Publications by authors named "Martha Nowosielski"

35 Publications

Perampanel in brain tumor and SMART-syndrome related epilepsy - A single institutional experience.

J Neurol Sci 2021 04 5;423:117386. Epub 2021 Mar 5.

Department of Neurology, Medical University of Innsbruck, Austria.

Epilepsy is common in patients with brain tumors and frequently presents as the first clinical manifestation of an underlying tumor. Despite a number of available antiepileptic drugs (AED), brain tumor related epilepsy (BTRE) may still be difficult to control. Recently, the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptor antagonist perampanel (PER) is increasingly acknowledged as an attractive novel add-on AED for seizure control in BTRE. We present a single institutional experience reporting five individual cases with refractory BTRE treated with PER. In two of these five brain tumor patients, worsening of seizure control was caused by SMART-syndrome (stroke-like migraine attacks after radiation therapy). Efficacy of PER was assessed by the responder rate and by evaluating overall changes in seizure frequency before and during PER treatment. In our case series, a reduction in seizure frequency was observed in four out of five patients and the responder rate was 40%. In addition, both cases with symptomatic epilepsy associated with SMART-syndrome were successfully treated with PER. This case series supports the growing evidence that PER may become a promising add-on AED for the treatment of refractory BTRE as well as for seizure control in SMART-syndrome.
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http://dx.doi.org/10.1016/j.jns.2021.117386DOI Listing
April 2021

Noninvasive Characterization of Tumor Angiogenesis and Oxygenation in Bevacizumab-treated Recurrent Glioblastoma by Using Dynamic Susceptibility MRI: Secondary Analysis of the European Organization for Research and Treatment of Cancer 26101 Trial.

Radiology 2020 10 28;297(1):164-175. Epub 2020 Jul 28.

From the Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany (P.K., G.B., I.P., M.S., M.F., U.N., S.H., M.B.); Center of Functionally Integrative Neuroscience and MINDLab, Aarhus University Hospital, Aarhus, Denmark (M.B.H., L.Ø.); Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany (M.N., T.K., A.W., W.W.); Department of Neurology, Medical University Innsbruck, Innsbruck, Austria (M.N.); Medical Image Computing, German Cancer Research Center (DKFZ), Heidelberg, Germany (F.I., K.H.M.H.); Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (T.K., W.W.); Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany (F.S., A.v.D.); Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany (F.S., A.v.D.); Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland (M.W.); Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, Mannheim, Germany (M.P.); Pattern Analysis and Learning Group, Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany (K.H.M.H.); Department of Neuroradiology, Aarhus University Hospital, Aarhus, Denmark (L.Ø.); Brain Tumor Center at Erasmus MC Cancer Institute, Rotterdam, the Netherlands (M.J.v.d.B.); and European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium (T.G.).

Background Relevance of antiangiogenic treatment with bevacizumab in patients with glioblastoma is controversial because progression-free survival benefit did not translate into an overall survival (OS) benefit in randomized phase III trials. Purpose To perform longitudinal characterization of intratumoral angiogenesis and oxygenation by using dynamic susceptibility contrast agent-enhanced (DSC) MRI and evaluate its potential for predicting outcome from administration of bevacizumab. Materials and Methods In this secondary analysis of the prospective randomized phase II/III European Organization for Research and Treatment of Cancer 26101 trial conducted between October 2011 and December 2015 in 596 patients with first recurrence of glioblastoma, the subset of patients with availability of anatomic MRI and DSC MRI at baseline and first follow-up was analyzed. Patients were allocated into those administered bevacizumab (hereafter, the BEV group; either bevacizumab monotherapy or bevacizumab with lomustine) and those not administered bevacizumab (hereafter, the non-BEV group with lomustine monotherapy). Contrast-enhanced tumor volume, noncontrast-enhanced T2 fluid-attenuated inversion recovery (FLAIR) signal abnormality volume, Gaussian-normalized relative cerebral blood volume (nrCBV), Gaussian-normalized relative blood flow (nrCBF), and tumor metabolic rate of oxygen (nTMRO) was quantified. The predictive ability of these imaging parameters was assessed with multivariable Cox regression and formal interaction testing. Results A total of 254 of 596 patients were evaluated (mean age, 57 years ± 11; 155 men; 161 in the BEV group and 93 in non-BEV group). Progression-free survival was longer in the BEV group (3.7 months; 95% confidence interval [CI]: 3.0, 4.2) compared with the non-BEV group (2.5 months; 95% CI: 1.5, 2.9; = .01), whereas OS was not different ( = .15). The nrCBV decreased for the BEV group (-16.3%; interquartile range [IQR], -39.5% to 12.0%; = .01), but not for the non-BEV group (1.2%; IQR, -17.9% to 23.3%; = .19) between baseline and first follow-up. An identical pattern was observed for both nrCBF and nTMRO values. Contrast-enhanced tumor and noncontrast-enhanced T2 FLAIR signal abnormality volumes decreased for the BEV group (-66% [IQR, -83% to -35%] and -33% [IQR, -71% to -5%], respectively; < .001 for both), whereas they increased for the non-BEV group (30% [IQR, -17% to 98%], = .001; and 10% [IQR, -13% to 82%], = .02, respectively) between baseline and first follow-up. None of the assessed MRI parameters were predictive for OS in the BEV group. Conclusion Bevacizumab treatment decreased tumor volumes, angiogenesis, and oxygenation, thereby reflecting its effectiveness for extending progression-free survival; however, these parameters were not predictive of overall survival (OS), which highlighted the challenges of identifying patients that derive an OS benefit from bevacizumab. © RSNA, 2020 See also the editorial by Dillon in this issue.
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http://dx.doi.org/10.1148/radiol.2020200978DOI Listing
October 2020

Encephalomyeloneuritis and arthritis after treatment with immune checkpoint inhibitors.

Neurol Neuroimmunol Neuroinflamm 2020 07 27;7(4). Epub 2020 May 27.

From the Department of Neurology (M.N., F.D.P., S.I., G.S.); Department of Dermatology and Venerology (N.H., V.A.N.); Department of Radiology (M.W.); and Department of Internal Medicine (J.G.), Medical University Innsbruck, Austria.

Objective: Immunotherapy revolutionized melanoma treatment; however, immune-related adverse events, especially neurotoxicity, may be severe and require early and correct diagnosis as well as early treatment commencement.

Methods: We report an unusual severe multiorgan manifestation of neurotoxicity after treatment with the anti-PDL1 immune checkpoint inhibitor, nivolumab, and the anticytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitor, ipilimumab, in a 47-year-old male patient with metastatic melanoma.

Results: The patient developed immune-mediated synovitis and cranial neuritis, followed by longitudinal transverse myelitis, encephalitis, and optic neuritis. Early treatment with high-dose steroids and maintenance therapy with rituximab resulted in a favorable neurologic outcome.

