Ulrike Ernemann

NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma With Procarbazine, Lomustine, and Vincristine or Temozolomide

PURPOSE The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas. PATIENTS AND METHODS Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence. RESULTS Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm. CONCLUSION Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation.

Hybrid PET/MRI of Intracranial Masses: Initial Experiences and Comparison to PET/CT

Simultaneous PET and MRI using new hybrid PET/MRI systems promises optimal spatial and temporal coregistration of structural, functional, and molecular image data. In a pilot study of 10 patients with intracranial masses, the feasibility of tumor assessment using a PET/MRI system comprising lutetium oxyorthosilicate scintillators coupled to avalanche photodiodes was evaluated, and quantification accuracy was compared with conventional PET/CT datasets. Methods: All measurements were performed with a hybrid PET/MRI scanner consisting of a conventional 3-T MRI scanner in combination with an inserted MRI-compatible PET system. Attenuation correction of PET/MR images was computed from MRI datasets. Diagnoses at the time of referral were low-grade astrocytoma (n = 2), suspicion of low-grade astrocytoma (n = 1), anaplastic astrocytoma (World Health Organization grade III; n = 1), glioblastoma (n = 2), atypical neurocytoma (n = 1), and meningioma (n = 3). In the glial tumors, 11C-methionine was used for PET; in the meningiomas, 68Ga-DOTATOC was administered. Tumor–to–gray matter and tumor–to–white matter ratios were calculated for gliomas, and tracer uptake of meningiomas was referenced to nasal mucosa. PET/MRI was performed directly after clinically indicated PET/CT examination. Results: In all patients, the PET datasets showed similar diagnostic image quality on the hybrid PET/MRI and the PET/CT studies; however, slight streak artifacts were visible in coronal and sagittal sections when using the higher intrinsic resolution of the PET/MRI insert. Prefiltering of images with a 4-mm gaussian filter at a resolution comparable to that of the PET/CT system virtually eliminated these artifacts. Although acquisition of the PET/MR images started at 30–60 min after PET/CT (20.4-min half-life of 11C) acquisition, the signal-to-noise ratio was good enough, thus underlining the high sensitivity of the PET insert, compared with whole-body PET systems. The computed tumor–to–reference tissue ratios exhibited an excellent accordance between the PET/MRI and PET/CT systems, with a Pearson correlation coefficient of 0.98. Mean paired relative error was 7.9% ± 12.2%. No significant artifacts or distortions were detected in the simultaneously acquired MR images using the PET/MRI scanner. Conclusion: Structural, functional, and molecular imaging in patients with brain tumors is feasible with diagnostic imaging quality using simultaneous hybrid PET/MR image acquisition.

High-Profile Flow Diverter (Silk) Implantation in the Basilar Artery: Efficacy in the Treatment of Aneurysms and the Role of the Perforators

Background and Purpose— The introduction of flow diverters (FDs) has expanded the possibilities for reconstructive treatment of difficult intracranial aneurysms. Concern remains as to the long-term patency of the perforating arteries and side branches covered during stent placement. Our purpose was to evaluate the performance of and early effect on covered branches after implantation of the Silk FD in the treatment of basilar artery aneurysms. Methods— Twelve patients with an aneurysm of the basilar artery that was treated by implantation of the Silk FD were included in our retrospective study. Both unruptured and previously ruptured, formerly untreated, and recurrent aneurysms were treated. During follow-up, patients were monitored for clinical evolution, patency of the covered vessels, and aneurysmal obliteration. Results— Of the 2 ruptured aneurysms, 1 was initially treated by FD implantation. The FD covered the basilar bifurcation and the origin of a P1 segment of the posterior cerebral artery in 9 cases, the origin of the superior cerebellar artery in 9, and of the anterior inferior cerebellar artery in 3. There was 1 acute basilar artery occlusion a few hours after FD implantation. During a mean follow-up of 16 weeks, 3 patients experienced a symptomatic neurologic event. Conclusions— Implantation of the Silk FD in the basilar artery was feasible and well tolerated in most cases to date. However, late ischemic events affecting perforating arteries may occur after FD implantation, suggesting that the indication should be restricted to otherwise untreatable aneurysms in this location.

Systematic Review of Early Recurrent Stenosis After Carotid Angioplasty and Stenting

Background and Purpose— Carotid angioplasty and stenting (CAS) has emerged as a potential alternative to endarterectomy (CEA) for the treatment of carotid artery disease. Aside from the periprocedural complication rates, the benefits of CAS will be affected by the incidence of recurrent carotid stenosis. Methods— We conducted a systematic analysis of all peer-reviewed studies reporting on the rate of restenosis (≥50%) after CAS based on duplex ultrasound or angiography that were published between January 1990 and July 2004. We identified 34 studies that reported on a total of 4185 patients with a follow-up of 3814 arteries over a median of 13 months (range, 6 to 31 months). The ultrasound criteria and the lower thresholds for defining a recurrent stenosis were very heterogeneous. Results— The cumulative restenosis rates after 1 and 2 years were ≈6% and 7.5% in those studies, which used a lower restenosis threshold ≥50% to 70% and ≈4% in the first 2 years after CAS in those studies, which used a lower restenosis threshold >70% to 80%. Conclusions— In reviewing the current literature, the early restenosis rates after CAS compare well with those reported for CEA. However, this analysis of the peer-reviewed literature also indicates that the early restenosis rates after CAS might be higher than previously suggested in observational surveys. Therefore, an active follow-up of all stented arteries seems to be warranted. Moreover, the bulk of endovascular data are derived from small studies with short follow-up periods so that the long-term durability of CAS still needs to be established in large trials. Ideally, these studies should use a clear and uniform definition of restenosis and identical follow-up schedules.

