Publications by authors named "Maximilian I Ruge"

40 Publications

Radiomics for prediction of radiation-induced lung injury and oncologic outcome after robotic stereotactic body radiotherapy of lung cancer: results from two independent institutions.

Radiat Oncol 2021 Apr 16;16(1):74. Epub 2021 Apr 16.

Department of Stereotactic and Functional Neurosurgery, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Objectives: To generate and validate state-of-the-art radiomics models for prediction of radiation-induced lung injury and oncologic outcome in non-small cell lung cancer (NSCLC) patients treated with robotic stereotactic body radiation therapy (SBRT).

Methods: Radiomics models were generated from the planning CT images of 110 patients with primary, inoperable stage I/IIa NSCLC who were treated with robotic SBRT using a risk-adapted fractionation scheme at the University Hospital Cologne (training cohort). In total, 199 uncorrelated radiomic features fulfilling the standards of the Image Biomarker Standardization Initiative (IBSI) were extracted from the outlined gross tumor volume (GTV). Regularized models (Coxnet and Gradient Boost) for the development of local lung fibrosis (LF), local tumor control (LC), disease-free survival (DFS) and overall survival (OS) were built from either clinical/ dosimetric variables, radiomics features or a combination thereof and validated in a comparable cohort of 71 patients treated by robotic SBRT at the Radiosurgery Center in Northern Germany (test cohort).

Results: Oncologic outcome did not differ significantly between the two cohorts (OS at 36 months 56% vs. 43%, p = 0.065; median DFS 25 months vs. 23 months, p = 0.43; LC at 36 months 90% vs. 93%, p = 0.197). Local lung fibrosis developed in 33% vs. 35% of the patients (p = 0.75), all events were observed within 36 months. In the training cohort, radiomics models were able to predict OS, DFS and LC (concordance index 0.77-0.99, p < 0.005), but failed to generalize to the test cohort. In opposite, models for the development of lung fibrosis could be generated from both clinical/dosimetric factors and radiomic features or combinations thereof, which were both predictive in the training set (concordance index 0.71- 0.79, p < 0.005) and in the test set (concordance index 0.59-0.66, p < 0.05). The best performing model included 4 clinical/dosimetric variables (GTV-D, PTV-D, Lung-D, age) and 7 radiomic features (concordance index 0.66, p < 0.03).

Conclusion: Despite the obvious difficulties in generalizing predictive models for oncologic outcome and toxicity, this analysis shows that carefully designed radiomics models for prediction of local lung fibrosis after SBRT of early stage lung cancer perform well across different institutions.
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http://dx.doi.org/10.1186/s13014-021-01805-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052812PMC
April 2021

Stereotactic radiosurgery for treating meningiomas eligible for complete resection.

Radiat Oncol 2021 Jan 28;16(1):22. Epub 2021 Jan 28.

Department of General Neurosurgery, Centre for Neurosurgery, Medical Faculty of the University of Cologne, Cologne, Germany.

Background: For meningiomas, complete resection is recommended as first-line treatment while stereotactic radiosurgery (SRS) is established for meningiomas of smaller size considered inoperable. If the patient´s medical condition or preference excludes surgery, SRS remains a treatment option. We evaluated the efficacy and safety of SRS in a cohort comprising these cases.

Methods: In this retrospective single-centre analysis we included patients receiving single fraction SRS either by modified LINAC or robotic guidance by Cyberknife for potentially resectable intracranial meningiomas. Treatment-related adverse events as well as local and regional control rates were determined from follow-up imaging and estimated by the Kaplan-Meier method.

Results: We analyzed 188 patients with 218 meningiomas. The median radiological, and clinical follow-up periods were 51.4 (6.2-289.6) and 55.8 (6.2-300.9) months. The median tumor volume was 4.2 ml (0.1-22), and the mean marginal radiation dose was 13.0 ± 3.1 Gy, with reference to the 80.0 ± 11.2% isodose level. Local recurrence was observed in one case (0.5%) after 239 months. The estimated 2-, 5-, 10- and 15-year regional recurrence rates were 1.5%, 3.0%, 6.6% and 6.6%, respectively. Early adverse events (≤ 6 months after SRS) occurred in 11.2% (CTCEA grade 1-2) and resolved during follow-up in 7.4% of patients, while late adverse events were documented in 14.4% (grade 1-2; one case grade 3). Adverse effects (early and late) were associated with the presence of symptoms or neurological deficits prior to SRS (p < 0.03) and correlated with the treatment volume (p < 0.02).

Conclusion: In this analysis SRS appears to be an effective treatment for patients with meningiomas eligible for complete resection and provides reliable long-term local tumor control with low rates of mild morbidity.
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http://dx.doi.org/10.1186/s13014-021-01748-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841895PMC
January 2021

Stereotactic radiosurgery of benign brain tumors in elderly patients: evaluation of outcome and toxicity.

Radiat Oncol 2020 Dec 9;15(1):274. Epub 2020 Dec 9.

Department of Stereotaxy and Functional Neurosurgery, Centre of Neurosurgery, Medical Faculty and University Hospital Cologne, University of Cologne, Kerpener Straße 62, 50937, Cologne, Germany.

