Tumor biomechanics as a novel imaging biomarker to assess response to immunotherapy in a murine glioma model.

Glioblastoma is the most common and aggressive primary malignant brain tumor with poor prognosis. Novel immunotherapeutic approaches are currently under investigation. Even though magnetic resonance imaging (MRI) is the most important imaging tool for treatment monitoring, response assessment is often hampered by therapy-related tissue changes. As tumor and therapy-associated tissue reactions differ structurally, we hypothesize that biomechanics could be a pertinent imaging proxy for differentiation. Longitudinal MRI and magnetic resonance elastography (MRE) were performed to monitor response to immunotherapy with a toll-like receptor 7/8 agonist in orthotopic syngeneic experimental glioma. Imaging results were correlated to histology and light sheet microscopy data. Here, we identify MRE as a promising non-invasive imaging method for immunotherapy-monitoring by quantifying changes in response-related tumor mechanics. Specifically, we show that a relative softening of treated compared to untreated tumors is linked to the inflammatory processes following therapy-induced re-education of tumor-associated myeloid cells. Mechanistically, combined effects of myeloid influx and inflammation including extracellular matrix degradation following immunotherapy form the basis of treated tumors being softer than untreated glioma. This is a very early indicator of therapy response outperforming established imaging metrics such as tumor volume. The overall anti-tumor inflammatory processes likely have similar effects on human brain tissue biomechanics, making MRE a promising tool for gauging response to immunotherapy in glioma patients early, thereby strongly impacting patient pathway.

In vivo nanoparticle-based T cell imaging can predict therapy response towards adoptive T cell therapy in experimental glioma.

Rationale: Intrinsic brain tumors, such as gliomas are largely resistant to immunotherapies including immune checkpoint blockade. Adoptive cell therapies (ACT) including chimeric antigen receptor (CAR) or T cell receptor (TCR)-transgenic T cell therapy targeting glioma-associated antigens are an emerging field in glioma immunotherapy. However, imaging techniques for non-invasive monitoring of adoptively transferred T cells homing to the glioma microenvironment are currently lacking. Methods: Ultrasmall iron oxide nanoparticles (NP) can be visualized non-invasively by magnetic resonance imaging (MRI) and dedicated MRI sequences such as T2* mapping. Here, we develop a protocol for efficient ex vivo labeling of murine and human TCR-transgenic and CAR T cells with iron oxide NPs. We assess labeling efficiency and T cell functionality by flow cytometry and transmission electron microscopy (TEM). NP labeled T cells are visualized by MRI at 9.4 T in vivo after adoptive T cell transfer and correlated with 3D models of cleared brains obtained by light sheet microscopy (LSM). Results: NP are incorporated into T cells in subcellular cytoplasmic vesicles with high labeling efficiency without interfering with T cell viability, proliferation and effector function as assessed by cytokine secretion and antigen-specific killing assays in vitro. We further demonstrate that adoptively transferred T cells can be longitudinally monitored intratumorally by high field MRI at 9.4 Tesla in a murine glioma model with high sensitivity. We find that T cell influx and homogenous spatial distribution of T cells within the TME as assessed by T2* imaging predicts tumor response to ACT whereas incomplete T cell coverage results in treatment resistance. Conclusion: This study showcases a rational for monitoring adoptive T cell therapies non-invasively by iron oxide NP in gliomas to track intratumoral T cell influx and ultimately predict treatment outcome.

MR microscopy to assess clot composition following mechanical thrombectomy predicts recanalization and clinical outcome.

