Interstitial Photodynamic Therapy of Glioblastomas: A Long-Term Follow-up Analysis of Survival and Volumetric MRI Data.

BACKGROUND: The treatment of glioblastomas, the most common primary malignant brain tumors, with a devastating survival perspective, remains a major challenge in medicine. Among the recently explored therapeutic approaches, 5-aminolevulinic acid (5-ALA)-mediated interstitial photodynamic therapy (iPDT) has shown promising results. METHODS: A total of 16 patients suffering from de novo glioblastomas and undergoing iPDT as their primary treatment were retrospectively analyzed regarding survival and the characteristic tissue regions discernible in the MRI data before treatment and during follow-up. These regions were segmented at different stages and were analyzed, especially regarding their relation to survival. RESULTS: In comparison to the reference cohorts treated with other therapies, the iPDT cohort showed a significantly prolonged progression-free survival (PFS) and overall survival (OS). A total of 10 of 16 patients experienced prolonged OS (≥ 24 months). The dominant prognosis-affecting factor was the MGMT promoter methylation status (methylated: median PFS of 35.7 months and median OS of 43.9 months) (unmethylated: median PFS of 8.3 months and median OS of 15.0 months) (combined: median PFS of 16.4 months and median OS of 28.0 months). Several parameters with a known prognostic relevance to survival after standard treatment were not found to be relevant to this iPDT cohort, such as the necrosis-tumor ratio, tumor volume, and posttreatment contrast enhancement. After iPDT, a characteristic structure (iPDT remnant) appeared in the MRI data in the former tumor area. CONCLUSIONS: In this study, iPDT showed its potential as a treatment option for glioblastomas, with a large fraction of patients having prolonged OS. Parameters of prognostic relevance could be derived from the patient characteristics and MRI data, but they may partially need to be interpreted differently compared to the standard of care.

Interstitial photodynamic therapy for newly diagnosed glioblastoma.

PURPOSE: Innovative, efficient treatments are desperately needed for people with glioblastoma (GBM). METHODS: Sixteen patients (median age 65.8 years) with newly diagnosed, small-sized, not safely resectable supratentorial GBM underwent interstitial photodynamic therapy (iPDT) as upfront eradicating local therapy followed by standard chemoradiation. 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX was used as the photosensitizer. The tumors were irradiated with light at 635 nm wavelength via stereotactically implanted cylindrical diffuser fibers. Outcome after iPDT was retrospectively compared with a positively-selected in-house patient cohort (n = 110) who underwent complete tumor resection followed by chemoradiation. RESULTS: Median progression-free survival (PFS) was 16.4 months, and median overall survival (OS) was 28.0 months. Seven patients (43.8%) experienced long-term PFS > 24 months. Median follow-up was 113.9 months for the survivors. Univariate regression revealed MGMT-promoter methylation but not age as a prognostic factor for both OS (p = 0.04 and p = 0.07) and PFS (p = 0.04 and p = 0.67). Permanent iPDT-associated morbidity was seen in one iPDT patient (6.3%). Patients treated with iPDT experienced superior PFS and OS compared to patients who underwent complete tumor removal (p < 0.01 and p = 0.01, respectively). The rate of long-term PFS was higher in iPDT-treated patients (43.8% vs. 8.9%, p < 0.01). CONCLUSION: iPDT is a feasible treatment concept and might be associated with long-term PFS in a subgroup of GBM patients, potentially via induction of so far unknown immunological tumor-controlling processes.