Background: Stereotactic radiosurgery (SRS) is widely accepted as a therapeutic option for meningiomas (M) and vestibular schwannomas (VS). However, data on outcome and toxicity in the elderly population have rarely been reported in detail.

Methods: All patients aged ≥ 65 years with M or VS who underwent single fraction SRS were included. Patient data were analyzed in terms of clinical tumor control and incidence of early and late treatment related complications, which were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), RESULTS: We identified 245 patients with benign brain tumors (129 M and 116 VS, median tumor volume 2.9 ml, range 0.1-28). The median age was 71 years (range 65-86) and the mean follow-up times were 42 months (range 2-181). Tumors were irradiated with a median dose of 12.4 Gy. Actuarial clinical and radiological tumor control rates at 2, 5, and 10 years after SRS were 98%, 93%, and 88%, respectively. Recurrent tumors after previous treatment had a higher probability of post-radiosurgical progression (p < 0.001). Permanent toxicity (CTCAE I/II) were noted in 5.7%. No severe adverse events were observed during early and late follow up, although patients > 70 years had a slightly higher risk for toxicity (p = 0.027). The presence and extent of co-morbidities had no significant influence on local tumor control or toxicity.

Conclusion: SRS provides favorable tumor control with low risk for treatment-related severe complications. Thus, SRS should always be considered as treatment option for benign intracranial tumors (meningiomas, schwannomas), especially in the group of elderly patients.
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http://dx.doi.org/10.1186/s13014-020-01714-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724716PMC
December 2020

Treatment Monitoring of Immunotherapy and Targeted Therapy Using F-FET PET in Patients with Melanoma and Lung Cancer Brain Metastases: Initial Experiences.

J Nucl Med 2021 04 4;62(4):464-470. Epub 2020 Sep 4.

Center of Integrated Oncology, Universities of Aachen, Bonn, Cologne, and Duesseldorf, Germany.

We investigated the value of -(2-F-fluoroethyl)-l-tyrosine (F-FET) PET for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastasis (BM) since contrast-enhanced MRI often remains inconclusive. We retrospectively identified 40 patients with 107 BMs secondary to melanoma ( = 29 with 75 BMs) or non-small cell lung cancer ( = 11 with 32 BMs) treated with ICI or TT who had F-FET PET ( = 60 scans) for treatment monitoring from 2015 to 2019. Most patients ( = 37; 92.5%) had radiotherapy during the course of the disease. In 27 patients, F-FET PET was used to differentiate treatment-related changes from BM relapse after ICI or TT. In 13 patients, F-FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 mo). In all lesions, static and dynamic F-FET PET parameters were obtained (i.e., mean tumor-to-brain ratios [TBR], time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathologic findings as a reference. A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% ( = 0.003). Metabolic responders to ICI or TT on F-FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; = 0.004). Furthermore, at follow-up, time to peak in metabolic responders increased significantly ( = 0.019). F-FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.
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http://dx.doi.org/10.2967/jnumed.120.248278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049362PMC
April 2021

Analysis of Driver Mutational Hot Spots in Blood-Derived Cell-Free DNA of Patients with Primary Central Nervous System Lymphoma Obtained before Intracerebral Biopsy.

J Mol Diagn 2020 10 1;22(10):1300-1307. Epub 2020 Aug 1.

Institute of Neuropathology, University of Cologne, Cologne, Germany.

In newly diagnosed systemic diffuse large B-cell lymphoma, next-generation sequencing of plasma-derived cell-free DNA (cfDNA) detects somatic mutations as accurate as genotyping of the tumor biopsy. A distinct diffuse large B-cell lymphoma entity confined to the central nervous system is primary central nervous system lymphoma (PCNSL), which requires intracerebral biopsy and neuropathologic analysis to establish the diagnosis. So far, a biomarker for diagnosis and follow-up of PCNSL that can be investigated in blood has not been identified. This article addresses the question whether somatic mutations of the CD79B and MYD88 driver genes of PCNSL can be detected in cfDNA at disease diagnosis. Stereotactic biopsies and cfDNA of 27 PCNSL patients were analyzed for CD79B and MYD88 mutations. As control, cfDNA derived from six healthy volunteers was used. CD79B and MYD88 hot spot mutations were identified in 16 of 27 (59%) and 23 of 27 (85%) PCNSL biopsies, respectively, but only in 0 of 27 (0%) and 1 of 27 (4%) corresponding cfDNA samples, respectively. In cfDNA of one of four patients with Waldenstrom disease, as a further control, the MYD88 L265P mutation was readily detected, despite complete clinical remission. These data suggest that in PCNSL even if they carry such mutations, alterations of CD79B and MYD88 cannot be reliably detected in blood-derived cfDNA obtained before intracerebral biopsy.
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http://dx.doi.org/10.1016/j.jmoldx.2020.07.002DOI Listing
October 2020

Primary Central Nervous System Lymphoma: Clinical Evaluation of Automated Segmentation on Multiparametric MRI Using Deep Learning.

J Magn Reson Imaging 2021 01 13;53(1):259-268. Epub 2020 Jul 13.

Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Precise volumetric assessment of brain tumors is relevant for treatment planning and monitoring. However, manual segmentations are time-consuming and impeded by intra- and interrater variabilities.

Purpose: To investigate the performance of a deep-learning model (DLM) to automatically detect and segment primary central nervous system lymphoma (PCNSL) on clinical MRI.

Study Type: Retrospective.

Population: Sixty-nine scans (at initial and/or follow-up imaging) from 43 patients with PCNSL referred for clinical MRI tumor assessment.

Field Strength/sequence: T -/T -weighted, T -weighted contrast-enhanced (T CE), and FLAIR at 1.0, 1.5, and 3.0T from different vendors and study centers.

Assessment: Fully automated voxelwise segmentation of tumor components was performed using a 3D convolutional neural network (DeepMedic) trained on gliomas (n = 220). DLM segmentations were compared to manual segmentations performed in a 3D voxelwise manner by two readers (radiologist and neurosurgeon; consensus reading) from T CE and FLAIR, which served as the reference standard.

Statistical Tests: Dice similarity coefficient (DSC) for comparison of spatial overlap with the reference standard, Pearson's correlation coefficient (r) to assess the relationship between volumetric measurements of segmentations, and Wilcoxon rank-sum test for comparison of DSCs obtained in initial and follow-up imaging.

Results: The DLM detected 66 of 69 PCNSL, representing a sensitivity of 95.7%. Compared to the reference standard, DLM achieved good spatial overlap for total tumor volume (TTV, union of tumor volume in T CE and FLAIR; average size 77.16 ± 62.4 cm , median DSC: 0.76) and tumor core (contrast enhancing tumor in T CE; average size: 11.67 ± 13.88 cm , median DSC: 0.73). High volumetric correlation between automated and manual segmentations was observed (TTV: r = 0.88, P < 0.0001; core: r = 0.86, P < 0.0001). Performance of automated segmentations was comparable between pretreatment and follow-up scans without significant differences (TTV: P = 0.242, core: P = 0.177).

Data Conclusion: In clinical MRI scans, a DLM initially trained on gliomas provides segmentation of PCNSL comparable to manual segmentation, despite its complex and multifaceted appearance. Segmentation performance was high in both initial and follow-up scans, suggesting its potential for application in longitudinal tumor imaging.

Level Of Evidence: 3 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27288DOI Listing
January 2021

Role of the default mode resting-state network for cognitive functioning in malignant glioma patients following multimodal treatment.

Neuroimage Clin 2020 26;27:102287. Epub 2020 May 26.

Institute of Neuroscience and Medicine (INM-1, -3, -4), Research Center Juelich, Wilhelm-Johnen-Str., 52428 Juelich, Germany; Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany.

Background: Progressive cognitive decline following multimodal neurooncological treatment is a common observation in patients suffering from malignant glioma. Alterations of the default-mode network (DMN) represent a possible source of impaired neurocognitive functioning and were analyzed in these patients.

Methods: Eighty patients (median age, 51 years) with glioma (WHO grade IV glioblastoma, n = 57; WHO grade III anaplastic astrocytoma, n = 13; WHO grade III anaplastic oligodendroglioma, n = 10) and ECOG performance score 0-1 underwent resting-state functional MRI (rs-fMRI) and neuropsychological testing at a median interval of 13 months (range, 1-114 months) after initiation of therapy. For evaluation of structural and metabolic changes after treatment, anatomical MRI and amino acid PET using O-(2-[F]fluoroethyl)-L-tyrosine (FET) were simultaneously acquired to rs-fMRI on a hybrid MR/PET scanner. A cohort of 80 healthy subjects matched for gender, age, and educational status served as controls.

Results: The connectivity pattern within the DMN (12 nodes) of the glioma patients differed significantly from that of the healthy subjects but did not depend on age, tumor grade, time since treatment initiation, presence of residual/recurrent tumor, number of chemotherapy cycles received, or anticonvulsive medication. Small changes in the connectivity pattern were observed in patients who had more than one series of radiotherapy. In contrast, structural tissue changes located at or near the tumor site (including resection cavities, white matter lesions, edema, and tumor tissue) had a strong negative impact on the functional connectivity of the adjacent DMN nodes, resulting in a marked dependence of the connectivity pattern on tumor location. In the majority of neurocognitive domains, glioma patients performed significantly worse than healthy subjects. Correlation analysis revealed that reduced connectivity in the left temporal and parietal DMN nodes was associated with low performance in language processing and verbal working memory. Furthermore, connectivity of the left parietal DMN node also correlated with processing speed, executive function, and verbal as well as visual working memory. Overall DMN connectivity loss and cognitive decline were less pronounced in patients with higher education.

Conclusion: Personalized treatment strategies for malignant glioma patients should consider the left parietal and temporal DMN nodes as vulnerable regions concerning neurocognitive outcome.
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http://dx.doi.org/10.1016/j.nicl.2020.102287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298724PMC
March 2021

Applications of radiomics and machine learning for radiotherapy of malignant brain tumors.

Strahlenther Onkol 2020 Oct 11;196(10):856-867. Epub 2020 May 11.