BACKGROUND: Mechanical thrombectomy (MT) is the standard of care for patients with a stroke and large vessel occlusion. Clot composition is not routinely assessed in clinical practice as no specific diagnostic value is attributed to it, and MT is performed in a standardized 'non-personalized' approach. Whether different clot compositions are associated with intrinsic likelihoods of recanalization success or treatment outcome is unknown. METHODS: We performed a prospective, non-randomized, single-center study and analyzed the clot composition in 60 consecutive patients with ischemic stroke undergoing MT. Clots were assessed by ex vivo multiparametric MRI at 9.4 T (MR microscopy), cone beam CT, and histopathology. Clot imaging was correlated with preinterventional CT and clinical data. RESULTS: MR microscopy showed red blood cell (RBC)-rich (21.7%), platelet-rich (white,38.3%) or mixed clots (40.0%) as distinct morphological entities, and MR microscopy had high accuracy of 95.4% to differentiate clots. Clot composition could be further stratified on preinterventional non-contrast head CT by quantification of the hyperdense artery sign. During MT, white clots required more passes to achieve final recanalization and were not amenable to contact aspiration compared with mixed and RBC-rich clots (maneuvers: 4.7 vs 3.1 and 1.2 passes, P<0.05 and P<0.001, respectively), whereas RBC-rich clots showed higher probability of first pass recanalization (76.9%) compared with white clots (17.4%). White clots were associated with poorer clinical outcome at discharge and 90 days after MT. CONCLUSION: Our study introduces MR microscopy to show that the hyperdense artery sign or MR relaxometry could guide interventional strategy. This could enable a personalized treatment approach to improve outcome of patients undergoing MT.

A Cellular Ground Truth to Develop MRI Signatures in Glioma Models by Correlative Light Sheet Microscopy and Atlas-Based Coregistration.

Glioblastoma is the most common malignant primary brain tumor with poor overall survival. Magnetic resonance imaging (MRI) is the main imaging modality for glioblastoma but has inherent shortcomings. The molecular and cellular basis of MR signals is incompletely understood. We established a ground truth-based image analysis platform to coregister MRI and light sheet microscopy (LSM) data to each other and to an anatomic reference atlas for quantification of 20 predefined anatomic subregions. Our pipeline also includes a segmentation and quantification approach for single myeloid cells in entire LSM datasets. This method was applied to three preclinical glioma models in male and female mice (GL261, U87MG, and S24), which exhibit different key features of the human glioma. Multiparametric MR data including T2-weighted sequences, diffusion tensor imaging, T2 and T2* relaxometry were acquired. Following tissue clearing, LSM focused on the analysis of tumor cell density, microvasculature, and innate immune cell infiltration. Correlated analysis revealed differences in quantitative MRI metrics between the tumor-bearing and the contralateral hemisphere. LSM identified tumor subregions that differed in their MRI characteristics, indicating tumor heterogeneity. Interestingly, MRI signatures, defined as unique combinations of different MRI parameters, differed greatly between the models. The direct correlation of MRI and LSM allows an in-depth characterization of preclinical glioma and can be used to decipher the structural, cellular, and, likely, molecular basis of tumoral MRI biomarkers. Our approach may be applied in other preclinical brain tumor or neurologic disease models, and the derived MRI signatures could ultimately inform image interpretation in a clinical setting.SIGNIFICANCE STATEMENT We established a histologic ground truth-based approach for MR image analyses and tested this method in three preclinical glioma models exhibiting different features of glioblastoma. Coregistration of light sheet microscopy to MRI allowed for an evaluation of quantitative MRI data in histologically distinct tumor subregions. Coregistration to a mouse brain atlas enabled a regional comparison of MRI parameters with a histologically informed interpretation of the results. Our approach is transferable to other preclinical models of brain tumors and further neurologic disorders. The method can be used to decipher the structural, cellular, and molecular basis of MRI signal characteristics. Ultimately, information derived from such analyses could strengthen the neuroradiological evaluation of glioblastoma as they enhance the interpretation of MRI data.

T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles.

Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a ß-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.

Brain tumor classification of virtual NMR voxels based on realistic blood vessel-induced spin dephasing using support vector machines.