Incidence of New Brain Lesions After Carotid Stenting With and Without Cerebral Protection

Background and Purpose— Diffusion-weighted imaging (DWI) may be a useful tool to evaluate the efficacy of cerebral protection devices in preventing thromboembolic complications during carotid angioplasty and stenting (CAS). The goals of this study were (1) to compare the frequency, number, and size of new DWI lesions after unprotected and protected CAS; and (2) to determine the clinical significance of these lesions. Methods— DWI was performed immediately before and within 48 hours after unprotected or protected CAS. Clinical outcome measures were stroke and death within 30 days. Results— The proportion of patients with any new ipsilateral DWI lesion (49% versus 67%; P<0.05) as well as the number of new ipsilateral DWI lesions (median=0; interquartile range [IQR]=0 to 3 versus median=1; IQR=0 to 4; P<0.05) were significantly lower after protected (n=139) than unprotected (n=67) CAS. The great majority of these lesions were asymptomatic and less than 10 mm in diameter. Although there were no significant differences in clinical outcome between patients treated and not treated with protection devices (7.5% versus 4.3%, not significant), the number of new DWI lesions was significantly higher in patients who developed a stroke (median=7.5; IQR=1.5 to 17) than in patients who did not (median=0; IQR=1 to 3.25; P<0.01). Conclusions— The use of cerebral protection devices significantly reduces the incidence of new DWI lesions after CAS of which the majority are asymptomatic and less than 10 mm in diameter. The frequent occurrence of these lesions and their close correlation with the clinical outcome indicates that DWI could become a sensitive surrogate end point in future randomized trials of unprotected versus protected CAS.

Longitudinal Changes in Fiber Tract Integrity in Healthy Aging and Mild Cognitive Impairment: A DTI Follow-Up Study

Cross-sectional studies using diffusion tensor imaging (DTI) suggest decline of the integrity of intracortically projecting fiber tracts with aging and in neurodegenerative diseases, such as Alzheimers disease (AD). Longitudinal studies on the change of fiber tract integrity in normal and pathological aging are still rare. Here, we prospectively studied 11 healthy elderly subjects and 14 subjects with amnestic mild cognitive impairment (MCI), a clinical risk group for AD, using high-resolution DTI and MRI at baseline and after 13 to 16 months follow-up. Fractional anisotropy (FA), a DTI measure of fiber tract integrity, was compared across time points and groups using a repeated measures linear model and tract based spatial statistics. Additionally, we determined rates of grey matter and white matter atrophy using automated deformation based morphometry. Healthy elderly subjects showed decline of FA in intracortical projecting fiber tracts, such as corpus callosum, superior longitudinal fasciculus, uncinate fasciculus, inferior fronto-occipital fasciculus, and cingulate bundle (p < 0.05, corrected for multiple comparisons). MCI subjects showed significant FA decline predominantly in the anterior corpus callosum (p < 0.05, corrected for multiple comparisons). Grey and white matter atrophy involved prefrontal, parietal, and temporal lobe areas in controls and prefrontal, cingulate, and parietal lobe areas in MCI subjects and agreed with the pattern of fiber tract changes. Our findings indicate that DTI allows detection of microstructural changes in subcortical fiber tracts over time that are related to aging as well as to early stages of AD type neurodegeneration. The underlying mechanisms for these changes are unknown.

Iterative Reconstruction in Head CT: Image Quality of Routine and Low-Dose Protocols in Comparison with Standard Filtered Back-Projection