Institute of Neuroscience and Medicine (INM-3, -4), Research Center Juelich, Wilhelm-Johnen-Straße, 52428, Juelich, Germany.

Background: Magnetic resonance imaging (MRI) and amino acid positron-emission tomography (PET) of the brain contain a vast amount of structural and functional information that can be analyzed by machine learning algorithms and radiomics for the use of radiotherapy in patients with malignant brain tumors.

Methods: This study is based on comprehensive literature research on machine learning and radiomics analyses in neuroimaging and their potential application for radiotherapy in patients with malignant glioma or brain metastases.

Results: Feature-based radiomics and deep learning-based machine learning methods can be used to improve brain tumor diagnostics and automate various steps of radiotherapy planning. In glioma patients, important applications are the determination of WHO grade and molecular markers for integrated diagnosis in patients not eligible for biopsy or resection, automatic image segmentation for target volume planning, prediction of the location of tumor recurrence, and differentiation of pseudoprogression from actual tumor progression. In patients with brain metastases, radiomics is applied for additional detection of smaller brain metastases, accurate segmentation of multiple larger metastases, prediction of local response after radiosurgery, and differentiation of radiation injury from local brain metastasis relapse. Importantly, high diagnostic accuracies of 80-90% can be achieved by most approaches, despite a large variety in terms of applied imaging techniques and computational methods.

Conclusion: Clinical application of automated image analyses based on radiomics and artificial intelligence has a great potential for improving radiotherapy in patients with malignant brain tumors. However, a common problem associated with these techniques is the large variability and the lack of standardization of the methods applied.
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http://dx.doi.org/10.1007/s00066-020-01626-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498494PMC
October 2020

Stereotactic Radiosurgery of Cavernous Sinus Meningiomas.

J Neurol Surg B Skull Base 2020 Apr 12;81(2):158-164. Epub 2019 Mar 12.

Department of Stereotaxy and Functional Neurosurgery, Centre of Neurosurgery, University Hospital Cologne, Cologne, Germany.

 Microsurgical resection of cavernous sinus meningiomas (CSM) is associated with a high rate of incomplete resection, recurrence, and the risk for permanent, severe cranial nerve deficits. Stereotactic radiosurgery (SRS) has evolved as alternative treatment for primary and recurrent CSM. Here, we report about the long-term clinical and radiological follow-up (FU) of a unique cohort of patients with CSM treated with LINAC or Cyberknife based SRS.  In this single-center retrospective analysis, we include all patients with CSM who underwent single fraction SRS between 1993 and 2016. Clinical and radiological tumor control were evaluated by the Kaplan-Meier method. Additionally, patient data were analyzed in terms of symptom control and incidence of side effects rated by the common terminology criteria for adverse events (CTCAE; v4.03).  116 patients (female/male = 91/25; median age, 54 years; range, 33-82 years) were included. Mean tumor volume was 5.7 ± 3.3 cm (range, 0.6-16.2 cm ), the median marginal dose was 12.6 Gy applied to isodose levels of 75%. Median clinical FU was 55 months (range, 3-226 months). Tumor control was 98% after 2 and 5 years and 90% after 10 years. Twelve patients (10.3%) had permanent or transient radiation related toxicity (CTCAE I-III). An improvement of symptoms was observed in 26.7% of the symptomatic patients (  = 20 of 75).  SRS for CSM provides excellent long-term tumor and symptom control without considerable permanent side effects. Thus, SRS should be considered when counseling patients suffering from CSM.
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http://dx.doi.org/10.1055/s-0039-1683430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082171PMC
April 2020

Observation after surgery for low grade glioma: long-term outcome in the light of the 2016 WHO classification.

J Neurooncol 2019 Dec 16;145(3):501-507. Epub 2019 Oct 16.

Department of General Neurosurgery, Center for Neurosurgery, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Purpose: To provide detailed long-term data after initial observation for patients after histological confirmation of low grade (WHO II) gliomas according to molecular stratification.

Methods: A series of 110 patients with watchful waiting strategy after initial surgery for LGG and re-surgery at tumor progression were analyzed. Progression-free survival, time to malignant transformation, post-recurrence survival, and overall survival were estimated with the Kaplan-Meier method. Prognostic factors were identified by the Log Rank test and Cox multivariate proportional hazards model.

Results: The cohort comprised 18 IDH wild type (IDH) and 53 IDH mutated (IDH) astrocytomas, and 39 IDH mutated and 1p 19q co-deleted (IDH) patients. The median follow-up was 126 (95% CI 109-143) months. Surgery was gross total resection in 58, subtotal resection in 28, and biopsy in 24 patients. Progression-free survival rates at 5, 10 and 15 years was 38% 18% and 1%. The corresponding malignant transformation rates were 17%, 39% and 71%. The initial extent of resection influenced progression-free survival, time to malignant transformation and overall survival. Molecular subtype IDH was the strongest prognostic factor for overall survival and for time to malignant transformation.