Remodeling of tissue microvasculature commonly promotes neoplastic growth; however, there is no imaging modality in oncology yet that noninvasively quantifies microvascular changes in clinical routine. Although blood capillaries cannot be resolved in typical magnetic resonance imaging (MRI) measurements, their geometry and distribution influence the integral nuclear magnetic resonance (NMR) signal from each macroscopic MRI voxel. We have numerically simulated the expected transverse relaxation in NMR voxels with different dimensions based on the realistic microvasculature in healthy and tumor-bearing mouse brains (U87 and GL261 glioblastoma). The 3D capillary structure in entire, undissected brains was acquired using light sheet fluorescence microscopy to produce large datasets of the highly resolved cerebrovasculature. Using this data, we trained support vector machines to classify virtual NMR voxels with different dimensions based on the simulated spin dephasing accountable to field inhomogeneities caused by the underlying vasculature. In prediction tests with previously blinded virtual voxels from healthy brain tissue and GL261 tumors, stable classification accuracies above 95% were reached. Our results indicate that high classification accuracies can be stably attained with achievable training set sizes and that larger MRI voxels facilitated increasingly successful classifications, even with small training datasets. We were able to prove that, theoretically, the transverse relaxation process can be harnessed to learn endogenous contrasts for single voxel tissue type classifications on tailored MRI acquisitions. If translatable to experimental MRI, this may augment diagnostic imaging in oncology with automated voxel-by-voxel signal interpretation to detect vascular pathologies.

Characterization of experimental diabetic neuropathy using multicontrast magnetic resonance neurography at ultra high field strength.

In light of the limited treatment options of diabetic polyneuropathy (DPN) available, suitable animal models are essential to investigate pathophysiological mechanisms and to identify potential therapeutic targets. In vivo evaluation with current techniques, however, often provides only restricted information about disease evolution. In the study of patients with DPN, magnetic resonance neurography (MRN) has been introduced as an innovative diagnostic tool detecting characteristic lesions within peripheral nerves. We developed a novel multicontrast ultra high field MRN strategy to examine major peripheral nerve segments in diabetic mice non-invasively. It was first validated in a cross-platform approach on human nerve tissue and then applied to the popular streptozotocin(STZ)-induced mouse model of DPN. In the absence of gross morphologic alterations, a distinct MR-signature within the sciatic nerve was observed mirroring subtle changes of the nerves' fibre composition and ultrastructure, potentially indicating early re-arrangements of DPN. Interestingly, these signal alterations differed from previously reported typical nerve lesions of patients with DPN. The capacity of our approach to non-invasively assess sciatic nerve tissue structure and function within a given mouse model provides a powerful tool for direct translational comparison to human disease hallmarks not only in diabetes but also in other peripheral neuropathic conditions.

Gibbs point field model quantifies disorder in microvasculature of U87-glioblastoma.

Microvascular proliferation in glioblastoma multiforme is a biological key mechanism to facilitate tumor growth and infiltration and a main target for treatment interventions. The vascular architecture can be obtained by Single Plane Illumination Microscopy (SPIM) to evaluate vascular heterogeneity in tumorous tissue. We make use of the Gibbs point field model to quantify the order of regularity in capillary distributions found in the U87 glioblastoma model in a murine model and to compare tumorous and healthy brain tissue. A single model parameter Γ was assigned that is linked to tissue-specific vascular topology through Monte-Carlo simulations. Distributions of the model parameter Γ differ significantly between glioblastoma tissue with mean 〈ΓG〉=2.1±0.4, as compared to healthy brain tissue with mean 〈ΓH〉=4.9±0.4, suggesting that the average Γ-value allows for tissue differentiation. These results may be used for diagnostic magnetic resonance imaging, where it has been shown recently that Γ is linked to tissue-inherent relaxation parameters.

Carbon analysis of steel using compact spectrometer and passively Q-switched laser for laser-induced breakdown spectroscopy.

Laser-induced breakdown spectroscopy (LIBS) is carried out with compact 1064 nm laser and spectrometer components which are suitable for handheld applications. Bursts of ∼0.6 mJ, 5 ns laser pulses are generated by a passively Q-switched laser with a 1 kHz triggered pump diode. The miniature spectrometer with a set wavelength range of ∼188-251 nm has an instrumental broadening at the carbon analyte line, C I 193.09 nm, of less than 36 pm. Analytical calibration curves of C, as well as Cr, Ni, and Si are taken with certified reference samples of iron and steel in an argon purged setup. The net duration of the laser bursts is ∼0.7-1.4 s for a measurement, depending on the number of repetitions on the sample surface. The limit of detection (LOD) is determined to a mass fraction of 34 µg/g for C. High-alloy steels 1.4306 (0.01% C) and 1.4541 (0.035% C) are separated clearly by the LIBS measurement of carbon.