Conclusions: The frequency of spinal cord involvement and neuronal toxicity after cancer immunotherapy is very low and requires an extensive diagnostic workup to differentiate between disease progression and side effects. Immune checkpoint inhibitors should be discontinued and treatment with corticosteroids should be initiated early as the drug of first choice. Therapy may be escalated by other immune-modulating treatments, such as rituximab.
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http://dx.doi.org/10.1212/NXI.0000000000000773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286649PMC
July 2020

Validation of diffusion MRI phenotypes for predicting response to bevacizumab in recurrent glioblastoma: post-hoc analysis of the EORTC-26101 trial.

Neuro Oncol 2020 11;22(11):1667-1676

Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.

Background: This study validated a previously described diffusion MRI phenotype as a potential predictive imaging biomarker in patients with recurrent glioblastoma receiving bevacizumab (BEV).

Methods: A total of 396/596 patients (66%) from the prospective randomized phase II/III EORTC-26101 trial (with n = 242 in the BEV and n = 154 in the non-BEV arm) met the inclusion criteria with availability of anatomical and diffusion MRI sequences at baseline prior treatment. Apparent diffusion coefficient (ADC) histograms from the contrast-enhancing tumor volume were fitted to a double Gaussian distribution and the mean of the lower curve (ADClow) was used for further analysis. The predictive ability of ADClow was assessed with biomarker threshold models and multivariable Cox regression for overall survival (OS) and progression-free survival (PFS).

Results: ADClow was associated with PFS (hazard ratio [HR] = 0.625, P = 0.007) and OS (HR = 0.656, P = 0.031). However, no (predictive) interaction between ADClow and the treatment arm was present (P = 0.865 for PFS, P = 0.722 for OS). Independent (prognostic) significance of ADClow was retained after adjusting for epidemiological, clinical, and molecular characteristics (P ≤ 0.02 for OS, P ≤ 0.01 PFS). The biomarker threshold model revealed an optimal ADClow cutoff of 1241*10-6 mm2/s for OS. Thereby, median OS for BEV-patients with ADClow ≥ 1241 was 10.39 months versus 8.09 months for those with ADClow < 1241 (P = 0.004). Similarly, median OS for non-BEV patients with ADClow ≥ 1241 was 9.80 months versus 7.79 months for those with ADClow < 1241 (P = 0.054).

Conclusions: ADClow is an independent prognostic parameter for stratifying OS and PFS in patients with recurrent glioblastoma. Consequently, the previously suggested role of ADClow as predictive imaging biomarker could not be confirmed within this phase II/III trial.
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http://dx.doi.org/10.1093/neuonc/noaa120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690360PMC
November 2020

Temporal muscle thickness is an independent prognostic marker in patients with progressive glioblastoma: translational imaging analysis of the EORTC 26101 trial.

Neuro Oncol 2019 12;21(12):1587-1594

Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Temporal muscle thickness (TMT) was described as a surrogate marker of skeletal muscle mass. This study aimed to evaluate the prognostic relevance of TMT in patients with progressive glioblastoma.

Methods: TMT was analyzed on cranial MR images of 596 patients with progression of glioblastoma after radiochemotherapy enrolled in the European Organisation for Research and Treatment of Cancer 26101 trial. An optimal TMT cutoff for overall survival (OS) and progression-free survival (PFS) was defined in the training cohort (n = 260, phase II). Patients were grouped as "below" or "above" the TMT cutoff and associations with OS and PFS were tested using the Cox model adjusted for important risk factors. Findings were validated in a test cohort (n = 308, phase III).

Results: An optimal baseline TMT cutoff of 7.2 mm was obtained in the training cohort for both OS and PFS (area under the curve = 0.64). Univariate analyses estimated a hazard ratio (HR) of 0.54 (95% CI: 0.42, 0.70; P < 0.0001) for OS and an HR of 0.49 (95% CI: 0.38, 0.64; P < 0.0001) for PFS for the comparison of training cohort patients above versus below the TMT cutoff. Similar results were obtained in Cox models adjusted for important risk factors with relevance in the trial for OS (HR, 0.54; 95% CI: 0.41, 0.70; P < 0.0001) and PFS (HR, 0.47; 95% CI: 0.36, 0.61; P < 0.0001). Results were confirmed in the validation cohort.

Conclusion: Reduced TMT is an independent negative prognostic parameter in patients with progressive glioblastoma and may help to facilitate patient management by supporting patient stratification for therapeutic interventions or clinical trials.
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http://dx.doi.org/10.1093/neuonc/noz131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917403PMC
December 2019

Imaging necrosis during treatment is associated with worse survival in EORTC 26101 study.

Neurology 2019 06 10;92(24):e2754-e2763. Epub 2019 May 10.

From the University Medical Center & German Cancer Research Center (M.N., F.S., I.H., P.K., M.P., M.B., W.W.), Heidelberg, Germany; EORTC Headquarters (T.G., V.G.), Brussels, Belgium; Brain Tumor Center at Erasmus MC Cancer Institute (J.E.C.B., W.T., M.J.v.d.B.), Rotterdam, the Netherlands; Medical Oncology Department (A.A.B.), AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italy; Haaglanden Medical Center (M.J.B.T.), the Hague; Leiden University Medical Center (M.J.B.T.), the Netherlands; Institut Gustave Roussy (J.D.), Villejuif; Sorbonne Université (A.I.), Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris; Institut de Cancerologie de l'Ouest (ICO)-Centre Rene Gauducheau (M.C.), Saint-Herblain, France; Leuven Cancer Institute-KU Leuven (P.M.C.), Belgium; Department of Neurology and Brain Tumor Center (M.W.), University Hospital and University of Zurich, Switzerland; Institut Régional du Cancer Montpellier (M.F.); University of Lille (E.L.R.), U-1192, Inserm; CHU Lille (E.L.R.), General and Stereotaxic Neurosurgery Service; Oscar Lambret Center (E.L.R.), Neurology, Lille, France; Department of Neurology (M.P.), Medical Faculty Mannheim, Heidelberg University, Germany; and Department of Neurology (M.N.), Medical University Innsbruck, Austria.

Objective: Imaging necrosis on MRI scans was assessed and compared to outcome measures of the European Organisation for Research and Treatment of Cancer 26101 phase III trial that compared single-agent lomustine with lomustine plus bevacizumab in patients with progressive glioblastoma.

Methods: MRI in this post hoc analysis was available for 359 patients (lomustine = 127, lomustine + bevacizumab = 232). First, imaging necrosis at baseline being formally measurable (>10 × 10 mm, given 2 slices) was assessed. At weeks 6 and 12 of treatment, it was analyzed whether this necrosis remained stable or increased >25% calculated by 2 perpendicular diameters or whether necrosis developed de novo. Univariate and multivariate associations of baseline necrosis with overall survival (OS) and progression-free survival (PFS) were tested by log-rank test. Hazard ratios (HR) with 95% confidence interval were calculated by Cox model.

