth patterns up to 2 years. Our case shows how archived MDR might complicate the preservation of HIV RNA suppression and highlights the importance of a tailored, multidisciplinary approach for pregnant women with MDR HIV and their newborns.

Different management strategies for cesarean scar pregnancy: Short-term outcomes and reproductive prognosis.

PURPOSE: To investigate the impact on future reproductive potential of systemic methotrexate (MTX) administration, uterine artery embolization (UAE) and expectant management as treatments of caesarean scar pregnancy (CSP) and to assess their efficacy and safety. BASIC PROCEDURES: We retrospectively analysed patients with a diagnosis of CSP treated in a five years' period (2014-2018). Hospitalization, hCG normalization, menstrual cycle recovery, ultrasound restitutio ad integrum times, reproductive desire accomplishment after the resolution of the picture, and outcomes of subsequent pregnancies were considered. Only patients for whom complete diagnosis, treatment and follow-up data were available could be considered for study entry. MAIN FINDINGS: A total of 21 patients were included. Three of them were managed expectantly. In two cases spontaneous abortion occurred and one case underwent caesarean delivery at 35 weeks of gestation for complete placenta previa with hysterectomy for post partum haemorrhage. Seven patients were treated with systemic MTX. Median [IQR] times of hospitalization, hCG normalization, menstrual cycle recovery and ultrasound restitutio ad integrum were 21 days [10-26 days], 52 days [18-64 days], 8 weeks [6-10 weeks] and 8 weeks [6-11 weeks] respectively. At the end of follow up, 80% (95%CI [38-96%]) of patients with reproductive desire achieved at least one live birth. Eleven patients were treated with UAE combined with MTX. Median [IQR] times of hospitalization, hCG normalization, menstrual cycle recovery and ultrasound restitutio ad integrum were 14 days [12-20 days], 43 days [30-52 days], 8 weeks [4-12 weeks] and 8 weeks [8-10 weeks], respectively. Of those who expressed a reproductive desire after treatment, 80% (95%CI [49-94%]) achieved at least one live birth. In all included patients, the menstrual cycle was restored. PRINCIPAL CONCLUSIONS: Reproductive potential of women treated for CSP was preserved after both systemic MTX administration and systemic MTX combined with UAE. Both strategies proved to be safe.

Assessment of post-partum haemorrhage risk among women with moderate thrombocytopenia.

It is unknown whether moderate thrombocytopenia represents a risk factor for post-partum haemorrhage (PPH). We assessed PPH risk among women with a platelet count of between 100 and 50 × 109 /l and stratified the risk for O/non-O blood group. We included consecutive women undergoing vaginal delivery or caesarean section with moderate thrombocytopenia. Women with >150 × 109 /l platelets at delivery were selected as controls and matched for age, type of birth and ethnicity. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated as risk estimates. A total of 94 thrombocytopenic women and 94 controls were included in the study. The rate of PPH was significantly higher in thrombocytopenic women than in controls (37% vs. 10%, p < 0.001); there was a higher risk of PPH in the thrombocytopenic group when compared to the control group (adjusted OR 4.7, 95% CI 2.1-10.8, p < 0.01) and this association was stronger in blood group O carriers (adjusted OR 11.0, 95% CI 2.4-49.6, p < 0.01). In conclusion, our study shows that a moderate thrombocytopenia is a risk factor for PPH, especially in blood group O carriers.

Prelabor rupture of membranes at term: A possible hematological triage in addition to vagino-rectal beta-hemolytic streptococcus screening for early labor induction.