Conclusion: The strongest determinant of the patients' course after initial watchful waiting was the molecular tumor status. Extensive resection may increase time to progression and malignant transformation. Observation may be justified in selected patients.
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http://dx.doi.org/10.1007/s11060-019-03316-7DOI Listing
December 2019

Frame-based stereotactic biopsy of deep-seated and midline structures in 511 procedures: feasibility, risk profile, and diagnostic yield.

Acta Neurochir (Wien) 2019 10 29;161(10):2065-2071. Epub 2019 Jul 29.

Department of Stereotaxy and Functional Neurosurgery, Center for Neurosurgery, University Hospital of Cologne, 50937, Köln, Germany.

Objectives: We evaluated the feasibility, safety, and diagnostic yield of frame-based stereotactic biopsies (SB) in lesions located in deep-seated and midline structures of the brain to analyze these parameters in comparison to other brain areas.

Patients And Methods: In a retrospective, tertiary care single-center analysis, we identified all patients who received SB for lesions localized in deep-seated and midline structures (corpus callosum, basal ganglia, pineal region, sella, thalamus, and brainstem) between January 1996 and June 2015. Study participants were between 1 and 82 years. We evaluated the feasibility, procedural complications (mortality, transient and permanent morbidity), and diagnostic yield. We further performed a risk analysis of factors influencing the latter parameters. Chi-square test, Student t test, and Mann-Whitney rank-sum test were used for statistical analysis.

Results: Four hundred eighty-nine patients receiving 511 SB procedures (median age 48.5 years, range 1-82; median Karnofsky Performance Score 80%, range 50-100%, 43.8% female/56.2% male) were identified. Lesions were localized in the corpus callosum (29.5%), basal ganglia (17.0%), pineal region (11.5%), sella (7.8%), thalamus (4.3%), brainstem (28.8%), and others (1.1%). Procedure-related mortality was 0%, and permanent morbidity was 0.4%. Transient morbidity was 9.6%. Histological diagnosis was possible in 99.2% (low-grade gliomas 16.2%, high-grade gliomas 40.3%, other tumors in 27.8%, no neoplastic lesions 14.5%, no definitive histological diagnosis 0.8%). Only the pons location correlated significantly with transient morbidity (p < 0.001).

Conclusion: In experienced centers, frame-based stereotactic biopsy is a safe diagnostic tool with a high diagnostic yield also for deep-seated and midline lesions.
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http://dx.doi.org/10.1007/s00701-019-04020-1DOI Listing
October 2019

Robotic Stereotactic Radiosurgery in Melanoma Patients with Brain Metastases under Simultaneous Anti-PD-1 Treatment.

Int J Mol Sci 2018 Sep 7;19(9). Epub 2018 Sep 7.

Department of Radiation Oncology and Cyberknife Center, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.

Combination concepts of radiotherapy and immune checkpoint inhibition are currently of high interest. We examined imaging findings, acute toxicity, and local control in patients with melanoma brain metastases receiving programmed death 1 (PD-1) inhibitors and/or robotic stereotactic radiosurgery (SRS). Twenty-six patients treated with SRS alone ( = 13; 20 lesions) or in combination with anti-PD-1 therapy ( = 13; 28 lesions) were analyzed. Lesion size was evaluated three and six months after SRS using a volumetric assessment based on cranial magnetic resonance imaging (cMRI) and acute toxicity after 12 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE). Local control after six months was comparable (86%, SRS + anti-PD-1, and 80%, SRS). All toxicities reported were less than or equal to grade 2. One metastasis (5%) in the SRS group and six (21%) in the SRS + anti-PD-1 group increased after three months, whereas four (14%) of the six regressed during further follow-ups. This was rated as pseudoprogression (PsP). Three patients (23%) in the SRS + anti-PD-1 group showed characteristics of PsP. Treatment with SRS and anti-PD-1 antibodies can be combined safely in melanoma patients with cerebral metastases. Early volumetric progression of lesions under simultaneous treatment may be related to PsP; thus, the evaluation of combined radioimmunotherapy remains challenging and requires experienced teams.
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http://dx.doi.org/10.3390/ijms19092653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164579PMC
September 2018

Combined FET PET/MRI radiomics differentiates radiation injury from recurrent brain metastasis.

Neuroimage Clin 2018 19;20:537-542. Epub 2018 Aug 19.

Inst. of Neuroscience and Medicine (INM-3, -4, -5), Forschungszentrum Juelich, Juelich, Germany; Dept. of Neurology, University of Cologne, Cologne, Germany; Center of Integrated Oncology (CIO), Universities of Cologne and Bonn, Cologne, Germany.

Background: The aim of this study was to investigate the potential of combined textural feature analysis of contrast-enhanced MRI (CE-MRI) and static O-(2-[F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation between local recurrent brain metastasis and radiation injury since CE-MRI often remains inconclusive.