Results: Imaging necrosis at baseline was detected in 191 patients (53.2%) and was associated with worse OS and PFS in univariate, but not in multivariate analysis. Baseline necrosis was predictive for OS in the lomustine-only group (HR 1.46, = 0.018). At weeks 6 and 12 of treatment, increase of baseline necrosis and de novo necrosis were strongly associated with worse OS and PFS in univariate and multivariate analysis (PFS both < 0.001, OS univariate < 0.001, multivariate = 0.0046).

Conclusion: Increase of and new development of imaging necrosis during treatment is a negative prognostic factor for patients with progressive glioblastoma. These data call for consideration of integrating the assessment of imaging necrosis as a separate item into the MRI response assessment criteria.
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http://dx.doi.org/10.1212/WNL.0000000000007643DOI Listing
June 2019

Automated quantitative tumour response assessment of MRI in neuro-oncology with artificial neural networks: a multicentre, retrospective study.

Lancet Oncol 2019 05 2;20(5):728-740. Epub 2019 Apr 2.

Medical Image Computing, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The Response Assessment in Neuro-Oncology (RANO) criteria and requirements for a uniform protocol have been introduced to standardise assessment of MRI scans in both clinical trials and clinical practice. However, these criteria mainly rely on manual two-dimensional measurements of contrast-enhancing (CE) target lesions and thus restrict both reliability and accurate assessment of tumour burden and treatment response. We aimed to develop a framework relying on artificial neural networks (ANNs) for fully automated quantitative analysis of MRI in neuro-oncology to overcome the inherent limitations of manual assessment of tumour burden.

Methods: In this retrospective study, we compiled a single-institution dataset of MRI data from patients with brain tumours being treated at Heidelberg University Hospital (Heidelberg, Germany; Heidelberg training dataset) to develop and train an ANN for automated identification and volumetric segmentation of CE tumours and non-enhancing T2-signal abnormalities (NEs) on MRI. Independent testing and large-scale application of the ANN for tumour segmentation was done in a single-institution longitudinal testing dataset from the Heidelberg University Hospital and in a multi-institutional longitudinal testing dataset from the prospective randomised phase 2 and 3 European Organisation for Research and Treatment of Cancer (EORTC)-26101 trial (NCT01290939), acquired at 38 institutions across Europe. In both longitudinal datasets, spatial and temporal tumour volume dynamics were automatically quantified to calculate time to progression, which was compared with time to progression determined by RANO, both in terms of reliability and as a surrogate endpoint for predicting overall survival. We integrated this approach for fully automated quantitative analysis of MRI in neuro-oncology within an application-ready software infrastructure and applied it in a simulated clinical environment of patients with brain tumours from the Heidelberg University Hospital (Heidelberg simulation dataset).

Findings: For training of the ANN, MRI data were collected from 455 patients with brain tumours (one MRI per patient) being treated at Heidelberg hospital between July 29, 2009, and March 17, 2017 (Heidelberg training dataset). For independent testing of the ANN, an independent longitudinal dataset of 40 patients, with data from 239 MRI scans, was collected at Heidelberg University Hospital in parallel with the training dataset (Heidelberg test dataset), and 2034 MRI scans from 532 patients at 34 institutions collected between Oct 26, 2011, and Dec 3, 2015, in the EORTC-26101 study were of sufficient quality to be included in the EORTC-26101 test dataset. The ANN yielded excellent performance for accurate detection and segmentation of CE tumours and NE volumes in both longitudinal test datasets (median DICE coefficient for CE tumours 0·89 [95% CI 0·86-0·90], and for NEs 0·93 [0·92-0·94] in the Heidelberg test dataset; CE tumours 0·91 [0·90-0·92], NEs 0·93 [0·93-0·94] in the EORTC-26101 test dataset). Time to progression from quantitative ANN-based assessment of tumour response was a significantly better surrogate endpoint than central RANO assessment for predicting overall survival in the EORTC-26101 test dataset (hazard ratios ANN 2·59 [95% CI 1·86-3·60] vs central RANO 2·07 [1·46-2·92]; p<0·0001) and also yielded a 36% margin over RANO (p<0·0001) when comparing reliability values (ie, agreement in the quantitative volumetrically defined time to progression [based on radiologist ground truth vs automated assessment with ANN] of 87% [266 of 306 with sufficient data] compared with 51% [155 of 306] with local vs independent central RANO assessment). In the Heidelberg simulation dataset, which comprised 466 patients with brain tumours, with 595 MRI scans obtained between April 27, and Sept 17, 2018, automated on-demand processing of MRI scans and quantitative tumour response assessment within the simulated clinical environment required 10 min of computation time (average per scan).

Interpretation: Overall, we found that ANN enabled objective and automated assessment of tumour response in neuro-oncology at high throughput and could ultimately serve as a blueprint for the application of ANN in radiology to improve clinical decision making. Future research should focus on prospective validation within clinical trials and application for automated high-throughput imaging biomarker discovery and extension to other diseases.

Funding: Medical Faculty Heidelberg Postdoc-Program, Else Kröner-Fresenius Foundation.
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http://dx.doi.org/10.1016/S1470-2045(19)30098-1DOI Listing
May 2019

Evaluating cellularity and structural connectivity on whole brain slides using a custom-made digital pathology pipeline.

J Neurosci Methods 2019 01 24;311:215-221. Epub 2018 Oct 24.

Institute of Neurology, Medical University of Vienna, Vienna, Austria.

Aims: In brain research, the histopathological examination of coronar whole-brain slides provides important insights into spatial disease characteristics. Regarding brain tumor research, this enables visualization of tumor heterogeneity, infiltration patterns and the relationship with the surrounding brain parenchyma. The precise correlation between radiological imaging and post-mortem brains is of special interest.

New Method: We developed a wide-field slide scanner, comprising a microscope, a high-precision remotely controllable x-y-stage, a camera and a computer workstation, for automatically scanning uncommonly large formats. We analyzed whole brain slides of three patients and constructed cellularity heatmaps and fiber tract maps using a custom-made image processing pipeline.

Results: The obtained cellularity heatmaps allow for distinguishing compact tumor (5714 ± 1786 cells/mm², mean ± standard deviation) from white matter (3581 ± 828 cells/mm²) and grey matter (2473 ± 716 cells/mm²). Compared to magnetic resonance imaging, the proposed histopathological work-up (i) reveals a larger zone of tumor infiltration around the compact tumor areas and (ii) shows how pre-existing tracts are displaced by the tumor bulk. Moreover, we highlight differences in the histological tumor growth pattern of two different radiological progression subtypes.

Comparison With Existing Method(s): Compared to existing (commercial) solutions, our slide scanning solution is adaptable and cost-efficient. Moreover, we showcase potential clinical applications by mapping whole brain histology to magnetic resonance imaging.

Conclusions: We herein provide instructions on how to (i) construct a custom-built slide scanner capable of scanning arbitrary slide formats, (ii) automatically evaluate the cell density and (iii) perform fiber tracking on whole brain slides.
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http://dx.doi.org/10.1016/j.jneumeth.2018.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269083PMC
January 2019

Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial.

