Abstract This study is the first one to compare WBRT + SRS to OP + WBRT for 1–3 brain metastases. Survival (OS), intracerebral control (IC) and local control (LC) of the treated metastases were retrospectively evaluated in 52 patients undergoing WBRT + SRS and in 52 patients undergoing OP + WBRT. Both groups were matched for WBRT schedule, age, gender, performance status, tumour, number of brain metastases, extracerebral metastases, RPA class and interval from tumour diagnosis to WBRT. One-year OS was 56% after WBRT + SRS and 47% after OP + WBRT ( p = 0.034). One-year IC was 66% and 50% ( p = 0.003). One-year LC was 82% and 66% ( p = 0.006). On multivariate analyses, it was found that improved OS was associated with younger age ( p = 0.044), no extracerebral metastases ( p < 0.001), RPA class 1 ( p < 0.001) and longer interval from tumour diagnosis to WBRT ( p = 0.001). IC was associated with younger age ( p = 0.002) and longer interval ( p = 0.004); WBRT + SRS achieved borderline significance ( p = 0.052). Improved LC was associated with longer interval ( p = 0.017); WBRT + SRS showed a trend ( p = 0.09). WBRT + SRS appears at least as effective as OP + WBRT.
Aims The efflux transporter P‐glycoprotein (ABCB1) acts at the blood–brain barrier (BBB) to restrict the distribution of many different drugs from blood to the brain. Previous data suggest an age‐associated decrease in the expression and function of ABCB1 at the BBB. In the present study, we investigated the influence of age on the magnitude of an ABCB1‐mediated drug–drug interaction (DDI) at the BBB. Methods We performed positron emission tomography scans using the model ABCB1 substrate (R)‐[11C]verapamil in five young [26 ± 1 years, (mean ± standard deviation)] and five elderly (68 ± 6 years) healthy male volunteers before and after intravenous administration of a low dose of the ABCB1 inhibitor tariquidar (3 mg kg−1). Results In baseline scans, the total distribution volume (VT) of (R)‐[11C]verapamil in whole‐brain grey matter was not significantly different between the elderly (VT = 0.78 ± 0.15) and young (VT = 0.79 ± 0.10) group. After partial (incomplete) ABCB1 inhibition, VT values were significantly higher (P = 0.040) in the elderly (VT = 1.08 ± 0.15) than in the young (VT = 0.80 ± 0.18) group. The percentage increase in (R)‐[11C]verapamil VT following partial ABCB1 inhibition was significantly greater (P = 0.032) in elderly (+40 ± 17%) than in young (+2 ± 17%) volunteers. Tariquidar plasma concentrations were not significantly different between the young (786 ± 178 nmol l−1) and elderly (1116 ± 347 nmol l−1) group. Conclusions Our results provide the first direct evidence of an increased risk for ABCB1‐mediated DDIs at the BBB in elderly persons, which may have important consequences for pharmacotherapy of the elderly.
Accurate and reproducible measurement of blood-brain barrier (BBB) integrity is critical in the assessment of the pathophysiology of the central nervous system disorders and in monitoring therapeutic effects. The widely-used low molecular weight marker [ C]sucrose is non-specific in the absence of chromatographic separation. The purpose of this study was to develop and validate a sensitive and reproducible LC–MS/MS method for the analysis of stable isotope-modified [ C ]sucrose in brain, plasma, and blood to determine BBB permeability to sucrose. After addition of internal standard (IS, [ C ]sucrose), the marker and IS were recovered from diluted rat blood, plasma, and brain homogenate by protein precipitation using acetonitrile. The recovery of the marker and IS was almost quantitative (90–106%) for all three matrices. The recovered samples were directly injected into an isocratic UPLC system with a run time of 6 min. Mass spectrometry was conducted using multiple reaction monitoring in negative mode. The method was linear ( ≥ 0.99) in the concentration ranges tested for the diluted blood and plasma (10–1000 ng/mL) and brain homogenate (1–200 ng/mL). The lower limit of quantitation of the assay was 0.5 pg injected on column. The assay was validated ( = 5) based on acceptable intra- and inter-run accuracy and precision values. The method was successfully used for the measurement of serial blood and plasma and terminal brain concentrations of [ C ]sucrose after a single intravenous dose (10 mg/kg) of the marker to rats. As expected, the apparent brain uptake clearance values of [ C ]sucrose were low in healthy rats. The method may be useful for determination of the BBB integrity in animal models.
The purpose of this study was to determine whether the brain uptake of [18F]FPEB is influenced by P‐glycoprotein (P‐gp) and breast cancer resistance protein (Bcrp) as efflux transporters in rodents. To assess this possible modulation, positron emission tomography studies were performed in animal models of pharmacological or genetic ablation of these transporters. Compared with the control conditions, when P‐gp was blocked with tariquidar, there was an 8%–12% increase in the brain uptake of [18F]FPEB. In P‐gp knockout mice, such as Mdr1a/b(−/−) and Mdr1a/b(−/−)Bcrp1(−/−), genetic ablation models, there was an increment of 8%–53% in [18F]FPEB uptake compared with that in the wild‐type mice. In contrast, Bcrp knockout mice showed a decrement of 5%–12% uptake and P‐gp/Bcrp knockout group displayed an increment of 5%–17% compared with wild type. These results indicate that [18F]FPEB is possibly a weak substrate for P‐gp. [18F]FPEB is a radiotracer for mGluR5. Pharmacological and genetic inhibition of efflux transporters in the blood–brain barrier demonstrated that it is a weak substrate P‐gp in the rodent.
