Julia Furtner

Invasion patterns in brain metastases of solid cancers

BACKGROUND Brain metastases are generally considered to be well demarcated from the surrounding brain parenchyma, although infiltrative growth patterns have been observed. We systemically investigated infiltration patterns and expression of adhesion molecules in a large and well-defined series of autopsy cases of brain metastases. METHODS Ninety-seven autopsy specimens from 57 brain metastasis patients (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 2 colorectal cancer, 1 kidney cancer, and 13 other) were evaluated for patterns of invasion into surrounding brain parenchyma. Expression of integrins αv; cytoplasmic β3, αvβ3, αvβ5, αvβ6, and αvβ8; and of E and N cadherin were evaluated using immunohistochemistry. RESULTS Three main invasion patterns were seen: well-demarcated growth (29/57, 51%), vascular co-option (10/57, 18%), and diffuse infiltration (18/57, 32%). There was no statistically significant association of invasion pattern with primary tumor type, although vascular co-option was most common in melanoma brain metastases (4/10). Invasion patterns of different brain metastases of the same patient were highly concordant (P < .001, chi-square test). Distance of infiltration from the main tumor mass ranged from 12.5 µm to 450 µm (median 56.2 µm) and was not significantly different between the vascular co-option and the diffuse infiltration groups. Levels of αvβ6 were significantly higher in the well-demarcated group than in the vascular co-option and the diffuse infiltration groups (P = .033, Kruskal-Wallis test). Expression of αvβ5 in tumor cells was higher in brain metastasis lesions previously treated with stereotactic radiosurgery (P = .034, chi-square test). CONCLUSIONS Distinct invasion patterns of brain metastases into the brain parenchyma are not specific for primary tumor types, seem to be influenced by expression of αv integrin complexes, and may help to guide clinical decision-making.

Pharmacokinetics and safety of gadobutrol-enhanced magnetic resonance imaging in pediatric patients.

Objectives:This clinical study investigated the pharmacokinetics and safety of gadobutrol, a magnetic resonance (MR) imaging extracellular contrast agent, in pediatric patients aged 2 to 17 years. Materials and Methods:In this open-label, multicenter study, patients scheduled for routine contrast-enhanced MR imaging of the brain, spine, liver or kidney, or MR angiography received a single intravenous injection of gadobutrol (0.1 mmol/kg/0.1 mL/kg). Patients were stratified by age groups (2–6, 7–11, and 12–17 years). Blood and urine samples were collected at prespecified time points and analyzed for gadolinium concentrations. Plasma data were evaluated by means of a nonlinear mixed effects model, and urine data were analyzed using descriptive statistics. In addition, the safety of gadobutrol was evaluated. Results:A total of 130 patients (2–6 years, n = 45; 7–11 years, n = 39; 12–17 years, n = 46) were included in the final population pharmacokinetic analysis. Gadobutrol pharmacokinetics in children aged 2 to 17 years were adequately described by an open 2-compartment model with elimination from the central compartment. The median estimates (2.5th percentile, 97.5th percentile) of body weight-normalized total body clearance (L/h/kg) per age group were 0.10 (0.05, 0.17) for all ages, 0.13 (0.09, 0.17) in the 2 to 6 year age group, 0.10 (0.05, 0.17) in the 7 to 11 year age group and 0.09 (0.05, 0.10) in the 12 to 17 year age group. The body weight-normalized median estimates of total volume of distribution (L/kg) were 0.20 (0.12, 0.28) for all ages, 0.24 (0.20, 0.28) in the 2 to 6 year age group, 0.19 (0.14, 0.23) in the 7 to 11 year age group and 0.18 (0.092, 0.23) in the 12 to 17 year age group. Median gadolinium plasma concentrations at 20 minutes postinjection were simulated using the population pharmacokinetic model and ranged from 414 (13 kg subject) to 518 &mgr;mol/L (65 kg subject). Body weight was identified as the major covariate influencing the pharmacokinetic parameters of total body clearance and central volume of distribution. Age was not found to be an additional independent parameter. The median amount of renally excreted gadolinium was 77.0% of the administered dose within 6 hours postinjection, indicating that gadobutrol was renally excreted in this pediatric population aged 2 to 17 years. Gadobutrol was well tolerated, with drug-related adverse events of mild intensity reported for 8 (5.8%) of 138 patients. Conclusions:Observed differences in pharmacokinetics were attributed to body weight, with no additional independent effect of age. Thus, no dose adjustment from the standard dose of gadobutrol in adults based on body weight (0.1 mmol/kg) is necessary in pediatric patients aged 2 to 17 years. Gadobutrol was safe and well tolerated in the pediatric population in this study.