Frequency and Longitudinal Course of Motor Signs In Genetic Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: Frontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the c9orf72, GRN and MAPT gene. As motor disorders are increasingly recognized as part of the clinical spectrum the current study aimed to describe motor phenotypes caused by genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. METHODS: We analyzed baseline visit data of known carriers of a pathogenic variant in the c9orf72, GRN or MAPT gene from the Genetic Frontotemporal dementia Initiative cohort study. Principal component analysis with varimax rotation was performed to identify motor sign clusters that were compared with respect to frequency and severity between groups. Associations with cross-sectional atrophy patterns were determined using voxel-wise regression. We applied linear mixed effects models to assess whether groups differed in the association between motor signs and estimated time to symptom onset. RESULTS: 322 pathogenic variant carriers were included in the analysis: 122 c9orf72 (79 presymptomatic), 143 GRN (112 presymptomatic) and 57 MAPT (43 presymptomatic) pathogenic variant carriers. Principal component analysis revealed five motor clusters, which we call progressive supranuclear palsy like (PSP-like), bulbar amyotrophic lateral sclerosis (ALS) like, mixed/ALS-like, Parkinson's disease like (PD-like), and corticobasal syndrome like motor phenotypes. There was no significant group difference in the frequency of signs of different motor phenotypes. However, mixed/ALS-like motor signs were most frequent, followed by PD-like motor signs. While the PSP-like phenotype was associated with mesencephalic atrophy, the mixed/ALS-like phenotype was associated with motor cortex and corticospinal tract atrophy. The PD-like phenotype was associated with widespread cortical and subcortical atrophy. Estimated time to onset, genetic group and their interaction, influenced motor signs. In c9orf72 pathogenic variant carriers, motor signs could be detected up to 25 years prior to expected symptom onset. DISCUSSION: These results indicate the presence of multiple natural clusters of motor signs in genetic FTD, each correlated with specific atrophy patterns. Their motor severity depends on time and the affected gene. These clinico-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Measurement of structural integrity of the spinal cord in patients with amyotrophic lateral sclerosis using diffusion tensor magnetic resonance imaging.

BACKGROUND: The value of conventional magnetic resonance imaging (MRI) for amyotrophic lateral sclerosis (ALS) is low. Functional and quantitative MRI could be more accurate. We aimed to examine the value of diffusion tensor imaging (DTI) with fractional anisotropy (FA) measurements of the cervical and upper thoracic spinal cord in patients with ALS. PATIENTS AND METHODS: Fourteen patients with ALS and 15 sex- and age-matched controls were examined with DTI at a 3T MRI scanner. Region-of-interest (ROI) based fractional anisotropy measurements were performed at the levels C2-C4, C5-C7 and Th1-Th3. ROIs were placed at different anatomical locations of the axial cross sections of the spinal cord. RESULTS: FA was significantly reduced in ALS patients in anterolateral ROIs and the whole cross section at the C2-C4 level and the cross section of the Th1-Th3 level. There was a trend towards a statistically significant FA reduction in the anterolateral ROIs at the C5-C7 level in ALS patients. No significant differences between patients and controls were found in posterior ROIs. CONCLUSION: FA was reduced in ROIs representing the motor tracts in ALS patients. DTI with FA measurements is a promising method in this circumstance. However, for DTI to become a valuable and established method in the diagnostic workup of ALS, larger studies and further standardisation are warranted.

Clinical spectrum, underlying etiologies and radiological characteristics of cortical superficial siderosis.

Cortical superficial siderosis (cSS) is an increasingly recognized MR-imaging marker most probably caused by focal convexity subarachnoid hemorrhage (SAH). There is accumulating evidence that cSS represents an important risk factor for subsequent intracranial hemorrhages. Here, we aimed to determine clinical symptoms, underlying etiologies, and radiological characteristics of cSS in a large patient cohort. We performed an electronic database search on all patients who presented between 2002 and 2013 to the university hospital Munich with non-traumatic and non-aneurysmal cSS. T2*-weighted gradient-echo sequences were analyzed regarding localization and extent of cSS as well as of acute SAH, intracerebral hemorrhages (ICH) and microbleeds. Besides, all available clinical, laboratory, imaging and histological data were analyzed. 113 subjects matched the inclusion criteria. The following etiologies for cSS were identified: definite (n = 6; 5 %), probable (n = 75; 66 %), and possible (n = 28; 25 %) cerebral amyloid angiopathy (CAA); reversible cerebral vasoconstriction syndrome: 2 (2 %); central nervous system vasculitis: 1; and hyperperfusion syndrome: 1. Acute ICH was evident in 55 (49 %) cases. Other clinical manifestations were: transient focal neurological episodes (TFNE): 38 (34 %); cognitive impairment: 14 (12 %); generalized seizure: 4 (4 %); and headache: 2 (2 %). Adjusting for age and gender, cognitive impairment was more frequent in disseminated cSS, while TFNE was more often found in focal cSS (p = 0.042). Our data indicate CAA to be the most common etiology of cSS. In absence of symptomatic ICH, patients with focal cSS frequently present with TFNE, while those with disseminated cSS commonly manifest with cognitive impairment.