We proposed to compare the outcomes of first‐line epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR‐TKI) alone with EGFR‐TKI plus whole‐brain radiotherapy (WBRT) for the treatment of brain metastases (BM) in patients with EGFR‐mutated lung adenocarcinoma. A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study. Among the 132 patients, 72 (54.5%) harbored a deletion in exon 19, 97 (73.5%) showed multiple intracranial lesions, and 67 (50.8%) had asymptomatic BM. Seventy‐nine patients (59.8%) were treated with EGFR‐TKI alone, 53 with concomitant WBRT. The intracranial objective response rate was significantly higher in the EGFR‐TKI plus WBRT treatment group (67.9%) compared with the EGFR‐TKI alone group (39.2%) (P = 0.001). After a median follow‐up of 36.2 months, 62.1% of patients were still alive. The median intracranial TTP was 24.7 months (95% CI, 19.5–29.9) in patients who received WBRT, which was significantly longer than in those who received EGFR‐TKI alone, with the median intracranial TTP of 18.2 months (95% CI, 12.5–23.9) (P = 0.004). There was no significant difference in overall survival between WBRT and EGFR‐TKI alone groups, (median, 48.0 vs 41.1 months; P = 0.740). The overall survival is significantly prolonged in patients who had an intracranial TTP exceeding 22 months compared to those who developed intracranial progression <22 months after treatment, (median, 58.0 vs 28.0 months; P = 0.001). For EGFR‐mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT achieved a higher response rate of BM and significant improvement in intracranial progression‐free survival compared with EGFR‐TKI alone. Though our study was limited by the retrospective nature, our analysis has the following strengths: it focuses on a specific histologic subtype of lung cancer, the findings showed that for EGFR‐mutated lung adenocarcinoma patients with BM, the combination of EGFR‐TKI plus WBRT had (i) higher intracranial objective response rate, (ii) longer time to intracranial progression, but (iii) similar overall survival.
Congenital HCMV infection is a leading infectious cause of long‐term neurodevelopmental sequelae. Infection of newborn mice with mouse cytomegalovirus (MCMV) intraperitoneally is a well‐established model of congenital human cytomegalovirus infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here, we used this model to investigate the role, dynamics, and phenotype of CD8+ T cells in the brain following infection of newborn mice. We show that CD8+ T cells infiltrate the brain and form a pool of tissue‐resident memory T cells (TRM cells) that persist for lifetime. Adoptively transferred virus‐specific CD8+ T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology, and remain in the brain as TRM cells. Brain CD8+ TRM cells were long‐lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8+ TRM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain. In a mouse model of congenital cytomegalovirus infection, CD8+ T cells infiltrate the brain and form a pool of tissue‐resident memory T cells (TRM cells) that persist for lifetime. Brain CD8+ TRM cells control cytomegalovirus and their depletion results in virus reactivation and enhanced brain inflammation.
To investigate the local control and radiation-induced brain necrosis in patients with brain metastases >2 cm in size who received single-fraction or multifraction stereotactic radiosurgery (SRS); factors associated with clinical outcomes and the development of brain radionecrosis were assessed. Two hundred eighty-nine consecutive patients with brain metastases >2.0 cm who received SRS as primary treatment at Sant'Andrea Hospital, University of Rome Sapienza, Rome, Italy, were analyzed. Cumulative incidence analysis was used to compare local control and radiation-induced brain necrosis between groups from the time of SRS. To achieve a balanced distribution of baseline covariates between treatment groups, a propensity score analysis was used. The 1-year cumulative local control rates were 77% in the single-fraction SRS (SF-SRS) group and 91% in the multifraction SRS (MF-SRS) group ( =.01). Recurrences occurred in 25 and 11 patients who received SF-SRS or MF-SRS ( =.03), respectively. Thirty-one patients (20%) undergoing SF-SRS and 11 (8%) subjected to MF-SRS experienced brain radionecrosis ( =.004); the 1-year cumulative incidence rate of radionecrosis was 18% and 9% ( =.01), respectively. Significant differences between the 2 groups in terms of local control and risk of radionecrosis were maintained after propensity score adjustment. Multifraction SRS at a dose of 27 Gy in 3 daily fractions seems to be an effective treatment modality for large brain metastases, associated with better local control and a reduced risk of radiation-induced radionecrosis as compared with SF-SRS.
Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis. In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12–20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with , number . Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1–18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45–5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86–3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35–0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS 41 [85%] of 48 evaluable patients assigned to WBRT; difference −33·6% [95% CI −45·3 to −21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7–16·0, 69 deaths) for SRS and 11·6 months (9·9–18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76–1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] five [5%]). There were no treatment-related deaths. Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population. National Cancer Institute.
The purpose of the present study was to estimate the relative contributions of degradation and brain-to-blood elimination processes to the clearance of microinjected human amyloid-β peptide(1-40) (hAβ(1-40)) from mouse cerebral cortex, using a solid-phase extraction method together with a newly developed ultraperformance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) quantitation method for intact hAβ(1-40). The clearance rate constant of hAβ(1-40) in mouse cerebral cortex was determined to be 3.21 × 10−2/min under conditions where the saturable brain-to-blood elimination process across the blood–brain barrier (BBB) was expected to be saturated. Thus, this clearance rate constant should mainly reflect degradation. The [125I]hAβ(1-40) elimination rate across the BBB under nonsaturating conditions was determined to be 1.48 × 10−2/min. Inhibition studies suggested that processes sensitive to insulin and phosphoramidon, which inhibit neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme, are involved not only in degradation, but also in elimination of hAβ(1-40). In conclusion, our results suggest a dominant contribution of degradation to cerebral hAβ(1-40) clearance, and also indicate that a sequential process of degradation and elimination of degradation products is involved in cerebral hAβ(1-40) clearance.