CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1-Mediated ERK and BCL2/Cyclin D1 Pathways.

CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471-83. ©2017 AACR.

Sedation or general anesthesia for patients undergoing transcatheter aortic valve implantation--does it affect outcome? An observational single-center study.

UNLABELLED: Aortic stenosis is one of the most common valvular lesions. Nowadays, a new treatment is emerging: the transcatheter aortic valve implantation (TAVI). It is considered a suitable alternative for the surgical approach in selected high-risk patients. This procedure may be performed under sedation (SED) or under general anesthesia (GEA). STUDY OBJECTIVE: Assess the feasibility and safety of TAVI under sedation. DESIGN: Observational study. SETTING: Single-center study conducted between the years 2009 and 2012. PATIENTS: A total of 204 American Society of Anesthesiologists physical status 3 to 4 patients who underwent TAVI in the study period and for whom complete data were obtained were included. Demographic and periprocedural data were acquired from the patients' files. The patients were divided into SED and GEA groups. INTERVENTIONS: The study was not an interventional study. MEASUREMENTS: The study did not include measurements. MAIN RESULTS: The 2 groups had similar demographic characteristics and echocardiographic parameters. The rate of conversion from SED to GEA was 4.6%. The SED group received significantly less catecholamines and intravenous fluids during the procedure. The total procedural time was significantly shorter for the SED group. There was a trend toward more postprocedural pulmonary complications in the GEA group. In-hospital mortality and total length of stay were similar between the groups. CONCLUSIONS: The results of the current study, which included a relatively large number of patients, suggest that both anesthetic modalities are safe for patients undergoing TAVI. The anesthesiologist should thus tailor the anesthetic approach to the patient, taking into account the team's experience as well as the hemodynamic status of the patient. With growing experience, our team recommends performing TAVI under SED and in selected cases under GEA.

TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.

Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor with up to 50% of NB patients classified as having high-risk disease with poor long-term survival rates. The poor clinical outcome and aggressiveness of high-risk NB strongly correlates with enhanced angiogenesis, suggesting anti-angiogenic agents as attractive additions to the currently insufficient therapeutics. TL-118, a novel drug combination has been recently developed to inhibit tumor angiogenesis. In the current study, we used the SK-N-BE (2) cell line to generate orthotopic NB tumors in order to study the combinational therapeutic potential of TL-118 with either Gemcitabine (40 mg/kg; IP) or Retinoic acid (40 mg/kg; IP). We show that TL-118 treatment (n = 9) significantly inhibited tumor growth, increased cell apoptosis, reduced proliferation and extended mouse survival. Moreover, the reciprocal effect of TL-118 and Gemcitabine treatment (n = 10) demonstrated improved anti-tumor activity. The synergistic effect of these drugs in combination was more effective than either TL or Gemcitabine alone (n = 9), via significantly reduced cell proliferation (p<0.005), increased apoptosis (p<0.05) and significantly prolonged survival (2-fold; p<0.00001). To conclude, we demonstrate that the novel drug combination TL-118 has the ability to suppress the growth of an aggressive NB tumor. The promising results with TL-118 in this aggressive animal model may imply that this drug combination has therapeutic potential in the clinical setting.

Fluid management during video-assisted thoracoscopic surgery for lung resection: a randomized, controlled trial of effects on urinary output and postoperative renal function.

BACKGROUND: Increased perioperative fluid administration is an independent risk factor for lung injury after pulmonary resection. In clinical practice, fluid therapy is heavily guided by urinary output; however, diuretic response to plasma volume expansion has been reported to be blunted during anesthesia and surgery. We therefore hypothesized that in patients undergoing video-assisted thoracoscopic surgery, different regimens of intraoperative fluid management would not affect urinary output as would be expected in the nonsurgical scenario. Moreover, a restrictive perioperative fluid approach, as indicated in these operations, will not harm renal function. METHODS: One hundred two patients undergoing video-assisted thoracoscopic surgery were randomly allocated to receive intraoperatively either high (8 mL/[kg · h]; n = 51) or low (2 mL/[kg · h]; n = 51) amounts of Ringer's lactate solution. The primary end point was intraoperative urinary output. Secondary end points included postoperative creatinine serum levels and postoperative complication rate. RESULTS: Demographic and surgical data were comparable between groups. Regardless of the intraoperatively fluids administered (mean ± SD, 2131 ± 850 vs 1035 ± 652 mL in high and low groups, respectively; P < .0001), urinary output was similar (median 300 mL). Perioperative creatinine serum levels decreased significantly postoperatively and were not significantly different among the groups. CONCLUSIONS: In patients undergoing video-assisted thoracoscopic surgery, intraoperative urinary output and postoperative renal function are not affected by administration of fluids in the range of 2 to 8 mL/(kg · h). The clinical practice of administering fluids to enhance diuresis in the perioperative period should therefore be abandoned.

fMRI-based hierarchical SVM model for the classification and grading of liver fibrosis.

We present a novel method for the automatic classification and grading of liver fibrosis based on hepatic hemodynamic changes measured noninvasively from functional MRI (fMRI) scans combined with hypercapnia and hyperoxia. The supervised learning method automatically creates a classification and grading model for liver fibrosis grade from training datasets. It constructs a statistical model of liver fibrosis by evaluating the signal intensity time course and local variance in T2(*)-W fMRI scans acquired during the breathing of air, air-carbon dioxide, and carbogen with a hierarchical multiclass binary-based support vector machine (SVM) classifier. Two experimental studies on 162 slices from 34 mice with the hierarchical multiclass binary-based SVM classifier yield 96.9% separation accuracy between healthy and histological-based fibrosis graded subjects, and an overall accuracy of 75.3% for healthy, fibrotic, and cirrhotic subjects. These results outperform existing image-based methods that can discriminate between healthy and mild-grade fibrosis subjects.