Plasma MicroRNA-21 concentration may be a useful biomarker in glioblastoma patients.

Background: MicroRNAs are proposed as plasma biomarkers in cancer. Glioblastoma is the most frequent primary brain tumor of adults. MicroRNA-21 was shown to induce glioblastoma growth. Aims: To evaluate the circulating microRNA-21 in glioblastoma patients. Methods: MicroRNA-21 copies in glioblastoma plasma (n = 10, before surgery and during/after concomitant chemoradiotherapy), control plasma (n = 10), and tissue samples were analyzed using RT-qPCR. Results: MicroRNA-21 in glioblastoma was significantly higher than controls (p = .02) and decreased significantly in 9 patients (p = .05). One patient with increasing microRNA-21 developed a histopathologically proven recurrence after the second sample collection. Discussion: Circulating microRNA-21 might be a useful biomarker in glioblastoma.

Kinetics of tumor size and peritumoral brain edema before, during, and after systemic therapy in recurrent WHO grade II or III meningioma

BACKGROUND The efficacy of systemic antineoplastic therapy on recurrent World Health Organization (WHO) grades II and III meningiomas is unclear. METHODS We performed a retrospective multicenter analysis of serial cranial MRI in patients with recurrent WHO II and III meningiomas treated with antineoplastic systemic therapies. Growth rates for tumor volume and diameter, as well as change rates for edema size, were calculated for all lesions. RESULTS We identified a total of 34 patients (23 atypical, 11 anaplastic meningiomas) with a total of 57 meningioma lesions who had been treated at 6 European institutions. Systemic therapies included bevacizumab, cytotoxic chemotherapy, somatostatin analogues, and tyrosine kinase inhibitors. Overall, tumor growth rates decreased during systemic therapy by 51% for tumor diameter and 14% for tumor volume growth rates compared with the period before initiation of systemic therapy. The most pronounced decrease in meningioma growth rates during systemic therapy was evident in patients treated with bevacizumab, with a reduction of 80% in diameter and 59% in volume growth. Furthermore, a decrease in size of peritumoral edema after initiation of systemic therapy was exclusively observed in patients treated with bevacizumab (-107%). CONCLUSIONS Our data indicate that systemic therapy may inhibit growth of recurrent WHO grades II and III meningiomas to some extent. In our small cohort, bevacizumab had the most pronounced inhibitory effect on tumor growth, as well as some anti-edematous activity. Prospective studies are needed to better define the role of medical therapies in this tumor type.

Non-invasive assessment of intratumoral vascularity using arterial spin labeling: A comparison to susceptibility-weighted imaging for the differentiation of primary cerebral lymphoma and glioblastoma

Using conventional MRI methods, the differentiation of primary cerebral lymphomas (PCNSL) and other primary brain tumors, such as glioblastomas, is difficult due to overlapping imaging characteristics. This study was designed to discriminate tumor entities using normalized vascular intratumoral signal intensity values (nVITS) obtained from pulsed arterial spin labeling (PASL), combined with intratumoral susceptibility signals (ITSS) from susceptibility-weighted imaging (SWI). Thirty consecutive patients with glioblastoma (n=22) and PCNSL (n=8), histologically classified according to the WHO brain tumor classification, were included. MRIs were acquired on a 3T scanner, and included PASL and SWI sequences. nVITS was defined by the signal intensity ratio between the tumor and the contralateral normal brain tissue, as obtained by PASL images. ITSS was determined as intratumoral low signal intensity structures detected on SWI sequences and were divided into four different grades. Potential differences in the nVITS and ITSS between glioblastomas and PCNSLs were revealed using statistical testing. To determine sensitivity, specificity, and diagnostic accuracy, as well as an optimum cut-off value for the differentiation of PCNSL and glioblastoma, a receiver operating characteristic analysis was used. We found that nVITS (p=0.011) and ITSS (p=0.001) values were significantly higher in glioblastoma than in PCNSL. The optimal cut-off value for nVITS was 1.41 and 1.5 for ITSS, with a sensitivity, specificity, and accuracy of more than 95%. These findings indicate that nVITS values have a comparable diagnostic accuracy to ITSS values in differentiating glioblastoma and PCNSL, offering a completely non-invasive and fast assessment of tumoral vascularity in a clinical setting.