High-resolution anatomy of the human brain stem using 7-T MRI: improved detection of inner structures and nerves?

INTRODUCTION: The purpose of this paper is to assess the value of 7 Tesla (7 T) MRI for the depiction of brain stem and cranial nerve (CN) anatomy. METHODS: Six volunteers were examined at 7 T using high-resolution SWI, MPRAGE, MP2RAGE, 3D SPACE T2, T2, and PD images to establish scanning parameters targeted at optimizing spatial resolution. Direct comparisons between 3 and 7 T were performed in two additional subjects using the finalized sequences (3 T: T2, PD, MPRAGE, SWAN; 7 T: 3D T2, MPRAGE, SWI, MP2RAGE). Artifacts and the depiction of structures were evaluated by two neuroradiologists using a standardized score sheet. RESULTS: Sequences could be established for high-resolution 7 T imaging even in caudal cranial areas. High in-plane resolution T2, PD, and SWI images provided depiction of inner brain stem structures such as pons fibers, raphe, reticular formation, nerve roots, and periaqueductal gray. MPRAGE and MP2RAGE provided clear depiction of the CNs. 3D T2 images improved depiction of inner brain structure in comparison to T2 images at 3 T. Although the 7-T SWI sequence provided improved contrast to some inner structures, extended areas were influenced by artifacts due to image disturbances from susceptibility differences. CONCLUSIONS: Seven-tesla imaging of basal brain areas is feasible and might have significant impact on detection and diagnosis in patients with specific diseases, e.g., trigeminal pain related to affection of the nerve root. Some inner brain stem structures can be depicted at 3 T, but certain sequences at 7 T, in particular 3D SPACE T2, are superior in producing anatomical in vivo images of deep brain stem structures.

Early relapses in patients with primary CNS lymphoma treated with methotrexate-based chemotherapy without consolidating whole brain irradiation.

Methotrexate (MTX)-based chemotherapy is used as upfront treatment for most patients with primary CNS lymphoma. Whether consolidating whole brain irradiation (WBI) should be recommended for patients who achieve complete remission (CR) is still a matter of debate. Patients who are predicted to experience an early relapse (ER, ≤12 months from diagnosis) might especially benefit from consolidating treatment. We therefore evaluated the incidence and prognostic impact of ER in patients with CR following chemotherapy without WBI. We identified 40 patients between 2000 and 2010 who had achieved CR following MTX-based chemotherapy. Of 36 evaluable patients 11 (31 %) experienced an ER. These patients had significantly impaired overall survival (46.0 vs. 79.0 months, p = 0.001). Normal cerebrospinal fluid cell count (11.0 vs. 76.0 months, p = 0.001) and frequent reduction of MTX dose due to impaired creatinine clearance (10.0 vs. 48.0 months, p = 0.005) had a significantly negative impact on relapse-free survival. Patients with CR following MTX-based induction chemotherapy represent a heterogeneous population. In these patients, ER is an independent risk factor for impaired overall survival. Therefore, these patients might especially benefit from consolidating treatment. These results have to be validated by prospective trials.

Superficial siderosis is a warning sign for future intracranial hemorrhage.

Supratentorial superficial siderosis (SS) is a frequent imaging marker of cerebral amyloid angiopathy (CAA). It is most probably caused by focal subarachnoid hemorrhages (fSAHs). Based on single-case observations, it has been proposed that such fSAHs might be a predisposing factor for future intracranial hemorrhage. Here we tested the hypothesis if a SS as a residue of fSAHs must be regarded as a warning sign for future intracranial hemorrhage. Fifty-one consecutive patients with SS and no apparent cause other than possible or probable CAA were identified through a database search and followed-up for a median interval of 35.3 months (range 6-120 months). Main outcome measures were rate and location of new intracranial hemorrhages. Twenty-four patients (47.1 %) had experienced any new intracranial hemorrhage, 18 patients (35.3 %) had an intracerebral hemorrhage (ICH), and in 13 of them (25.5 %), the hemorrhage was located at the site of pre-existing siderosis. Six patients (11.7 %) had developed a new subarachnoid hemorrhage (SAH), four of them at the site of siderosis. Patients with SS are at substantial risk for subsequent intracranial hemorrhage. SS can be considered a warning sign of future ICH or SAH, which frequently occur adjacent to pre-existing SS. Prospective studies are needed to confirm these findings.