Methods: Fifty-two patients with new or progressive contrast-enhancing brain lesions on MRI after radiotherapy (predominantly stereotactic radiosurgery) of brain metastases were additionally investigated using FET PET. Based on histology ( = 19) or clinicoradiological follow-up ( = 33), local recurrent brain metastases were diagnosed in 21 patients (40%) and radiation injury in 31 patients (60%). Forty-two textural features were calculated on both unfiltered and filtered CE-MRI and summed FET PET images (20-40 min p.i.), using the software LIFEx. After feature selection, logistic regression models using a maximum of five features to avoid overfitting were calculated for each imaging modality separately and for the combined FET PET/MRI features. The resulting models were validated using cross-validation. Diagnostic accuracies were calculated for each imaging modality separately as well as for the combined model.

Results: For the differentiation between radiation injury and recurrence of brain metastasis, textural features extracted from CE-MRI had a diagnostic accuracy of 81% (sensitivity, 67%; specificity, 90%). FET PET textural features revealed a slightly higher diagnostic accuracy of 83% (sensitivity, 88%; specificity, 75%). However, the highest diagnostic accuracy was obtained when combining CE-MRI and FET PET features (accuracy, 89%; sensitivity, 85%; specificity, 96%).

Conclusions: Our findings suggest that combined FET PET/CE-MRI radiomics using textural feature analysis offers a great potential to contribute significantly to the management of patients with brain metastases.
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http://dx.doi.org/10.1016/j.nicl.2018.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118093PMC
January 2019

FET PET in Primary Central Nervous System Vasculitis.

Clin Nucl Med 2018 Sep;43(9):e322-e323

Stereotactic and Functional Neurosurgery, University Hospital Cologne, Cologne.

Primary central nervous system vasculitis is confined to the brain and spinal cord. While serological markers of inflammation are usually normal, conventional angiography may confirm the diagnosis. The diagnostic method of choice is central nervous system biopsy. A 57-year-old man suffered from a first generalized epileptic seizure. MRI revealed a contrast-enhancing lesion, and O-(2-[F]fluoroethyl)-L-tyrosine amino acid PET displayed increased metabolic activity, both findings highly suggestive of a malignant glioma. Surprisingly, histology obtained following stereotactic biopsy revealed small-vessel vasculitis.
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http://dx.doi.org/10.1097/RLU.0000000000002197DOI Listing
September 2018

Acoustic Neuroma Treated with Stereotactic Radiosurgery: Follow-up of 335 Patients.

World Neurosurg 2018 Aug 30;116:e194-e202. Epub 2018 Apr 30.

Department of Stereotaxy and Functional Neurosurgery, Centre of Neurosurgery, University Hospital of Cologne, Cologne, Germany.

Objective: To determine the clinical and radiologic outcome of patients with acoustic neuroma (AN) treated with linear accelerator (LINAC) or CyberKnife-based stereotactic radiosurgery with respect to tumor control, preservation of serviceable hearing, and toxicity.

Methods: A retrospective monocentric analysis including all patients who underwent single-fraction LINAC- or CyberKnife-based radiosurgery for AN between 1991 and 2015. Patient data were analyzed in terms of radiologic and clinical tumor control (no further intervention needed), treatment-related complications, preservation of serviceable hearing, and objectified hearing loss using pure tone average levels.

Results: We included 335 patients (median age 58.2 years, treated either by LINAC-based [n = 270] or CyberKnife [n = 65] stereotactic radiosurgery). The median tumor volume was 1.1 mL (0.1-23.7 mL). The median radiation dose was 12 Gy (LINAC 12 Gy, 11-20 Gy; CyberKnife 13 Gy, 12-13 Gy) at an isodose level of 71.7% (LINAC 68.3%, 31.9%-86.2%; CyberKnife 80%, 65%-81%). The median follow-up was 30 months (LINAC 43 months, 2-224 months; CyberKnife 13 months, 4-37 months). Clinical tumor control was 98%, 89%, and 88% at 2, 5, and 10 years. The objective actuarial hearing preservation rate was 89%, 80%, and 55% at 1, 2, and 5 years. New symptoms were observed in 11.3% and classified as Common Terminology Criteria for Adverse Events grade 1/2, apart from 4 patients (1.2%), who developed Common Terminology Criteria for Adverse Events grade 3.

Conclusions: Our study shows that in AN, high tumor control and considerable hearing preservation rates can be achieved by single-dose radiosurgery at low toxicity rates, resulting in a positive impact on long-term clinical outcome.
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http://dx.doi.org/10.1016/j.wneu.2018.04.149DOI Listing
August 2018

Radiotoxicity in robotic radiosurgery: proposing a new quality index for optimizing the treatment planning of brain metastases.

Radiat Oncol 2017 Aug 17;12(1):136. Epub 2017 Aug 17.

Department of Stereotaxy and Functional Neurosurgery, University Hospital Cologne, Cologne, Germany.

Background: As irradiated brain volume at 12 Gy (V12) is a predictor for radionecrosis, the purpose of the study was to develop a model for Cyberknife (CK) plans that is able to predict the lowest achievable V12 at a given tumor size and prescription dose (PD), and to suggest a new quality index regarding V12 for optimizing the treatment planning of brain metastases.