Prognostic Value of Blood Flow Measurements Using Arterial Spin Labeling in Gliomas

The period of event-free survival (EFS) within the same histopathological glioma grades may have high variability, mainly without a known cause. The purpose of this study was to reveal the prognostic value of quantified tumor blood flow (TBF) values obtained by arterial spin labeling (ASL) for EFS in patients with histopathologically proven astrocytomas independent of WHO (World Health Organization) grade. Twenty-four patients with untreated gliomas underwent tumor perfusion quantification by means of pulsed ASL in 3T. The clinical history of the patients was retrospectively extracted from the local database. Six patients had to be excluded due to insufficent follow-up data for further evaluation or histopathologically verified oligodendroglioma tumor components. Receiver operating characteristic (ROC) curves were used to define an optimal cut-off value of maximum TBF (mTBF) values for subgrouping in low-perfused and high-perfused gliomas. Kaplan-Meier curves and Cox proportional hazard regression model were used to determine the prognostic value of mTBF for EFS. An optimal mTBF cut-off value of 182 ml/100 g/min (sensitivity  = 83%, specificity  = 100%) was determined. Patients with low-perfused gliomas had significantly longer EFS compared to patients with high-perfused gliomas (p = 0.0012) independent of the WHO glioma grade. Quantified mTBF values obtained by ASL offer a new and totally non-invasive marker to prognosticate the EFS, independently on histopathological tumor grading, in patients with gliomas.

Arterial Spin-Labeling Assessment of Normalized Vascular Intratumoral Signal Intensity as a Predictor of Histologic Grade of Astrocytic Neoplasms

BACKGROUND AND PURPOSE: Pulsed arterial spin-labeling is a noninvasive MR imaging perfusion method performed with the use of water in the arterial blood as an endogenous contrast agent. The purpose of this study was to determine the inversion time with the largest difference in normalized intratumoral signal intensity between high-grade and low-grade astrocytomas. MATERIALS AND METHODS: Thirty-three patients with gliomas, histologically classified as low-grade (n = 7) or high-grade astrocytomas (n = 26) according to the World Health Organization brain tumor classification, were included. A 3T MR scanner was used to perform pulsed arterial spin-labeling measurements at 8 different inversion times (370 ms, 614 ms, 864 ms, 1114 ms, 1364 ms, 1614 ms, 1864 ms, and 2114 ms). Normalized intratumoral signal intensity was calculated, which was defined by the signal intensity ratio of the tumor and the contralateral normal brain tissue for all fixed inversion times. A 3-way mixed ANOVA was used to reveal potential differences in the normalized vascular intratumoral signal intensity between high-grade and low-grade astrocytomas. RESULTS: The difference in normalized vascular intratumoral signal intensity between high-grade and low-grade astrocytomas obtained the most statistically significant results at 370 ms (P = .003, other P values ranged from .012–.955). CONCLUSIONS: The inversion time by which to differentiate high-grade and low-grade astrocytomas by use of normalized vascular intratumoral signal intensity was 370 ms in our study. The normalized vascular intratumoral signal intensity values at this inversion time mainly reflect the labeled intra-arterial blood bolus and therefore could be referred to as normalized vascular intratumoral signal intensity. Our data indicate that the use of normalized vascular intratumoral signal intensity values allows differentiation between low-grade and high-grade astrocytomas and thus may serve as a new, noninvasive marker for astrocytoma grading.