Cancers (Basel) 2018 Oct 5;10(10). Epub 2018 Oct 5.

Clinical Division of Medical Oncology, Department for Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3⁻20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436⁻671 versus control: 568 days, 95% CI: 349⁻680; = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.
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http://dx.doi.org/10.3390/cancers10100372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210090PMC
October 2018

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space.

Nat Med 2018 10 27;24(10):1611-1624. Epub 2018 Aug 27.

Department of Internal Medicine, Neuromed Campus Wagner-Jauregg, Kepler University Hospital, Johannes Kepler University of Linz, Linz, Austria.

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.
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http://dx.doi.org/10.1038/s41591-018-0156-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181207PMC
October 2018

Imaging Criteria in Neuro-oncology.

Semin Neurol 2018 02 16;38(1):24-31. Epub 2018 Mar 16.

Department of Neurology and Neurooncology, University Medical Center, German Cancer Research Center (DKFZ), Heidelberg, Germany.

The identification of more effective therapies for brain tumors has been limited in part by the lack of reliable criteria for determining response and progression. Since its introduction in 1990, the MacDonald criteria have been used in neuro-oncology clinical trials to determine response, but they fail to address issues such as pseudoprogression, pseudoresponse, and nonenhancing tumor progression that have arisen with more recent therapies. The Response Assessment in Neuro-Oncology (RANO) working group, a multidisciplinary international group consisting of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, and neuropsychologists, was formed to improve response assessment and clinical trial endpoints in neuro-oncology. Although it was initially focused on response assessment for gliomas, the scope of the RANO group has been broadened to include brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas. In addition, subgroups have focused on response assessment during immunotherapy and use of positron emission tomography, as well as determination of neurologic function, clinical outcomes assessment, and seizures. The RANO criteria are currently a collective work in progress, and refinements will be needed in the future based on data from clinical trials and improved imaging techniques.
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http://dx.doi.org/10.1055/s-0038-1627468DOI Listing
February 2018

Radiologic progression of glioblastoma under therapy-an exploratory analysis of AVAglio.

Neuro Oncol 2018 03;20(4):557-566

University Medical Center, Neurology, and Neurooncology, German Cancer Research Center and the German Cancer Consortium, Heidelberg, Germany.

Background: In this exploratory analysis of AVAglio, a randomized phase III clinical study that investigated the addition of bevacizumab (Bev) to radiotherapy/temozolomide in newly diagnosed glioblastoma, we aim to radiologically characterize glioblastoma on therapy until progression and investigate whether the type of radiologic progression differs between treatment arms and is related to survival and molecular data.

Methods: Five progression types (PTs) were categorized using an adapted algorithm according to MRI contrast enhancement behavior in T1- and T2-weighted images in 621 patients (Bev, n = 299; placebo, n = 322). Frequencies of PTs (designated as classic T1, cT1 relapse, T2 diffuse, T2 circumscribed, and primary nonresponder), time to progression (PFS), and overall survival (OS) were assessed within each treatment arm and compared with molecular subtypes and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status.

Results: PT frequencies differed between the Bev and placebo arms, except for "T2 diffuse" (12.4% and 7.1%, respectively). PTs showed differences in PFS and OS; with "T2 diffuse" being associated with longest survival. Complete disappearance of contrast enhancement during treatment ("cT1 relapse") showed longer survival than only partial contrast enhancement decrease ("classic T1"). "T2 diffuse" was more commonly MGMT hypermethylated. Only weak correlations to molecular subtypes from primary tissue were detected.

Conclusions: Progression of glioblastoma under therapy can be characterized radiologically. These radiologic phenotypes are influenced by treatment and develop differently over time with differential outcomes. Complete resolution of contrast enhancement during treatment is a favorable factor for outcome.
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http://dx.doi.org/10.1093/neuonc/nox162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909665PMC
March 2018

Diagnostic challenges in meningioma.

Neuro Oncol 2017 Nov;19(12):1588-1598

University Medical Center, Neurology, and Neurooncology, German Cancer Research Center and German Consortium for Translational Cancer Research, Heidelberg, Germany; Medical University Innsbruck, Department of Neurology, Innsbruck, Austria; Institute of Neuroscience and Medicine, Research Center Jülich, Jülich, Germany; Department of Neurology, University of Cologne, Cologne, Germany; Center of Integrated Oncology, Universities of Cologne and Bonn, Cologne, Germany; University Medical Center, Neuroradiology, Heidelberg, Germany; University Medical Center, Neuropathology, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.

Advances in molecular profiling and the application of advanced imaging techniques are currently refreshing diagnostic considerations in meningioma patients. Not only technical refinements but also sophisticated histopathological and molecular studies have the potential to overcome some of the challenges during meningioma management. Exact tumor delineation, assessment of tumor growth, and pathophysiological parameters were recently addressed by "advanced" MRI and PET. In the field of neuropathology, high-throughput sequencing and DNA methylation analysis of meningioma tissue has greatly advanced the knowledge of molecular aberrations in meningioma patients. These techniques allow for more reliable prediction of the biological behavior and clinical course of meningiomas and subsequently have the potential to guide individualized meningioma therapy. However, higher costs and longer duration of full molecular work-up compared with histological assessment may delay the implementation into clinical routine.This review highlights the diagnostic challenges of meningiomas from both the neuroimaging as well as the neuropathological side and presents the latest scientific achievements and studies potentially helping in overcoming these challenges. It complements the recently proposed European Association of Neuro-Oncology guidelines on treatment and diagnosis of meningiomas by integrating data on nonstandard imaging and molecular assessments most likely impacting the future.
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http://dx.doi.org/10.1093/neuonc/nox101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716093PMC
November 2017

Large-scale Radiomic Profiling of Recurrent Glioblastoma Identifies an Imaging Predictor for Stratifying Anti-Angiogenic Treatment Response.

Clin Cancer Res 2016 Dec 10;22(23):5765-5771. Epub 2016 Oct 10.

Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.

Purpose: Antiangiogenic treatment with bevacizumab, a mAb to the VEGF, is the single most widely used therapeutic agent for patients with recurrent glioblastoma. A major challenge is that there are currently no validated biomarkers that can predict treatment outcome. Here we analyze the potential of radiomics, an emerging field of research that aims to utilize the full potential of medical imaging.

Experimental Design: A total of 4,842 quantitative MRI features were automatically extracted and analyzed from the multiparametric tumor of 172 patients (allocated to a discovery and validation set with a 2:1 ratio) with recurrent glioblastoma prior to bevacizumab treatment. Leveraging a high-throughput approach, radiomic features of patients in the discovery set were subjected to a supervised principal component (superpc) analysis to generate a prediction model for stratifying treatment outcome to antiangiogenic therapy by means of both progression-free and overall survival (PFS and OS).