Vessel architecture imaging using multiband gradient-echo/spin-echo EPI.

OBJECTIVES: To apply the MB (multiband) excitation and blipped-CAIPI (blipped-controlled aliasing in parallel imaging) techniques in a spin and gradient-echo (SAGE) EPI sequence to improve the slice coverage for vessel architecture imaging (VAI). MATERIALS AND METHODS: Both MB excitation and blipped-CAIPI with in-plane parallel imaging were incorporated into a gradient-echo (GE)/spin-echo (SE) EPI sequence for simultaneous tracking of the dynamic MR signal changes in both GE and SE contrasts after the injection of contrast agent. MB and singleband (SB) excitation were compared using a 20-channel head coil at 3 Tesla, and high-resolution MB VAI could be performed in 32 glioma patients. RESULTS: Whole-brain covered high resolution VAI can be achieved after applying multiband excitation with a factor of 2 and in-plane parallel imaging with a factor of 3. The quality of the images resulting from MB acceleration was comparable to those from the SB method: images were reconstructed without any loss of spatial resolution or severe distortions. In addition, MB and SB signal-to-noise ratios (SNR) were similar. A relative low g-factor induced from the MB acceleration method was achieved after using a blipped-CAIPI technique (1.35 for GE and 1.33 for SE imaging). Performing quantitative VAI, we found that, among all VAI parametric maps, microvessel type indicator (MTI), distance map (I) and vascular-induced bolus peak-time shift (VIPS) were highly correlated. Likewise, VAI parametric maps of slope, slope length and short axis were highly correlated. CONCLUSIONS: Multiband accelerated SAGE successfully doubles the number of readout slices in the same measurement time when compared to conventional readout sequences. The corresponding VAI parametric maps provide insights into the complexity and heterogeneity of vascular changes in glioma.

Vessel radius mapping in an extended model of transverse relaxation.

OBJECTIVES: Spin dephasing of the local magnetization in blood vessel networks can be described in the static dephasing regime (where diffusion effects may be ignored) by the established model of Yablonskiy and Haacke. However, for small capillary radii, diffusion phenomena for spin-bearing particles are not negligible. MATERIAL AND METHODS: In this work, we include diffusion effects for a set of randomly distributed capillaries and provide analytical expressions for the transverse relaxation times T2* and T2 in the strong collision approximation and the Gaussian approximation that relate MR signal properties with microstructural parameters such as the mean local capillary radius. RESULTS: Theoretical results are numerically validated with random walk simulations and are used to calculate capillary radius distribution maps for glioblastoma mouse brains at 9.4 T. For representative tumor regions, the capillary maps reveal a relative increase of mean radius for tumor tissue towards healthy brain tissue of [Formula: see text] (p < 0.001). CONCLUSION: The presented method may be used to quantify angiogenesis or the effects of antiangiogenic therapy in tumors whose growth is associated with significant microvascular changes.

Micro-Multileaf Collimator LINAC Radiosurgery for Vestibular Schwannomas.

OBJECTIVE: This study evaluates the efficacy of linear accelerator (LINAC) radiosurgery using micro multi-leaf collimator technique (µMLC) in the treatment of a consecutive series of patients with vestibular schwannomas. PATIENTS AND METHODS: In this retrospective study, we enrolled 50 patients with non-neurofibromatosis type 2 vestibular schwannoma who were treated with µMLC LINAC-based SRS at University Hospital of Cologne, Germany. A minimum clinical follow-up of 24 months was conducted. Thirty-nine out of the 50 tumors (78 %) were treated with µMLC LINAC as a primary treatment (a newly diagnosed tumor). The remaining 11 vestibular schwannomas (22%) were treated as a salvage treatment (5 patients with a residual tumor; and 6 patients with a recurrent tumor following a microsurgical resection). The median tumor volume was 1.4 ml. The median tumor surface dose, median maximal dose and median therapeutic isodose were 12 Gy, 16 Gy and 77% respectively. RESULTS: Follow-up MR images showed that a tumor progression-free status was achieved for 95.7% of patients. Partial tumor shrinkage was observed after µMLC LINAC SRS for 21.3% of patients. No change in tumor size (a stable tumor) was noted for 74.5% of patients. Tumor progression was observed for 4.3% of patients. At the end of follow-up, the actuarial 5- year and 10 year progression-free survival after radiosurgery were both 95.7%. CONCLUSIONS: LINAC radiosurgery using a micro multi-leaf collimator for vestibular schwannomas smaller than 3 cm is effective in yielding a high local tumor control, whereas the treatment-related morbidity remains low.