INTRODUCTION: A potential complication of term prelabor rupture of membranes (term PROM) is chorioamnionitis with an increased burden on neonatal outcomes of chronic lung disease and cerebral palsy. The purpose of the study was to analyze the efficacy of a standing clinical protocol designed to identify women with term PROM at low risk for chorioamnionitis, who may benefit from expectant management, and those at a higher risk for chorioamnionitis, who may benefit from early induction. MATERIAL AND METHODS: This retrospective study enrolled all consecutive singleton pregnant women with term PROM. Subjects included women with at least one of the following factors: white blood cell count ≥ 15×100/µL, C-reactive protein ≥ 1.5 mg/dL, or positive vaginal swab for beta-hemolytic streptococcus. These women comprised the high risk (HR) group and underwent immediate induction of labor by the administration of intravaginal dinoprostone. Women with none of the above factors and those with a low risk for chorioamnionitis waited for up to 24 hours for spontaneous onset of labor and comprised the low-risk (LR) group. RESULTS: Of the 884 consecutive patients recruited, 65 fulfilled the criteria for HR chorioamnionitis and underwent immediate induction, while 819 were admitted for expectant management. Chorioamnionitis and Cesarean section rates were not significantly different between the HR and LR groups. However, the prevalence of maternal fever (7.7% vs. 2.9%; p = 0.04) and meconium-stained amniotic fluid was significantly higher in the HR group than in LR group (6.1% vs. 2.2%; p = 0.04). This study found an overall incidence of 4.2% for chorioamnionitis, 10.9% for Cesarean section, 0.5% for umbilical artery blood pH < 7.10, and 1.9% for admission to the neonatal intensive care unit. Furthermore, no confirmed cases of neonatal sepsis were encountered. CONCLUSIONS: A clinical protocol designed to manage, by immediate induction, only those women with term PROM who presented with High Risk factors for infection/inflammation achieved similar maternal and perinatal outcomes between such women and women without any risks who received expectant management. This reduced the need for universal induction of term PROM patients, thereby reducing the incidence of maternal and fetal complications without increasing the rate of Cesarean sections.

An hypothetical external validation of the ARRIVE trial in a European academic hospital.

BACKGROUND: Recent evidence supports elective induction of labor at 39 weeks in low-risk pregnancies to improve maternal and perinatal outcomes. This evidence includes the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management). However, concerns have been raised on the external validity of the ARRIVE trial, especially with regard to the demographic and clinical characteristics of the pregnant women recruited. OBJECTIVE: This study compared the outcomes in a cohort of consecutive pregnant women, who fulfilled the criteria of the ARRIVE trial and were managed expectantly in an Italian referral academic hospital, with those reported in the expectant and induction arms of the ARRIVE trial. STUDY DESIGN: This was a retrospective single-center study. Consecutive low-risk nulliparous women who fulfilled the ARRIVE trial criteria were evaluated for eligibility at 36-38 weeks of gestation. Those who neither developed complications nor delivered spontaneously before 39 weeks were eligible for this comparative analysis. Maternal and fetal growth and wellbeing were screened and monitored from 36 to 38 weeks of gestation. RESULTS: A total of 1696 patients met the established criteria at recruitment. Of these, 343 spontaneously delivered in <39 weeks, 82 delivered because of maternal indication, and 37 for fetal indication. A total of 1234 pregnant women were eligible for comparison with the elective induction and the expectant management groups of the ARRIVE trial. The socioeconomic status was significantly better, maternal age was significantly higher, and body mass index was significantly lower in our cohort. Cesarean section rate in our cohort was lower than that of the expectant group of the ARRIVE trial (18.7 vs. 22.2%; p = 0.02) and similar to that of the elective induction group (18.7 vs. 18.6%). A new diagnosis of hypertensive disorders during expectant management was noted in 1.6% in our cohort vs. 14.1% in the ARRIVE arm. Among the different obstetric outcomes, only the prevalence of postpartum hemorrhage was not significantly lower in our cohort. The primary perinatal composite outcome was significantly better in our cohort than in both arms of the ARRIVE trial (2.1 vs. 5.4% in the expectant group and 4.3% in the induction group). We did not record cases with an Apgar score ≤ 3 or hypoxic-ischemic encephalopathy. CONCLUSION: In our cohort, expectant management in low-risk pregnancies with late preterm screening of feto-maternal well-being seemed to achieve better maternal and perinatal outcomes than a universal policy of induction at 39 weeks. The results of the ARRIVE trial should be carefully evaluated in different demographic and clinical settings and cannot be extended to the general population.