Results: The superpc predictor stratified patients in the discovery set into a low or high risk group for PFS (HR = 1.60; P = 0.017) and OS (HR = 2.14; P < 0.001) and was successfully validated for patients in the validation set (HR = 1.85, P = 0.030 for PFS; HR = 2.60, P = 0.001 for OS).

Conclusions: Our radiomic-based superpc signature emerges as a putative imaging biomarker for the identification of patients who may derive the most benefit from antiangiogenic therapy, advances the knowledge in the noninvasive characterization of brain tumors, and stresses the role of radiomics as a novel tool for improving decision support in cancer treatment at low cost. Clin Cancer Res; 22(23); 5765-71. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503450PMC
December 2016

How to facilitate early diagnosis of CNS involvement in malignant lymphoma.

Expert Rev Hematol 2016 Nov 21;9(11):1081-1091. Epub 2016 Oct 21.

k Penn State College of Medicine , Hershey , PA , USA.

Introduction: Making the diagnosis of secondary CNS involvement in lymphoma can be difficult due to unspecific signs and symptoms, limited accessibility of brain/myelon parenchyma and low sensitivity and/or specifity of imaging and cerebrospinal fluid (CSF) examination currently available. Areas covered: MRI of the total neuroaxis followed by CSF cytomorphology and flow cytometry are methods of choice when CNS lymphoma (CNSL) is suspected. To reduce the numerous pitfalls of these examinations several aspects should be considered. New CSF biomarkers might be of potential diagnostic value. Attempts to standardize response criteria are presented. Expert commentary: Diagnosing CNSL remains challenging. Until diagnostic methods combining high sensitivity with high specifity are routinely introduced, high level of awareness and optimal utilization of examinations currently available are needed to early diagnose this potentially devastating disease.
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http://dx.doi.org/10.1080/17474086.2016.1242405DOI Listing
November 2016

Radiogenomics of Glioblastoma: Machine Learning-based Classification of Molecular Characteristics by Using Multiparametric and Multiregional MR Imaging Features.

Radiology 2016 Dec 16;281(3):907-918. Epub 2016 Sep 16.

From the Department of Neuroradiology, University of Heidelberg Medical Center, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany (P.K., S.B., O.E., M.B.); German Cancer Research Center (DKFZ), Department of Radiology, Heidelberg, Germany (D.B., H.P.S., A.R.); Department of Neurology, Medical University Innsbruck, Austria (M.N.); Department of Neuropathology, University of Heidelberg Medical Center, Heidelberg, Germany (A.K., A.v.D., D.C.); German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.K., A.v.D., D.C.); Division of Biostatistics, DKFZ, Heidelberg, Germany (M.S.); Neurology Clinic, University of Heidelberg Medical Center, Heidelberg, Germany (M.N., S.B., A.W., W.W.); Department of Radiation Oncology, University of Heidelberg Medical Center, Heidelberg, Germany (J.D.); Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (J.D.); Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg Medical Center, Heidelberg, Germany (C.H.M.); Department of Neurosurgery, University of Heidelberg Medical Center, Heidelberg, Germany (A.U.); Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (D.J., S.P.); German Cancer Consortium (DKTK) Core Center Heidelberg, Heidelberg, Germany (D.J., S.P.); Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany (S.P.); and German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany (W.W.).

Purpose To evaluate the association of multiparametric and multiregional magnetic resonance (MR) imaging features with key molecular characteristics in patients with newly diagnosed glioblastoma. Materials and Methods Retrospective data evaluation was approved by the local ethics committee, and the requirement to obtain informed consent was waived. Preoperative MR imaging features were correlated with key molecular characteristics within a single-institution cohort of 152 patients with newly diagnosed glioblastoma. Preoperative MR imaging features (n = 31) included multiparametric (anatomic and diffusion-, perfusion-, and susceptibility-weighted images) and multiregional (contrast-enhancing regions and hyperintense regions at nonenhanced fluid-attenuated inversion recovery imaging) information with histogram quantification of tumor volumes, volume ratios, apparent diffusion coefficients, cerebral blood flow, cerebral blood volume, and intratumoral susceptibility signals. Molecular characteristics determined included global DNA methylation subgroups (eg, mesenchymal, RTK I "PGFRA," RTK II "classic"), MGMT promoter methylation status, and hallmark copy number variations (EGFR, PDGFRA, MDM4, and CDK4 amplification; PTEN, CDKN2A, NF1, and RB1 loss). Univariate analyses (voxel-lesion symptom mapping for tumor location, Wilcoxon test for all other MR imaging features) and machine learning models were applied to study the strength of association and discriminative value of MR imaging features for predicting underlying molecular characteristics. Results There was no tumor location predilection for any of the assessed molecular parameters (permutation-adjusted P > .05). Univariate imaging parameter associations were noted for EGFR amplification and CDKN2A loss, with both demonstrating increased Gaussian-normalized relative cerebral blood volume and Gaussian-normalized relative cerebral blood flow values (area under the receiver operating characteristics curve: 63%-69%, false discovery rate-adjusted P < .05). Subjecting all MR imaging features to machine learning-based classification enabled prediction of EGFR amplification status and the RTK II glioblastoma subgroup with a moderate, yet significantly greater, accuracy (63% for EGFR [P < .01], 61% for RTK II [P = .01]) than prediction by chance; prediction accuracy for all other molecular parameters was not significant. Conclusion The authors found associations between established MR imaging features and molecular characteristics, although not of sufficient strength to enable generation of machine learning classification models for reliable and clinically meaningful prediction of molecular characteristics in patients with glioblastoma. RSNA, 2016 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2016161382DOI Listing
December 2016

Clinical parameters outweigh diffusion- and perfusion-derived MRI parameters in predicting survival in newly diagnosed glioblastoma.

Neuro Oncol 2016 12 13;18(12):1673-1679. Epub 2016 Jun 13.

Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany (S.B., P.K., O.E., D.B., L.W., M.B., A.R.); Division of Bioststatistics, German Cancer Research Center, Heidelberg, Germany (D.T.); Department of Neurology, University of Heidelberg Medical Center, Heidelberg, Germany (A.W., S.L., A.H., W.W.); Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (M.N.); Department of Radiology, German Cancer Research Center, Heidelberg, Germany (H.S.).

Background: The purpose of this study was to determine the relevance of clinical data, apparent diffusion coefficient (ADC), and relative cerebral blood volume (rCBV) from dynamic susceptibility contrast (DSC) perfusion and the volume transfer constant (k) from dynamic contrast-enhanced (DCE) perfusion for predicting overall survival (OS) and progression-free survival (PFS) in newly diagnosed treatment-naïve glioblastoma patients.

Methods: Preoperative MR scans including standardized contrast-enhanced T1 (cT1), T2 - fluid-attenuated inversion recovery (FLAIR), ADC, DSC, and DCE of 125 patients with subsequent histopathologically confirmed glioblastoma were performed on a 3 Tesla MRI scanner. ADC, DSC, and DCE parameters were analyzed in semiautomatically segmented tumor volumes on contrast-enhanced (CE) cT1 and hyperintense signal changes on T2 FLAIR (ED). Univariate and multivariable Cox regression analyses including age, sex, extent of resection (EOR), and KPS were performed to assess the influence of each parameter on OS and PFS.