Stereotactic intracavitary brachytherapy with P-32 for cystic craniopharyngiomas in children.

PURPOSE: Although microsurgery remains the first-line treatment, gross total resection of cystic craniopharyngeomas (CP) is associated with significant morbidity and mortality and the addition of external irradiation to subtotal resection proves to achieve similar tumor control. However, concern regarding long-term morbidity associated with external irradiation in children still remains. With this retrospective analysis, the authors emphasize intracavitary brachytherapy using phosphorus-32 (P-32) as a treatment option for children with cystic CP. PATIENTS AND METHODS: Between 1992 and 2009, 17 children (median age 15.4 years; range 7-18 years) with cystic CP underwent intracavitary brachytherapy using P-32. Eleven patients were treated for recurrent tumor cysts; 6 patients were treated primarily. MR imaging revealed solitary cysts in 7 patients; 10 patients had mixed solid-cystic lesions (median tumor volume 11.1 ml; range 0.5-78.9 ml). The median follow-up time was 61.9 months (range 16.9-196.6 months). RESULTS: Local cyst control could be achieved in 14 patients (82 %). Three patients showed progression of the treated cystic formation (in-field progression) after a median time of 8.3 months (range 5.3-10.3 months), which led to subsequent interventions. The development of new, defined cysts and progression of solid tumor parts (out-of-field progression) occurred in 5 patients and led to additional interventions in 4 cases. There was neither surgery-related permanent morbidity nor mortality in this study. The overall progression-free survival was 75, 63, and 52 % after 1, 3, and 5 years, respectively. CONCLUSION: Intracavitary brachytherapy using P-32 represents a safe and effective treatment option for children harboring cystic CP, even as primary treatment. However, P-32 does not clearly affect growth of solid tumor parts or the development of new cystic formations.

Motor Improvement and Emotional Stabilization in Patients With Tourette Syndrome After Deep Brain Stimulation of the Ventral Anterior and Ventrolateral Motor Part of the Thalamus.

BACKGROUND: Since its first application in 1999, the potential benefit of deep brain stimulation (DBS) in reducing symptoms of otherwise treatment-refractory Tourette syndrome (TS) has been documented in several publications. However, uncertainty regarding the ideal neural targets remains, and the eventuality of so far undocumented but possible negative long-term effects on personality fuels the debate about the ethical implications of DBS. METHODS: In this prospective open-label trial, eight patients (three female, five male) 19-56 years old with severe and medically intractable TS were treated with high-frequency DBS of the ventral anterior and ventrolateral motor part of the thalamus. To assess the course of TS, its clinical comorbidities, personality parameters, and self-perceived quality of life, patients underwent repeated psychiatric assessments at baseline and 6 and 12 months after DBS onset. RESULTS: Analysis indicated a strongly significant and beneficial effect of DBS on TS symptoms, trait anxiety, quality of life, and global functioning with an apparently low side-effect profile. In addition, presurgical compulsivity, anxiety, emotional dysregulation, and inhibition appeared to be significant predictors of surgery outcome. CONCLUSIONS: Trading off motor effects and desirable side effects against surgery-related risks and negative implications, stimulation of the ventral anterior and ventrolateral motor part of the thalamus seems to be a valuable option when considering DBS for TS.

Stereotactic interstitial brachytherapy for the treatment of oligodendroglial brain tumors.

