胎儿头面部异常的临床咨询

胎儿头面部异常，是较为常见的结构异常。文章就常见的胎儿头面异常，包括唇腭裂、小颌畸形、耳郭畸形、巨舌症、眼畸形、颈项透明层增厚和颈部淋巴水囊瘤的分型与发生率、影像学诊断、病因、临床处理及预后分别进行论述，为临床决策和咨询提供参考。       

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor,in patients with advanced solid tumors

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)₂‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.     

Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High-grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell-cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox-treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral-mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X-ray repair cross-complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

The key role of macrophage depolarization in the treatment of COPD with ergosterol both in vitro and in vivo

Macrophages are the most abundant immune cells in the lung, which play an important role in COPD. The anti-inflammatory and anti-oxidation of ergosterol are well documented. However, the effect of ergosterol on macrophage polarization has not been studied. The objective of this work was to investigate the effect of ergosterol on macrophage polarization in CSE-induced RAW264.7 cells and Sprague-Dawley (SD) rats COPD model. Our results demonstrate that CSE-induced macrophages tend to the M1 polarization via increasing ROS, IL-6 and TNF-α, as well as increasing MMP-9 to destroy the lung construction in both RAW264.7 cells and SD rats. However, treatment of RAW264.7 cells and SD rats with ergosterol inhibited CSE-induced inflammatory by decreasing ROS, IL-6 and TNF-α, and increasing IL-10 and TGF-β, shuffling the dynamic polarization of macrophages from M1 to M2 both in vitro and in vivo. Ergosterol also decreased the expression of M1 marker CD40, while increased that of M2 marker CD163. Moreover, ergosterol improved the lung characters in rats by decreasing MMP-9. Furthermore, ergosterol elevated HDAC3 activation and suppressed P300/CBP and PCAF activation as well as acetyl NF-κB/p65 and IKKβ, demonstrating that HDAC3 deacetylation was involved in the effect of ergosterol on macrophage polarization. These results also provide a proof in immunoregulation of ergosterol for therapeutic effects of cultured C. sinensis on COPD patients.     

Re-engineering the interpretation of electronic fetal monitoring to identify reversible risk for cerebral palsy: a case control series

Background: Even key opinion leaders now concede that electronic fetal monitoring (EFM) cannot reliably identify fetal acidemia which many vouch as the only labor mediated pathophysiologic precursor for cerebral palsy (CP). We have developed the “Fetal Reserve Index” – an algorithm combining five dynamic components of EFM (1. Rate, 2. Variability, 3. Accelerations, 4. Decelerations, and 5. Excessive uterine activity) considered individually that are combined with the presence of: 6. maternal, 7. obstetrical, and 8. fetal risk factors.

Objective: Here, we compare this 8-point fetal reserve index (FRI) against the performance of ACOG monograph criteria and ACOG Category systems for predicting risk for both CP and the need for emergency operative delivery (EOD). We then studied how varied management for screen positives (Red zone-defined below) impacts the outcome of such cases.

Study design: Four hundred twenty term patients were studied: all entered labor with normal EFMs and no apparent cause of harm except events of labor and delivery. Sixty subsequently developed CP, and 360 were apparently normal controls. An FRI, normal on all eight parameters scored 100%, 4 of the 8 was 50%, etc. We divided cases into Green zone >50%, Yellow 50–26%, and Red ≤25%. An FRI in the Red zone was considered a positive screen. We then compared performance metrics for the three evaluation schemes and differences between controls that reached Red against those controls whose worst scores were Green/Yellow.

Results: For detection of injury during labor, the FRI performed much better than the ACOG Category criteria (sensitivity 28%), and Category III (45%) (p?Conclusions: FRI shows better discrimination for adverse fetal outcome and EOD than traditional EFM interpretation. The Category system is a very poor, subjective screening method as the vast majority of CP babies never reach the “action point” result of Category III. While reaching the Red zone does not ordain a bad outcome, how it is managed, does. Compared to CP cases, Red controls were delivered faster, had higher FRIs, and often had prompt management including IR maneuvers, which improved the FRI and lowered the risk of EODs even for cases with normal outcomes. With further study and validation, the quantitative FRI approach may replace the current, very subjective interpretation with a quantitative “lab test” approach.     

Prenatal Diagnosis of Aortopulmonary Window by 2‐Dimensional Echocardiography: Summary of 8 Cases

Aortopulmonary window (APW) is a rare congenital heart anomaly. A total of 8 cases with APW confirmed by echocardiography and surgery were retrospectively reviewed and the echocardiographic features analyzed. Among the 8 APW cases, 5 were type II and 3 were type III, the latter of which includes 2 cases complicated with Berry syndrome. Prenatal echocardiography can provide accurate information for the diagnosis of fetal APW. The prognosis depends on the timing of surgery and the nature of the associated cardiac anomalies.