Results: Univariate Cox regression analysis demonstrated a significant association of age, KPS, and EOR with PFS and age, KPS, EOR, lower ADC, and higher rCBV with OS. Multivariable analysis showed independent significance of male sex, KPS, EOR, and increased rCBV for PFS, and age, sex, KPS, and EOR for OS.

Conclusions: MRI parameters help to predict OS in a univariate Cox regression analysis, and increased rCBV is associated with shorter PFS in the multivariable model. In summary, however, our findings suggest that the relevance of MRI parameters is outperformed by clinical parameters in a multivariable analysis, which limits their prognostic value for survival prediction at the time of initial diagnosis.
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http://dx.doi.org/10.1093/neuonc/now122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744248PMC
December 2016

Amino acid positron emission tomography to monitor chemotherapy response and predict seizure control and progression-free survival in WHO grade II gliomas.

Neuro Oncol 2016 05 17;18(5):744-51. Epub 2015 Nov 17.

Department of Neurology and Brain Tumor Center, Cantonal Hospital, Aarau, Switzerland (U.R.); Institute for Pharmacology and Toxicology, ETH and University of Zürich, Zürich, Switzerland (M.T.W.); Neuroscience Center, ETH and University of Zürich, Zürich, Switzerland (M.T.W.); Department of Neurology, Medical University, Innsbruck, Austria (M.N.); Department of Neuro-Oncology, University Hospital, Torino, Italy (R.R., R.S.); Department of Neurology, University Hospital, Switzerland (P.R., M.W.); Department of Oncology, University Hospital, Zürich, Switzerland (S.H.); Department of Neurology, University Hospital, Cologne, Germany, and Research Center, Jülich, Germany (N.G.); Medicina Nucleare, Istituto Nazionale dei Tumori, Milano, Italy (F.C.).

Background: Patients with WHO grade II glioma may respond to chemotherapy that is currently not standardized regarding timing and treatment duration. Metabolic changes during chemotherapy may precede structural tumor volume reductions. We therefore compared time courses of amino acid PET and MRI responses to temozolomide (TMZ) and assessed whether responses correlated with seizure control and progression-free survival (PFS).

Methods: PET and MRI were performed before and during TMZ chemotherapy. Tumor volumes were calculated using regions-of-interest analysis. Amino acid uptake was also quantified as metabolically active tumor volume and tumor-to-cerebellum uptake ratio.

Results: One hundred twenty-five PET and 125 MRI scans from 33 patients were analyzed. Twenty-five patients showed metabolic responses that exhibited an exponential time course with a 25% reduction of the active volume on average after 2.3 months. MRI responses followed a linear course with a 25% reduction after 16.8 months. Reduction of metabolically active tumor volumes, but not reduction of PET uptake ratios or MRI tumor volumes, correlated with improved seizure control following chemotherapy (P = .012). Receiver-operating-characteristic curve analysis showed that a decrease of the active tumor volume of ≥80.5% predicts a PFS of ≥60 months (P = .018) and a decrease of ≥64.5% a PFS of ≥48 months (P = .037).

Conclusions: Amino acid PET is superior to MRI for evaluating TMZ responses in WHO grade II glioma patients. The response delay between both imaging modalities favors amino acid PET for individually tailoring the duration of chemotherapy. Additional studies should investigate whether this personalized approach is appropriate with regard to outcome.
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http://dx.doi.org/10.1093/neuonc/nov282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827046PMC
May 2016

Dual Anti-angiogenic Chemotherapy with Temozolomide and Celecoxib in Selected Patients with Malignant Glioma Not Eligible for Standard Treatment.

Anticancer Res 2015 Sep;35(9):4955-60

Department of Neurosurgery, Innsbruck Medical University, Innsbruck, Austria

Aim: Due to their high rate of neo-angiogenesis, malignant gliomas may qualify for treatment with anti-angiogenic substances. We report on a series of patients with malignant glioma not eligible for standard postoperative combined radiochemotherapy due to decreased health status.

Patients And Methods: A total of nine patients with malignant glioma, postoperatively presenting with a Karnofsky performance score (KPS) below 70, were treated with standalone metronomic low-dose chemotherapy with temozolomide and celecoxib (cyclo-oxygenase-2 inhibitor). Overall survival was defined as the primary end-point and the functional status (KPS) and time to progression as secondary end-points of our analysis.

Results: The median KPS after surgery was 60. Treatment achieved a decrease in tumor and edema volume and, more importantly, preserved the functional status defined as the ability to care for self (KPS 70%) until disease progression. No notable side-effects were recorded.

Conclusion: In patients with decreased general condition (KPS <70), not eligible for standard treatment, anti-angiogenic therapy offers a reasonable alternative approach. Our results indicate prolonged survival and preserved quality of life in comparison to best supportive care.
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September 2015

The emerging role of advanced neuroimaging techniques for brain metastases.

Chin Clin Oncol 2015 Jun;4(2):23

Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany; Department of Radiology, DKFZ, Heidelberg, Germany.

Brain metastases are an increasingly encountered and frightening manifestation of systemic cancer. More effective therapeutic strategies for the primary tumor are resulting in longer patient survival on the one hand while on the other, better brain tumor detection has resulted from increased availability and development of more precise brain imaging methods. This review focuses on the emerging role of functional neuroimaging techniques; magnetic resonance imaging (MRI) as well as positron emission tomography (PET), in establishing diagnosis, for monitoring treatment response with an emphasis on new targeted as well as immunomodulatory therapies and for predicting prognosis in patients with brain metastases.
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http://dx.doi.org/10.3978/j.issn.2304-3865.2015.05.04DOI Listing
June 2015

Nuclear Overhauser Enhancement imaging of glioblastoma at 7 Tesla: region specific correlation with apparent diffusion coefficient and histology.

PLoS One 2015 19;10(3):e0121220. Epub 2015 Mar 19.

Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany; Neurooncologic Imaging, Department of Radiology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.

Objective: To explore the correlation between Nuclear Overhauser Enhancement (NOE)-mediated signals and tumor cellularity in glioblastoma utilizing the apparent diffusion coefficient (ADC) and cell density from histologic specimens. NOE is one type of chemical exchange saturation transfer (CEST) that originates from mobile macromolecules such as proteins and might be associated with tumor cellularity via altered protein synthesis in proliferating cells.

Patients And Methods: For 15 patients with newly diagnosed glioblastoma, NOE-mediated CEST-contrast was acquired at 7 Tesla (asymmetric magnetization transfer ratio (MTRasym) at 3.3ppm, B1 = 0.7 μT). Contrast enhanced T1 (CE-T1), T2 and diffusion-weighted MRI (DWI) were acquired at 3 Tesla and coregistered. The T2 edema and the CE-T1 tumor were segmented. ADC and MTRasym values within both regions of interest were correlated voxelwise yielding the correlation coefficient rSpearman (rSp). In three patients who underwent stereotactic biopsy, cell density of 12 specimens per patient was correlated with corresponding MTRasym and ADC values of the biopsy site.