PURPOSE: We evaluated the treatment of oligodendroglial brain tumors with interstitial brachytherapy (IBT) using (125)iodine seeds ((125)I) and analyzed prognostic factors. PATIENTS AND METHODS: Between January 1991 and December 2010, 63 patients (median age 43.3 years, range 20.8-63.4 years) suffering from oligodendroglial brain tumors were treated with (125)I IBT either as primary, adjuvantly after incomplete resection, or as salvage therapy after tumor recurrence. Possible prognostic factors influencing disease progression and survival were retrospectively investigated. RESULTS: The actuarial 2-, 5-, and 10-year overall and progression-free survival rates after IBT for WHO II tumors were 96.9, 96.9, 89.8 % and 96.9, 93.8, 47.3 %; for WHO III tumors 90.3, 77, 54.9 % and 80.6, 58.4, 45.9 %, respectively. Magnetic resonance imaging demonstrated complete remission in 2 patients, partial remission in 13 patients, stable disease in 17 patients and tumor progression in 31 patients. Median time to progression for WHO II tumors was 87.6 months and for WHO III tumors 27.8 months. Neurological status improved in 10 patients and remained stable in 20 patients, while 9 patients deteriorated. There was no treatment-related mortality. Treatment-related morbidity was transient in 11 patients. WHO II, KPS ≥ 90 %, frontal location, and tumor surface dose > 50 Gy were associated with increased overall survival (p ≤ 0.05). Oligodendroglioma and frontal location were associated with a prolonged progression-free survival (p ≤ 0.05). CONCLUSION: Our study indicates that IBT achieves local control rates comparable to surgery and radio-/chemotherapy treatment, is minimally invasive, and safe. Due to the low rate of side effects, IBT may represent an attractive option as part of a multimodal treatment schedule, being supplementary to microsurgery or as a salvage therapy after chemotherapy and conventional irradiation.

Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and safety after a follow-up of over 12 years.

PURPOSE: The efficacy and safety of stereotactic radiosurgery (SRS) for treatment of intracranial meningiomas has been demonstrated in numerous studies with short- and intermediate-term follow-up. In this retrospective single-center study, we present long-term outcomes of SRS performed with a linear accelerator (LINAC) for typical intracranial meningiomas. PATIENTS AND METHODS: Between August 1990 and December 2007, 148 patients with 168 typical intracranial meningiomas were treated with stereotactic LINAC-SRS, either as primary treatment or after microsurgical resection. A median tumor surface dose of 12 Gy (range 7-20 Gy) and a median maximum dose of 24.1 Gy (range 11.3-58.6 Gy) was applied. The median target volume was 4.7 ml (range 0.2-32.8 ml, SD ± 4.8 ml). RESULTS: Overall mean radiological follow-up was 12.6 years. Tumor shrinkage was seen in 75 (44.6 %) and stable disease in 85 (50.6 %) cases. Eight of 168 meningiomas (4.8 %) showed local tumor progression. The tumor control rate (TCR) after 5, 10, and 15 years was 93.6 % at each time point, and the progression-free survival (PSF) rates were 92, 89, and 89 %, respectively. The neurological symptoms existing prior to LINAC-SRS improved in 77 patients (59.7 %), remained unchanged in 42 (32.6 %), and deteriorated in 10 (7.8 %) patients. CONCLUSION: Our study emphasizes the efficacy of LINAC-SRS for de novo, residual and recurrent typical intracranial meningiomas. A high long-term local TCR with a low morbidity rate could be achieved. LINAC-SRS should thus be considered as a primary treatment option, as one arm of a combined treatment approach for incompletely resected meningiomas, or as a salvage therapy for recurrences.

Stereotactic LINAC-Radiosurgery for Glomus Jugulare Tumors: A Long-Term Follow-Up of 27 Patients.