Quantification of supra-aortic arterial wall inflammation in patients with arteritis using high resolution dynamic contrast-enhanced magnetic resonance imaging: initial results in correlation to [18F]-FDG PET/CT.

OBJECTIVES: : To compare [F]- -fluoro-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), used in clinical routine to detect inflamed arteries in patients with arteritis, with high resolution dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in its ability to measure inflammation in carotid and vertebral arteries. MATERIALS AND METHODS: : This study was performed with written informed consent, Health Insurance Portability and Accountability Act (HIPAA) compliance, and institutional review board approval. DCE-MRI of the carotid and vertebral arteries of 17 patients with suspected arteritis was acquired at 3T (2D saturation-recovery spoiled gradient echo, in plane resolution 0.625 × 0.625 mm) using a dedicated 4-channel carotid coil. Patients underwent [F] FDG-PET/CT within 1 week of the MRI scan. The blood pool-corrected mean standardized uptake value (mean target-to-background ratio [TBRmean]) was measured on PET/CT images at the identical location as the region-of-interest in the magnetic resonance images. MRI signal intensity data was analyzed to generate estimates of the tissue extraction fraction and interstitial volume using a 2-compartment model. RESULTS: : [F]-FDG PET/CT TBRmean was significantly higher in patients with than without arteritis (1.55 ± 0.34 vs. 1.06 ± 0.14, P = 0.001). Patients diagnosed with arteritis had significantly higher extraction fractions as measured by DCE-MRI than patients without arteritis (8.79% ± 2.19% vs. 5.82% ± 1.13%, P = 0.002). TBRmean correlated significantly with the extraction fraction (r = 0.73, P < 0.001). DCE-MRI and FDG-PET/CT yielded the same sensitivity (86%) and specificity (90%) for the detection of arteritis. Intra- and interreader reproducibility was good with Intraclass Correlation Coefficients of 0.82 and 0.78, respectively. CONCLUSIONS: : DCE-MRI is able to measure arterial inflammation reliably and noninvasively with good correlation to [F]-FDG PET/CT in patients suffering from arteritis of the supraaortic arteries.

High resolution carotid black-blood 3T MR with parallel imaging and dedicated 4-channel surface coils.

BACKGROUND: Most of the carotid plaque MR studies have been performed using black-blood protocols at 1.5 T without parallel imaging techniques. The purpose of this study was to evaluate a multi-sequence, black-blood MR protocol using parallel imaging and a dedicated 4-channel surface coil for vessel wall imaging of the carotid arteries at 3 T. MATERIALS AND METHODS: 14 healthy volunteers and 14 patients with intimal thickening as proven by duplex ultrasound had their carotid arteries imaged at 3 T using a multi-sequence protocol (time-of-flight MR angiography, pre-contrast T1w-, PDw- and T2w sequences in the volunteers, additional post-contrast T1w- and dynamic contrast enhanced sequences in patients). To assess intrascan reproducibility, 10 volunteers were scanned twice within 2 weeks. RESULTS: Intrascan reproducibility for quantitative measurements of lumen, wall and outer wall areas was excellent with intraclass correlation coefficients >0.98 and measurement errors of 1.5%, 4.5% and 1.9%, respectively. Patients had larger wall areas than volunteers in both common carotid and internal carotid arteries and smaller lumen areas in internal carotid arteries (p < 0.001). Positive correlations were found between wall area and cardiovascular risk factors such as age, hypertension, coronary heart disease and hypercholesterolemia (Spearman's r = 0.45-0.76, p < 0.05). No significant correlations were found between wall area and body mass index, gender, diabetes or a family history of cardiovascular disease. CONCLUSION: The findings of this study indicate that high resolution carotid black-blood 3 T MR with parallel imaging is a fast, reproducible and robust method to assess carotid atherosclerotic plaque in vivo and this method is ready to be used in clinical practice.