Results: Eight of 15 patients showed a weak or moderate positive correlation of MTRasym and ADC within the T2 edema (0.16≤rSp≤0.53, p<0.05). Seven correlations were statistically insignificant (p>0.05, n = 4) or yielded rSp≈0 (p<0.05, n = 3). No trend towards a correlation between MTRasym and ADC was found in CE-T1 tumor (-0.310.05, n = 6). The biopsy-analysis within CE-T1 tumor revealed a strong positive correlation between tumor cellularity and MTRasym values in two of the three patients (rSppatient3 = 0.69 and rSppatient15 = 0.87, p<0.05), while the correlation of ADC and cellularity was heterogeneous (rSppatient3 = 0.545 (p = 0.067), rSppatient4 = -0.021 (p = 0.948), rSppatient15 = -0.755 (p = 0.005)).

Discussion: NOE-imaging is a new contrast promising insight into pathophysiologic processes in glioblastoma regarding cell density and protein content, setting itself apart from DWI. Future studies might be based on the assumption that NOE-mediated CEST visualizes cellularity more accurately than ADC, especially in the CE-T1 tumor region.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366097PMC
February 2016

Relative cerebral blood volume is a potential predictive imaging biomarker of bevacizumab efficacy in recurrent glioblastoma.

Neuro Oncol 2015 Aug 9;17(8):1139-47. Epub 2015 Mar 9.

Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany (P.K., S.B., S.H., M.B., A.R.); Neurology Clinic, University of Heidelberg Medical Center, Heidelberg, Germany (B.W., A.W., W.W.); German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ, Heidelberg, Germany (B.W., W.W.); Department of Neurology, Medical University Innsbruck, Innsbruck, Austria (M.N.); Department of Radiology, DKFZ, Heidelberg, Germany (H.-P.S., A.R.).

Background: To analyze the relevance of dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) derived relative cerebral blood volume (rCBV) analysis for predicting response to bevacizumab (BEV) in patients with recurrent glioblastoma (rGB).

Methods: A total of 127 patients diagnosed with rGB receiving either bevacizumab (71 patients, BEV cohort) or alkylating chemotherapy (56 patients, non-BEV cohort) underwent conventional anatomic MRI and DSC-MRI at baseline and at first follow-up after treatment initiation. The mean rCBV of the contrast-enhancing tumor (cT1) as well as cT1 and fluid-attenuated inversion recovery (FLAIR) volumes at both time points were correlated with progression-free survival (PFS) and overall survival (OS) using Cox proportional hazard models, logistic regression, and the log-rank test.

Results: Baseline rCBV was associated with both PFS (hazard ratio [HR] = 1.3; P < .01) and OS (HR = 1.3; P < .01) in the BEV cohort and predicted 6-month PFS in 82% and 12-month OS in 79% of patients, whereas it was not associated with PFS (HR = 1.0; P = .70) or OS (HR = 1.0; P = .47) in the non-BEV cohort. Corresponding median OS and PFS rates in the BEV cohort for patients with rCBV-values less than 3.92 (optimal threshold from receiver operating characteristic [ROC] analysis of 12-month OS data) were 14.2 and 6.0 months, as compared to 6.6 and 2.8 months for patients with rCBV-values greater than 3.92 (P < .01, respectively). cT1 and FLAIR volumes at first follow-up were significant predictors of 6-month PFS and 12-month OS in the BEV cohort but not in the non-BEV cohort. Corresponding volumes at baseline were not significant in any cohort.

Conclusions: Pretreatment rCBV is a potential predictive imaging biomarker in BEV-treated rGB but not alkylating chemotherapy-treated rGB, which is superior to volumetric analysis of conventional anatomic MRI and predicts 6-month PFS and 12-month OS in 80% of BEV-treated patients.
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http://dx.doi.org/10.1093/neuonc/nov028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490872PMC
August 2015

Quantification of tumor vessels in glioblastoma patients using time-of-flight angiography at 7 Tesla: a feasibility study.

PLoS One 2014 21;9(11):e110727. Epub 2014 Nov 21.

Dept. of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Baden-Württemberg, Germany.

Purpose: To analyze if tumor vessels can be visualized, segmented and quantified in glioblastoma patients with time of flight (ToF) angiography at 7 Tesla and multiscale vessel enhancement filtering.

Materials And Methods: Twelve patients with newly diagnosed glioblastoma were examined with ToF angiography (TR = 15 ms, TE = 4.8 ms, flip angle = 15°, FOV = 160 × 210 mm(2), voxel size: 0.31 × 0.31 × 0.40 mm(3)) on a whole-body 7 T MR system. A volume of interest (VOI) was placed within the border of the contrast enhancing part on T1-weighted images of the glioblastoma and a reference VOI was placed in the non-affected contralateral white matter. Automated segmentation and quantification of vessels within the two VOIs was achieved using multiscale vessel enhancement filtering in ImageJ.

Results: Tumor vessels were clearly visible in all patients. When comparing tumor and the reference VOI, total vessel surface (45.3 ± 13.9 mm(2) vs. 29.0 ± 21.0 mm(2) (p<0.035)) and number of branches (3.5 ± 1.8 vs. 1.0 ± 0.6 (p<0.001) per cubic centimeter were significantly higher, while mean vessel branch length was significantly lower (3.8 ± 1.5 mm vs 7.2 ± 2.8 mm (p<0.001)) in the tumor.

Discussion: ToF angiography at 7-Tesla MRI enables characterization and quantification of the internal vascular morphology of glioblastoma and may be used for the evaluation of therapy response within future studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110727PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240575PMC
July 2015

Pseudoprogression in patients with glioblastoma: clinical relevance despite low incidence.

Neuro Oncol 2015 Jan 18;17(1):151-9. Epub 2014 Jul 18.

Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany (A.R., J.F., P.K., P.B., S.H., M.B.); Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (A.R., H.-P.S.); Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany (B.W., A.W., W.W.); German Cancer Consortium (DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (B.W., A.W., W.W.); Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (M.N.).

Background: According to the Response Assessment in Neuro-Oncology criteria, new enhancement within the radiation field on contrast enhanced T1-weighted images within 12 weeks after completion of radiotherapy should not qualify for progressive disease, since up to 50% of these cases may be pseudoprogression (PsP). To validate this concept, we assessed incidence and overall survival (OS) of patients with suspected and confirmed PsP dependent on different time intervals and definitions of PsP.

Methods: Patients with newly diagnosed glioblastoma and an enhancement increase of at least 25% after completion of standard radiochemotherapy at month 1, 4, 7, or 10 were eligible. Based on the development of the enhancement in follow-up examinations, patients were categorized as either PsP (subgrouped as complete resolution/decrease >50% and decrease <50%/stable) or true progression.

