No abstract

To investigate whether folic acid would have toxic effects on fetal cardiac, hepatic, and renal functions, this was the first in utero fetal study testing acute effects of folic acid at the last third of gestation. Folic acid (5 mg/day) or 0.9% saline as the control was intragastricly administrated into pregnant ewes. Both maternal and fetal blood were analyzed for pH, PO(2), PCO(2), SO(2)%, hemoglobin, hematocrit, glucose, lactic acid, osmolality, Na(+), and K(+) concentrations. Maternal and fetal cardiovascular functions were assessed by examining cardiac enzymes and cardiovascular responses in vivo. Fetal hepatic and renal functions were examined by analysis of biochemistry index and renal excretion. Folic acid did not alter the blood values in both ewes and fetuses. Cardiac enzyme activities remained unchanged, and no alteration in cardiovascular responses was observed. Folic acid did not affect fetal urine volume, urine electrolytes, and osmolality. Enzyme activities related to hepatic and renal functions were not changed. In addition, maternal application of folic acid had no effect on maternal and fetal lipid profile. The results showed that folic acid used (5 mg/day) during the last third of gestation did not cause biochemical changes related to cardiac, hepatic, and renal functions in both maternal and fetal sheep, providing new information for use of folic acid during late pregnancy.

We aimed to explore what kind of endocrine treatments are optimal for hormone receptor-positive and human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer in some specific clinical situations. We searched randomized controlled trials in Embase, Medline, the Cochrane library, and PubMed from inception to April 1, 2020 and performed a network meta-analysis based on a Bayesian fixed-effects model. Progression-free survival (PFS) with hazard ratios and corresponding 95% confidence interval was defined as the primary endpoint, while overall survival (OS), objective response rate (ORR), clinical benefit rate and serious adverse events were used as secondary endpoints. A total of 35 studies involving 12,285 patients and 24 treatment options were included. In general, most co-treatment options prolonged PFS compared to single-agent therapy, of which aromatase inhibitor (AI) plus everolimus and fulvestrant plus palbociclib were probably the most effective agents, and the latter had the best safety record. However, despite the superior efficacy of fulvestrant plus capecitabine for PFS and OS, palpable toxic effects have been demonstrated for this treatment, so its application must be scrupulously considered. The results of subgroup analysis indicated that fulvestrant combined with palbociclib improved prognosis for phosphatidylinositol 3-kinase (PI3K)-mutated patients, PI3K-unmutated patients, patients with endocrine therapy resistance, and visceral metastatic patients, while no obvious improvement was detected in OS. Moreover, the efficacy of fulvestrant plus cyclin-dependent kinase 4/6 (CDK4/6) inhibitors was slightly better than that of AI plus CDK4/6 inhibitors, while AI plus everolimus was more efficacious than fulvestrant combined with everolimus in terms of PFS, OS, and ORR. In conclusion, our results provide moderate evidence that fulvestrant plus palbociclib and AI plus everolimus were the most effective treatments, while the efficacy and safety of fulvestrant plus palbociclib was obviously superior in some specific clinical situations.