Wnt activation affects proliferation, invasiveness and radiosensitivity in medulloblastoma.

Medulloblastomas (MBs) associated with the Wnt activation represent a subgroup with a favorable prognosis, but it remains unclear whether Wnt activation confers a less aggressive phenotype and/or enhances radiosensitivity. To investigate this issue, we evaluated the biological behavior of an MB cell line, UW228-1, stably transfected with human ß-catenin cDNA encoding a nondegradable form of ß-catenin (UW-B) in standard culture conditions and after radiation treatment. We evaluated the expression, transcriptional activity, and localization of ß-catenin in the stably transfected cells using immunofluorescence and WB. We performed morphological analysis using light and electron microscopy. We then analyzed changes in the invasiveness, growth, and mortality in standard culture conditions and after radiation. We demonstrated that (A) Wnt activation inhibited 97 % of the invasion capability of the cells, (B) the growth of the UW-B cells was statistically significantly lower than that of all the other control cells (p < 0.01), (C) the mortality of irradiated UW-B cells was statistically significantly higher than that of the controls and their nonirradiated counterparts (p < 0.05), and (D) morphological features of neuronal differentiation were observed in the Wnt-activated cells. In tissue samples, the Ki-67 labeling index (LI) was lower in ß-catenin-positive samples compared to non-ß-catenin positive ones. The Ki-67 LI median (LI = 40) of the nuclear ß-catenin-positive tumor samples was lower than that of non-nuclear ß-catenin-positive samples (LI = 50), but the difference was not statistically significant. Overall, our data suggest that activation of the Wnt pathway reduces the proliferation and invasion of MBs and increases the tumor's radiosensitivity.

Lithium induces mortality in medulloblastoma cell lines.

Lithium is the main therapeutic agent for the treatment of bipolar disorders but nerve cells are not the sole target of this drug. Indeed, lithium has been reported to target numerous cell types and to affect cell proliferation, differentiation and death. Lithium targets a variety of enzymes among which there is GSK-3beta and a number of cell responses elicited by lithium are mediated by the Wnt pathway that is involved in medulloblastoma (MB) pathogenesis. We studied the in vitro effects of lithium on two different MB cell lines: D283MED and DAOY. High doses of lithium inhibited GSK3-beta, decreased cell proliferation and induced non-apoptotic cell death in both cell lines independently by intracellular levels of beta-catenin that is consistently high only in D283MED. At clinical doses, the anti-neoplastic effects were observed only in this cell line, highlighting the importance of a specific molecular background in determining the target therapy response. In conclusion, lithium could be a promising drug in MB, but an accurate molecular profile predictive of drug response still needs to be clarified.

Radiobiologic response of medulloblastoma cell lines: involvement of beta-catenin?

Medulloblastoma (MB) is the most common brain malignancy in children. Whole neural axis irradiation is the treatment of choice, but it often results in long-term neurocognitive and developmental impairment. Only insights into MB biology will lead to improved therapeutic outcome. Wingless (WNT) signalling deregulation occurs in up to 25% of sporadic tumors, but the specific role of nuclear beta-catenin and its involvement in the radioresponse remains unsettled. Therefore we studied the gamma-radiation response of two MB cell lines from cellular and molecular points of view. Our data show that the p53 wild-type cell line is more sensitive to ionizing radiations (IR) than the p53 mutated line, but apoptosis is also induced in p53-mutated cells, suggesting an alternative p53-independent mechanism. In addition, this study is the first to demonstrate that gamma-rays trigger the WNT system in our in vitro models. Further studies are required to test if this could explain the radiosensitivity of MB and the favorable prognostic value of nuclear beta-catenin in this tumor.