BACKGROUND AND PURPOSE: IR has recently demonstrated its capacity to reduce noise and permit dose reduction in abdominal and thoracic CT applications. The purpose of our study was to assess the potential benefit of IR in head CT by comparing objective and subjective image quality with standard FBP at various dose levels. MATERIALS AND METHODS: Ninety consecutive patients were randomly assigned to undergo nonenhanced and contrast-enhanced head CT at a standard dose (320 mAs; CTDI, 60.1) or 15% (275 mAs; CTDI, 51.8) and 30% (225 mAs; CTDI, 42.3) dose reduction. All acquisitions were reconstructed with IR in image space, and FBP and images were assessed in terms of quantitative and qualitative IQ. RESULTS: Compared with FBP, IR resulted in lower image noise (P ≤ .02), higher CNR (P ≤ .03), and improved subjective image quality (P ≤ .002) at all dose levels. While degradation of objective and subjective IQ at 15% dose reduction was fully compensated by IR (CNR, 1.98 ± 0.4 at 320 mAs with FBP versus 2.05 ± 0.4 at 275 mAs with IR; IQ, 1.8 versus 1.7), IQ was considerably poorer at 70% standard dose despite using the iterative approach (CNR, 1.98 ± 0.3 at 320 mAs with FBP versus 1.85 ± 0.4 at 225 mAs with IR, P = .18; IQ, 1.8 versus 2.2, P = .03). Linear regression analysis of CNR against tube current suggests that standard CNR may be obtained until approximately 20.4% dose reduction when IR is used. CONCLUSIONS: Compared with conventional FBP, IR of head CT is associated with significant improvement of objective and subjective IQ and may allow dose reductions in the range of 20% without compromising standard image quality.

Current concepts in the classification, diagnosis and treatment of vascular anomalies.

Patients with extended vascular anomalies may suffer from significant aesthetic and functional impairment and represent a challenge to therapeutic planning, which is best met by an interdisciplinary concept. In agreement with the International Society for the Study of Vascular Anomalies (ISSVA), vascular lesions are classified into haemangiomas as proliferating endothelial tumours on the one hand and congenital vascular malformations on the other. According to the preponderant vascular channels and hemodynamic characteristics, malformations are subdivided into low flow (venous, lymphatic and capillary) lesions and high-flow malformations. Diagnostic imaging should be targeted at the specific structural and functional informations required for treatment planning. The imaging modality of choice to provide these informations is magnetic resonance imaging (MRI) supplemented by magnetic resonance angiography (MRA) with high spatial and temporal resolution. Treatment indications for haemangiomas depend on the proliferative behaviour of the lesion and comprise beta-blockers in order to induce involution as well as cryotherapy, laser and open surgery. Interventional radiological procedures have evolved as an essential element in an interdisciplinary treatment plan for vascular malformations and include percutaneous sclerotherapy with ethanol and OK-432 for venous and lymphatic malformations and transarterial embolization for high-flow lesions.

Spinal Subdural and Epidural Haematomas: Diagnostic and Therapeutic Aspects in Acute and Subacute Cases

Summary Background. The diagnosis of spontaneous spinal haematomas mainly depends on magnetic resonance imaging. This study evaluates the MRI characteristics of spinal epidural and subdural haematomas. The results were correlated with medical history, coagulation abnormalities and therapeutic outcome to provide guidelines for early diagnosis and treatment of spinal epidural and subdural hematomas. Summary of Background Data. Imaging signs of epidural and subdural haematomas have been reported before, however without special attention to the differential-diagnostic and therapeutic implications of haematoma localisation. Method. Seven patients (3 women, 4 men, age range 55–86 years) with acute progressive neurological deficits and without a history of severe trauma were studied. In all cases neurological examinations were performed after admission followed by MRI studies with T2 and T1 weighted images, before and after administration of contrast agent. Spinal angiography was performed twice to exclude a vascular malformation. All patients underwent open surgery. Findings. Acute and subacute hematomas were detected once in the cervical spine, in five cases in the thoracic region and once in the lumbar region. The hematomas had an epidural location in three cases and a subdural in four. In the thoracic region subdural haemorrhage was much more common than epidural hematomas. Subdural blood collections were mainly found ventral to the spinal cord. Epidural haemorrhage was always located dorsal to the spinal cord. The evaluation of the haematoma localisation may be difficult occasionally, but delineation of the dura is frequently possible in good quality MRI. The clue to the diagnosis of ventrally located subdural haemorrhage is the absence of the “curtain sign”, which is typical for epidural tumours. Interpretation. Spontaneous spinal hematomas are frequently located in the thoracic spine. Subdural spinal haemorrhage is more frequent than epidural. Epidural haemorrhage is frequently located dorsal to the spinal cord because of the tight fixation of the dura to the vertebral bodies.

Multicenter stability of diffusion tensor imaging measures: A European clinical and physical phantom study

Diffusion tensor imaging (DTI) detects white matter damage in neuro-psychiatric disorders, but data on reliability of DTI measures across more than two scanners are still missing. In this study we assessed multicenter reproducibility of DTI acquisitions based on a physical phantom as well as brain scans across 16 scanners. In addition, we performed DTI scans in a group of 26 patients with clinically probable Alzheimers disease (AD) and 12 healthy elderly controls at one single center. We determined the variability of fractional anisotropy (FA) measures using manually placed regions of interest as well as automated tract based spatial statistics and deformation based analysis. The coefficient of variation (CV) of FA was 6.9% for the physical phantom data. The mean CV across the multicenter brain scans was 14% for tract based statistics, and 29% for deformation based analysis. The degree of variation was higher in less organized fiber tracts. Our findings suggest that a clinical and physical phantom study involving more than two scanners is indispensable to detect potential sources of bias and to reliably estimate effect size in multicenter diagnostic trials using DTI.