Rapid Detection of Bone Metastasis at Thoracoabdominal CT: Accuracy and Efficiency of a New Visualization Algorithm

PURPOSE To retrospectively assess the use of a combination of cancellous bone reconstructions (CBR) and multiplanar reconstructions (MPRs) for the detection of bone metastases at thoracoabdominal computed tomography (CT) compared with the use of MPRs alone. MATERIALS AND METHODS The study was approved by the local institutional review board. Included were 156 consecutive patients with confirmed cancer who underwent a whole-body positron emission tomography (PET)/CT examination for clinical purposes (93 male and 63 female patients; mean age ± standard deviation, 59.8 years ± 14.9; range, 11-85 years). Only the CT images were processed with the CBR algorithm, which segments the bones and removes the cortical layer from the images. The PET images served as part of the reference standard. Images from 15 patients were used as a training set. Four radiologists independently evaluated images of half of the remaining 141 patients by using CBRs and MPRs together, and the other half by using MPRs only. Radiologists were blinded to patient names, and patient order was randomized. Results for detection rates and reporting time were recorded and compared with a standard of reference for each patient that was created by one senior radiologist and one nuclear medicine specialist by using all available CT and PET data, CBRs, and follow-up examinations. General estimation equations were used for statistical analysis. RESULTS There were 349 lesions found in 103 patients, with 203 classified as malignant. Each patient was assessed by two readers per method, leading to a total of 698 lesions. The detection rate for all bone lesions was 35% (247 of 698) for MPRs and 74% (520 of 698) when CBRs and MPRs were used together, which was significantly higher (P < .001). The average reading time decreased from 85 to 43 seconds (P < .001) when both reconstructions were used. CONCLUSION Advanced visualization of cancellous bone significantly increased the detection of bone metastases and reduced the time for interpretation.

Alleviation of brain edema and restoration of functional independence by bevacizumab in brain-metastatic breast cancer: a case report.

Background: Brain metastases (BM) are an increasing challenge in modern oncology, as treatment options especially after exhaustion of local treatment approaches are very limited. Patient and Methods: A long-term surviving patient with brain-only metastatic breast cancer, who presented at our department with massive corticosteroid-refractory brain edema with serious neurological symptoms after exhaustion of all local therapy options, was started on bevacizumab. Results: Initiation of bevacizumab monotherapy led to rapid decrease of contrast-enhancing lesions and alleviation of brain edema, and allowed tapering and termination of corticosteroid administration. Neurological and neurocognitive function was restored and marked improvement in quality of life was observed. Conclusion: Our case highlights that bevacizumab may represent a feasible and effective salvage treatment option in selected patients with BM.

MR-based morphometry of the posterior fossa in fetuses with neural tube defects of the spine.

Objectives In cases of “spina bifida,” a detailed prenatal imaging assessment of the exact morphology of neural tube defects (NTD) is often limited. Due to the diverse clinical prognosis and prenatal treatment options, imaging parameters that support the prenatal differentiation between open and closed neural tube defects (ONTDs and CNTDs) are required. This fetal MR study aims to evaluate the clivus-supraocciput angle (CSA) and the maximum transverse diameter of the posterior fossa (TDPF) as morphometric parameters to aid in the reliable diagnosis of either ONTDs or CNTDs. Methods The TDPF and the CSA of 238 fetuses (20–37 GW, mean: 28.36 GW) with a normal central nervous system, 44 with ONTDS, and 13 with CNTDs (18–37 GW, mean: 24.3 GW) were retrospectively measured using T2-weighted 1.5 Tesla MR -sequences. Results Normal fetuses showed a significant increase in the TDPF (r = .956; p<.001) and CSA (r = .714; p<.001) with gestational age. In ONTDs the CSA was significantly smaller (p<.001) than in normal controls and CNTDs, whereas in CNTDs the CSA was not significantly smaller than in controls (p = .160). In both ONTDs and in CNTDs the TDPF was significantly different from controls (p<.001). Conclusions The skull base morphology in fetuses with ONTDs differs significantly from cases with CNTDs and normal controls. This is the first study to show that the CSA changes during gestation and that it is a reliable imaging biomarker to distinguish between ONTDs and CNTDs, independent of the morphology of the spinal defect.