Purpose: The blood–brain barrier (BBB) is modified to a blood–tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (i) quantified the permeability of experimental brain metastases, (ii) determined the composition of the BTB, and (iii) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability. Experimental Design: A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline was established. Experimental brain metastases from this model system and two previously reported models (triple-negative MDA-231-BR6, HER2⁺ JIMT-1-BR3) were serially sectioned; low- and high-permeability lesions were identified with systemic 3-kDa Texas Red dextran dye. Adjoining sections were used for quantitative immunofluorescence to known BBB and neuroinflammatory components. One-sample comparisons against a hypothesized value of one were performed with the Wilcoxon signed-rank test. Results: When uninvolved brain was compared with any brain metastasis, alterations in endothelial, pericytic, astrocytic, and microglial components were observed. When metastases with relatively low and high permeability were compared, increased expression of a desmin⁺ subpopulation of pericytes was associated with higher permeability (231-BR6 P = 0.0002; JIMT-1-BR3 P = 0.004; SUM190-BR3 P = 0.008); desmin⁺ pericytes were also identified in human craniotomy specimens. Trends of reduced CD13⁺ pericytes (231-BR6 P = 0.014; JIMT-1-BR3 P = 0.002, SUM190-BR3, NS) and laminin α2 (231-BR6 P = 0.001; JIMT-1-BR3 P = 0.049; SUM190-BR3 P = 0.023) were also observed with increased permeability. Conclusions: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin⁺ pericytes and laminin α2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287–99. ©2016 AACR.

Brain metastases are devastating complications of cancer. The blood–brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood–tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients’ brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability.

Validation of a translated, culturally adapted questionnaire. To translate and culturally adapt a Polish version of the Oswestry Disability Index (ODI) and to validate its use in Polish patients. The ODI is among the most popular questionnaires used to evaluate back pain-related disability. To our knowledge no validated Polish version of the index was available at the time our study was initiated. The questionnaire was translated and culturally adapted by 2 independent translators and approved by expert committee. Final version was included in the booklet consisting in addition of a previously validated Roland-Morris disability questionnaire, VAS for low back and leg and 3 Likert scale questions (pain medications, pain frequency, disability). It was tested on 169 patients with chronic low back pain, 164 (97%) of them were enrolled, and 84 of 164 (53%) returned the completed retest booklet within 2 to 14 days after the baseline test. There were no differences between the 2 groups in demographic and clinical parameters. Test-retest reliability, internal consistency, and construct validity were investigated. The mean ODI (standard deviation [SD]) was 48.45 (18.94); minimum 2, maximum 94. The Cronbach α for baseline questionnaires (n = 164) was 0.90. Concurrent validity, measured by comparing ODI responses with the results of the Roland-Morris disability questionnaire score was very good (r = 0.607, P < 0.001). The correlation with VAS back was fair (r = 0.37, P < 0.001) and with VAS leg was good (r = 0.56, P < 0.001). The tested ODI had excellent test-retest reliability, the intraclass correlation coefficient was 0.97 and standard error of measurements was 3.54, the resulting minimal detectable changes at the 95% confidence level was 10. The results of this study indicate that the Polish version of the ODI is a reliable and valid instrument for the measurement of disability in Polish-speaking patients with lower back pain.

Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite tre

A comparative clinical study of two main corrective manoeuvres in scoliosis surgery. To compare the effectiveness of two main corrective manoeuvres: single concave rod rotation (SCRR) and direct vertebral rotation (DVR) in regard to apical vertebral rotation (AVR) and rib hump correction in adolescent idiopathic scoliosis (AIS) surgery. It remains unclear whether SCRR manoeuvre alone causes apical vertebral derotation (AVD) and rib hump correction. Although the influence of DVR on AVD and rib hump change has been described, it has been evaluated mainly with indirect methods. This is the first study to evaluate separately the derotational effectiveness of these two manoeuvres during the low-dose intraoperative computed tomography (ICT). A study group consisted of 38 AIS patients treated by posterior scoliosis surgery (PSS) with all pedicle screw constructs. All examined patients had dow-dose ICT evaluation (before correction, after SCRR, and after DVR). We found SCRR ineffective - mean postcorrectional AVR increased insignificantly 1.5° (16.1% worsening) P = 0.170. On the contrary, an average postcorrectional AVR after DVR decreased significantly mean 3.1° (33.3% improvement) P = 0.049. Precorrectional rib hump angle was 19.3°, after SCRR 15°, and after DVR 12.3°. It was found that despite the lack of true derotation after SCRR there was a significant 22.3% decrease of the rib hump P = 0.043. Although the rib hump decreased significantly 36.3% after DVR as well P = 0.023. There was also significant difference between a rib hump angle after SCRR and DVR (P = 0.049). SCRR does not lead to AVD. The true spinal derotation is possible only when DVR systems are used. The decrease of rib hump is achieved after both SCRR and DVR, but the improvement is significantly better after DVR. 3.