BackgroundElevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer.MethodsEligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed.ResultsEight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3–9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0–10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF.ConclusionsBEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease.Trial registrationClinicalTrials.gov identifying number NCT01281696.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1290-1) contains supplementary material, which is available to authorized users.

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A greater understanding of brain metastases is imperative for developing novel therapeutic strategies. Our previous study showed that insulin-like growth factor (IGF) signaling pathway was activated in brain-tropic cancer cells. In this study, we investigated the clinical relevance of activated (phosphorylated) IGF-1 receptor (pIGF1R) expression in brain metastases originating from lung adenocarcinomas. All pathologically confirmed brain metastases from lung adenocarcinomas, with available archived specimens from January 1998 to December 2009 at National Taiwan University Hospital, were assessed immunohistochemically for pIGF1R expression using H-score criteria. A median H-score was used as a cutoff point to define high or low pIGF1R expression. The mutation status in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) was examined using direct sequencing. The prognostic significance of pIGF1R expression, its correlations with clinicopathological characteristics, and EGFR status were evaluated. In the 86 cases, high membranous/cytoplasmic pIGF1R expression in brain metastases correlated with a shorter median survival (10.8 vs 27.8 mo, P = 0.003). This correlation was more significant in patients with EGFR mutations [hazard ratio (HR) 2.38, 95 % confidence interval (CI) 1.19-4.77 for EGFR mutations; HR 1.99, 95 % CI 0.95-4.15 for EGFR wild type] and remained statistically significant in multivariate analysis after adjusting for the effects of other potential prognostic factors, including the graded prognostic assessment score, solitary brain metastasis, extracranial metastatic status, EGFR mutations, and treatment using EGFR tyrosine kinase inhibitors. Although we also identified nuclear pIGF1R expression, this result was prognostically non-significant. Our study results showed that high membranous/cytoplasmic pIGF1R expression in brain metastases was a poor prognostic factor, more significantly in patients with EGFR mutations than in those with wild-type EGFRs.

Relaxation of the CH stretch in liquid C H Br 3 : Solvent effects and decay rates using classical nonequilibrium simulations Molecular dynamics simulations were carried out to determine the vibrational energy relaxation rates for C-H,D,T stretches on hydrogen-, deuterium-, and tritium-terminated H,D,T/C͑111͒ and H,D,T/C͑110͒ diamond surfaces at high temperatures based on the Bloch-Redfield theory and the calculated power spectra of fluctuating force along C-H,D,T stretches. The lifetime of C-H stretches on H/͑110͒ surfaces at room temperature was found to be 0.8 ps, which is much shorter than the calculated lifetime of 30 ps on a H/C͑111͒ surface attributed to 1:3 resonance. This is due to the blueshift of the 1:2 resonance domain in the force power spectra for a H/C͑110͒ surface. The lifetimes of C-H stretches on a H/C͑110͒ surface and C-D,T stretches on both D,T/C͑111͒ and D,T/C͑110͒ surfaces, which all undergo 1:2 resonance energy relaxation, are all on the time scale of tenths of a picosecond at room temperature and are approximately inversely proportional to the square of the temperature at high temperatures. For C-H stretches on a H/C͑111͒ surface, the lifetimes at high temperatures are shortened much further not only by the rise in the temperature but also due to the thermal broadening of the resonance peaks in the force power spectra. The characteristics of power spectra and the resulting relaxation rates were analyzed using a simple model of a constrained diatomic bond in a harmonic bending potential field. The present results suggest that, since the resonance frequencies of C-H stretches are located within the border region between the 1:2 and 1:3 resonance domains, the vibrational energy relaxation of C-H stretches may differ by more than an order of one on different monohydrided low index unreconstructed diamond surfaces in contrast to the lifetimes of C-D,T stretches on these diamond surfaces, which are all on the same time scale at a given temperature.