BACKGROUND: The optimal treatment of glomus jugulare tumors (GJTs) remains controversial. Due to the critical location, microsurgery still provides high treatment-related morbidity and a decreased quality of life. Thus, we performed stereotactical radiosurgery (SRS) for the treatment of GJTs and evaluated the long-term outcome. METHODS: Between 1991 and 2011, 32 patients with GJTs underwent SRS using a linear accelerator (LINAC) either as primary or salvage therapy. Twenty-seven patients (median age 59.9 years, range 28.7-79.9 years) with a follow-up greater than five years (median 11 years, range 5.3-22.1 years) were selected for retrospective analysis. The median therapeutic single dose applied to the tumor surface was 15 Gy (range 11-20 Gy) and the median tumor volume was 9.5 ml (range 2.8-51 ml). RESULTS: Following LINAC-SRS, 10 of 27 patients showed a significant improvement of their previous neurological complaints, whereas 12 patients remained unchanged. Five patients died during follow-up due to old age or other, not treatment-related reasons. MR-imaging showed a partial remission in 12 and a stable disease in 15 patients. No tumor progression was observed. The actuarial overall survival rates after five, ten and 20 years were 100%, 95.2% and 79.4%, respectively. CONCLUSIONS: Stereotactic LINAC-Radiosurgery can achieve an excellent long-term tumor control beside a low rate of morbidity in the treatment of GJTs. It should be considered as an alternative therapy regime to surgical resection or fractionated external beam radiation either as primary, adjuvant or salvage therapy.

Intraoperative functional magnetic resonance imaging for monitoring the effect of deep brain stimulation in patients with obsessive-compulsive disorder.

OBJECTIVES: To investigate the effects of low- and high-frequency deep brain stimulation (DBS) on the nucleus accumbens (ACC) and the adjacent internal capsule in 3 patients with obsessive-compulsive disorder (OCD) using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) under intraoperative conditions. METHODS: After placement of the electrode in the right ACC, the patients underwent an MR scan inside the operating room. BOLD imaging was performed and interpreted using a boxcar paradigm with alternating high-frequency stimulation of the ACC and the internal capsule versus rest. Correlation maps were calculated employing SPM99. RESULTS: During high-frequency stimulation of the right ACC, focal activation could be found in the right striatum, the right frontal lobe and the right hippocampus, whereas low-frequency stimulation was correlated to right insular activation. INTERPRETATION: Intraoperative BOLD-fMRI is feasible during DBS surgery of OCD patients. Our results support the existence of an ipsilateral hemispheric circuit involving the frontal lobe, anterior cingulate, parahippocampal gyrus and striatum. Intraoperative fMRI may be used to acquire additional information regarding the pathophysiology of OCD that can be used to improve the results of DBS in OCD.

Laser-induced breakdown spectroscopy for 24/7 automatic liquid slag analysis at a steel works.

Laser-induced breakdown spectroscopy (LIBS) is applied for the inline analysis of liquid slag at a steel works. The slag in the ladle of a slag transporter is measured at a distance of several meters during a short stop of the transporter. The slag surface with temperatures from ≈600 to ≈1400 °C consists of liquid slag and solidified slag parts. Automatic measurements at varying filling levels of the ladle are realized, and the duration amounts to 2 min including data transmission to the host computer. Analytical results of the major components such as CaO, Fe, SiO2, MgO, Mn, and Al2O3 are compared with reference values from the steel works laboratory for solid pressed slag samples as well as for samples from the liquid slag. Stable 24/7 operation during the first three-month test run was achieved.

Deep brain stimulation in the ventrolateral thalamus/subthalamic area in dystonia with head tremor.

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) effectively ameliorates idiopathic dystonia, although approximately 15% of patients respond insufficiently. Although various thalamic and subthalamic targets have been suggested for dystonic tremor, no systematic studies have been published on thalamic DBS in dystonic tremor. We assessed the effect of thalamic/subthalamic area DBS (Th-DBS) on dystonic head tremor and dystonia in a single-blind design. METHODS: Dystonic head tremor and dystonia before and 3 months after surgery were quantified via blinded video-ratings using the Fahn-Tolosa-Marin-Tremor-Scale and the Burke-Fahn-Marsden-Dystonia-Rating-Scale in seven patients with idiopathic cervical or segmental dystonia, dystonic head tremor, and bilateral Th-DBS. Pain, side effects, adverse events, and stimulation parameters were assessed. RESULTS: Th-DBS improved dystonic tremor and dystonia (P < 0.05; 57.1% and 70.4%, respectively). Head tremor amplitude and pain were also improved (P < 0.05; 77.5% and 90.0%, respectively). Side effects included dysarthria, gait disturbance, slowness of movement, and weight gain. CONCLUSION: Dystonic head tremor and dystonia can be improved with Th-DBS.