Method: In our model V12 was approximated as a spherical shell around the tumor volume. The radial distance between tumor surface and the 12 Gy isodose line was calculated using an approximation of the mean dose gradient in that area. Assuming a radially symmetrical irradiation from the upper half space, the dose distribution is given by the superposition of single fields. The dose profiles of a single field were derived by the measured off-center ratios (OCR) of the CK system. Using the calculated gradients of the sum dose profiles, minimal-V12 was estimated for different tumor sizes. The model calculation was tested using a phantom dataset and retrospectively applied on clinical cases.

Results: Our model allows the prediction of a best-case scenario for V12 at a given tumor size and PD which was confirmed by the results of the isocentric phantom plans. The results of the non-isocentric phantom plans showed that an optimization of coverage caused an increase in V12. This was in accordance with the results of the retrospective analysis. V12 s of the clinical cases were on average twice that of the predicted model calculation. A good agreement was achieved for plans with an optimal conformity index (nCI). Re-planning of cases with high V12 showed that lower values could be reached by selecting smaller collimators and by allowing a larger number of total MU and more MU per beam.

Conclusions: V12 is a main parameter for assessing plan quality in terms of radiotoxicity. The index f12 defined as the ratio of V12 from the actual plan with the evaluated V12 from our model describes the conformity of an optimally possible V12 and thus can be used as a new quality index for optimizing treatment plans.
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http://dx.doi.org/10.1186/s13014-017-0867-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561581PMC
August 2017

Stereotactic biopsy in elderly patients: risk assessment and impact on treatment decision.

J Neurooncol 2017 Sep 21;134(2):303-307. Epub 2017 Jun 21.

Department of Stereotaxy and Functional Neurosurgery, Center of Neurosurgery, University Hospital of Cologne, Albertus-Magnus University Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

To evaluate risk profile, diagnostic yield and impact on treatment decision of stereotactic biopsy (SB) in elderly patients with unclear cerebral lesions. In this single center retrospective analysis we identified all patients aged ≥70 years receiving SB between January 2005 and December 2015. Demographic data, Karnofsky Performance Status (KPS), histology, comorbidity (by CHA2DS2-VASc Score) and use of anticoagulation were retrieved. We scrutinized diagnostic yield, procedural complications (mortality, transient and permanent morbidity), hospitalization time and therapeutic consequence. For correlation analysis Chi-Square, Mann-Whitney rank sum test and binary regression were used. Two hundred and thirty patients were included. In 229 patients SB was technically successful. Median age was 74 (70-87) years, 56.1% of patients were male and median preoperative KPS was 80% (30-100). Median CHA2DS2-VASc Score was 4 (1-9), with 29.6% receiving anticoagulation. Median hospital stay was 8 (2-29) days. Pathological diagnosis was conclusive in 97% revealing neoplastic lesions in 91.7% (high-grade glioma 62.6%, lymphoma 18.3%, metastasis 4.8%, low-grade glioma 3.0% and other tumors 3.0%) and non-neoplastic lesions in 5.3% of cases. Procedure-related mortality was 0.4%, transient and permanent morbidity occurred in 19 patients (8.3%) and eight patients (3.5%). Complication rate was not associated with any of the above-mentioned parameters. Adjuvant therapy was initiated in 171 (74.3%) patients. Decision against disease-specific therapy was only influenced by preoperative KPS (p < 0.001). SB in elderly patients is characterized by a favorable risk profile and high diagnostic yield, allowing tissue based therapeutic consequences even in patients with high comorbidity and anticoagulant medication.
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http://dx.doi.org/10.1007/s11060-017-2522-9DOI Listing
September 2017

Update on the diagnostic value and safety of stereotactic biopsy for pediatric brainstem tumors: a systematic review and meta-analysis of 735 cases.

J Neurosurg Pediatr 2017 Sep 16;20(3):261-268. Epub 2017 Jun 16.

Departments of 1 General Neurosurgery.

OBJECTIVE Recent studies have shed light on the molecular makeup of diffuse intrinsic pontine gliomas and led to the identification of potential treatment targets for these lesions, which account for the majority of pediatric brainstem tumors (pedBSTs). Therefore, stereotactic biopsy-driven molecular characterization of pedBSTs may become an important prerequisite for the management of these fatal brain tumors. The authors conducted a systemic review and meta-analysis to precisely determine the safety and diagnostic success of stereotactic biopsy of pedBSTs. METHODS A systematic search of PubMed, EMBASE, and the Web of Science yielded 944 potentially eligible abstracts. Meta-analysis was conducted on 18 studies (including the authors' own institutional series), describing a total of 735 biopsy procedures for pedBSTs. The primary outcome measures were diagnostic success and procedure-related complications. Pooled estimates were calculated based on the Freeman-Tukey double-arcsine transformation and DerSimonian-Laird random-effects model. Heterogeneity, sensitivity, and meta-regression analyses were also conducted. RESULTS The weighted average proportions across the analyzed studies were 96.1% (95% CI 93.5%-98.1%) for diagnostic success, 6.7% (95% CI 4.2%-9.6%) for overall morbidity, 0.6% (95% CI 0.2%-1.4%) for permanent morbidity, and 0.6% (95% CI 0.2%-1.3%) for mortality. Subgroup analyses at the study level identified no significant correlation between the outcome measures and the distribution of the chosen biopsy trajectories (transfrontal vs transcerebellar), age, year of publication, or the number of biopsy procedures annually performed in each center. CONCLUSION Stereotactic biopsy of pedBSTs is safe and allows successful tissue sampling as a prerequisite for the molecular characterization and the identification of potentially druggable targets toward more individualized treatment concepts to improve the outcome for children harboring such lesions.
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http://dx.doi.org/10.3171/2017.2.PEDS1665DOI Listing
September 2017

Feasibility, Risk Profile and Diagnostic Yield of Stereotactic Biopsy in Children and Young Adults with Brain Lesions.