Results: Out of 548 patients, 79 fulfilled the inclusion criteria. Of these 79 patients, 9 (11.4%) showed PsP (6/45 patients at 1 month, 2/17 at 4 months, 1/9 at 7 months, and 0/8 at 10 months). Complete resolution of the enhancement was found in 1, decrease >50% in 3, decrease <50% in 2, and stable enhancement in 3 patients with PsP. Patients with PsP showed a significantly longer OS (P < .012). No difference in OS was found among PsP subgroups.

Conclusions: This series challenges the current concept of PsP. Even though we could confirm a prolonged OS of patients with PsP, the incidence of PsP was lower than reported previously and extended beyond 12 weeks.
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http://dx.doi.org/10.1093/neuonc/nou129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483046PMC
January 2015

An intra-individual comparison of MRI, [18F]-FET and [18F]-FLT PET in patients with high-grade gliomas.

PLoS One 2014 23;9(4):e95830. Epub 2014 Apr 23.

Department of Neurology, Innsbruck Medical University, Innsbruck, Austria; Department of Neurology and Wilhelm-Sander Neurooncology Unity, University Hospital and Medical School Regensburg, Regensburg, Germany.

Objectives: Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [18F]-FET and the nucleoside PET tracer [18F]-FLT in high-grade gliomas (HGG).

Methods: MRI, [18F]-FET and [18F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for [18F]-FET and [18F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearman's rank correlation coefficient and the Mann-Whitney U test.

Results: [18F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [18F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [18F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [18F]-FET PET detected 22 of 23 (96%) HGG. [18F]-FET uptake beyond areas of cT1 was found in 61% of cases and [18F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [18F]-FET compared to [18F]-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001).

Conclusion: In HGG [18F]-FET but not [18F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [18F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [18F]-FLT tracer uptake.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095830PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997484PMC
January 2015

Progression types after antiangiogenic therapy are related to outcome in recurrent glioblastoma.

Neurology 2014 May 11;82(19):1684-92. Epub 2014 Apr 11.

From the Departments of Neurology (M.N., M.H., G.S.) and Medical Statistics, Informatics and Health Economics (G.G.), Innsbruck Medical University, Austria; the Department of Neurooncology (B.W., W.W.), Neurology Clinic and National Center for Tumor Diseases, and the Department of Neuroradiology (M.N., M.B., A.R.), University of Heidelberg; the Department of Neurology (M.H.), Regensburg Medical University; the Department of Radiology (H.P.S.), the Clinical Cooperation Unit Neurooncology (B.W., W.W.), and Department of Radiology, Neurooncologic Imaging (E012) (A.R.), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Objective: This retrospective study analyzed whether the type of radiologic progression, classified according to contrast enhancement on MRI T1-weighted sequences and changes in T2-hyperintense signal, is relevant for outcome in patients with progressive glioblastoma (pGB) treated with bevacizumab.

Methods: MRI scans of 83 patients with pGB treated with bevacizumab were evaluated prior to and at disease progression. Based on initial decrease in and subsequent flare-up of contrast enhancement in T1 and 2 patterns of T2-hyperintense tumor progression, progression types (PTs) were categorized as cT1 flare-up, T2-diffuse, T2-circumscribed, or primary nonresponder. Overall survival (OS), survival from start of bevacizumab therapy (OS_Bev), survival after bevacizumab failure (OS_PostBev), time from initial diagnosis until initiation of bevacizumab therapy (StartBevT), and time to bevacizumab progression were evaluated using Kaplan-Meier curves, log-rank test, and Cox regression analyses.

Results: The time observed for development of a T2-diffuse (n = 15) or a cT1 flare-up (n = 35) progression was longer than for progression in primary nonresponders (n = 16) or T2-circumscribed progression (n = 17). The T2-diffuse PT showed longer OS, OS_Bev, OS_PostBev, and StartBevT compared to the other PTs. Postprogression therapy tended to be relevant only for patients with a T2-circumscribed PT.

Conclusions: Radiologic PTs following bevacizumab treatment failure show differences in time to development and are related to outcome. We therefore hypothesize that these PTs reflect a different glioma biology, including differential resistance mechanisms to bevacizumab, and may be associated with different responses to postprogression therapy.
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http://dx.doi.org/10.1212/WNL.0000000000000402DOI Listing
May 2014

A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07).

Neuro Oncol 2014 Jan 4;16(1):92-102. Epub 2013 Dec 4.

Corresponding author: Markus Hutterer, MD, Department of Neurology and Wilhelm-Sander NeuroOncology Unit, University of Regensburg Medical School, Franz Josef Strauß-Allee 11, D-93053 Regensburg, Germany.

Background: Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing.

Methods: This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules.

Results: Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity.

Conclusion: Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.
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http://dx.doi.org/10.1093/neuonc/not161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870838PMC
January 2014

Polyarteritis nodosa complicating multiple myeloma - a case report and review of the literature.

Clin Neuropathol 2014 Mar-Apr;33(2):143-51

Introduction: Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small to-medium-sized vessels, rarely associated with hematologic neoplasms.

Case Report: We report a 44-year-old man with a history of monoclonal gammopathy of undetermined significance (MGUS) who presented with rapidly progressing sensorimotor peripheral neuropathy. Two weeks after onset the patient developed severe acute acral and retinal ischemia. MR-angiography and nerve biopsy revealed a systemic necrotizing vasculitis (PAN type). At this time, bone marrow biopsy identified a smoldering multiple myeloma. Immediate immunosuppressive and anti-neoplastic treatment (steroids, immunoglobulins, bortezomib combined with cyclophosphamide followed by lenalidomide maintenance) resulted in a favorable clinical outcome. After 4 years, the patient is in good clinical condition with sustained partial remission from myeloma and without evidence of relapse of PAN.

Conclusion: This is a remarkable case of a histologically confirmed peripheral neuropathy due to polyarteritis nodosa associated with progression of MGUS to multiple myeloma. Immediate diagnosis and combined immunosuppressive and anti-neoplastic treatment may improve the outcome of this potentially life-threatening clinical condition.
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http://dx.doi.org/10.5414/NP300686DOI Listing
May 2014

[18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma.

Neuro Oncol 2013 Mar 17;15(3):341-51. Epub 2013 Jan 17.

Department of Neurology, Wilhelm-Sander Neurooncology Therapy Unit, University Hospital of Regensburg, Universitätsstrasse 84, D-93053 Regensburg, Germany.

Background: To assess the sensitivity and specificity of [(18)F]-fluoro-ethyl-l-tyrosine ((18)F-FET) PET in brain tumors and various non-neoplastic neurologic diseases.

Methods: We retrospectively evaluated (18)F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). (18)F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense).

Results: Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed (18)F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher (18)F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). (18)F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions.

Conclusions: (18)F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood-brain barrier and (18)F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.
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http://dx.doi.org/10.1093/neuonc/nos300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578481PMC
March 2013