Klin Padiatr 2017 May 30;229(3):133-141. Epub 2017 May 30.

Department of Stereotaxy and Functional Neurosurgery, University of Cologne, Cologne, Germany.

To evaluate the feasibility, safety, and diagnostic yield of stereotactic biopsy (SB) in children and adolescents with cerebral lesions. We performed a systematic review of the literature and a retrospective analysis of all pediatric and adolescent patients who underwent SB for unclear brain lesions at our center. We collected patient and lesion-associated parameters, analysed the rate of procedural complications and diagnostic yield. Our institutional series consisted of 285 SBs in 269 children and young adults between 1989 and 2016 (median age, 9 (range 1-18) years). There was no procedure-related mortality. Permanent and transient morbidity was 0.7% and 5.8%, respectively. Lesions were located in brain lobes (26.3%) and in midline structures (73.7%). The diagnostic yield was 97.5% and histology consisted low-grade gliomas (44.2%), high-grade gliomas (15.1%), non-glial tumors (22.8%), and non-neoplastic disease (15.4%). Morbidity was not associated with tumor location, age, histology or intraoperative position of the patient. In order to compare our findings with previous reports, we reviewed 25 studies with 1 109 children and young adults which had underwent SB. The diagnostic yield ranged between 83% and 100%. The reported morbidity and mortality rates range from 0-27% and 0-3.3%, respectively. SB in this particular patient population is a safe and a high-yield diagnostic procedure and indicates therefore its importance in the light of personalized medicine with the development of individual molecular treatment strategies.
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http://dx.doi.org/10.1055/s-0043-101908DOI Listing
May 2017

Long-term follow-up after stereotactic radiosurgery of intracanalicular acoustic neurinoma.

Radiat Oncol 2017 Apr 21;12(1):68. Epub 2017 Apr 21.

Department of Stereotaxy and Functional Neurosurgery, Centre of Neurosurgery, University Hospital of Cologne, Kerpener Strasse 62, 50937, Köln, Germany.

Background: The management of solely intracanalicular acoustic neurinoma (iAN) includes observation, microsurgical resection and radiation therapy. Treatment goals are long-term tumor control, hearing preservation and concurrently low side-effects. Stereotactic radiosurgery (SRS) has evolved as an alternative first-line treatment for small AN. Here we report about the long-term follow-up of a unique cohort of patients with iAN after LINAC or Cyberknife® based SRS.

Methods: In this single center retrospective analysis, we included all patients with iAN who underwent single session LINAC or Cyberknife® based SRS between 1993 and 2015, and who had a minimum follow-up period of six weeks. Patient data were analyzed in terms of radiological and clinical tumor control (no further treatment necessary), subjective preservation of serviceable hearing, objective change in pure tone averages (PTA), and adverse events rated by the Common Terminology Criteria for Adverse Events (CTCAE; v4.03).

Results: Forty-nine patients (f/m = 21/28, median age 54 ± 12, range 20-77 years) were identified. Mean tumor volumes were 0.24 ± 0.12 cm (range, 0.1-0.68 cm), the mean marginal dose was 12.6 ± 0.6 Gy (range, 11.0-14.0 Gy) and the prescription isodose was 75 ± 7.4% (range, 47-86%). Mean follow-up time was 65 months (range, 4-239 months). Radiological tumor control was 100% during further follow-up. 17 (35%) out of 49 patients had lost serviceable hearing prior to SRS. Those with preserved serviceable hearing remained stable in 78% (n = 25/32) at the last follow-up (LFU). The median PTA (n = 16) increased from 25.6 dB prior to SRS to 43.8 dB at LFU. Mild adverse events were observed temporarily in two patients (4%): one with CTCAE grade 1 facial nerve disorder after 3 months, resolving three months later, and one with CTCAE grade 2 facial muscle weakness resolving after 12 months. Three patients described permanent mild symptoms CTCAE grade 1 without limiting daily life (facial weakness n = 1, vertigo n = 2).

Conclusion: SRS for iAN shows long-term reliable tumor control with a high rate of hearing preservation without considerable permanent side effects, and can be proposed as a safe and effective treatment alternative to microsurgical resection.
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http://dx.doi.org/10.1186/s13014-017-0805-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399376PMC
April 2017

Impact of Resection on Survival of Isocitrate Dehydrogenase 1-Mutated World Health Organization Grade II Astrocytoma After Malignant Progression.

World Neurosurg 2017 Jul 2;103:180-185. Epub 2017 Apr 2.

Department of Neurosurgery, University of Cologne, Cologne, Germany.

Objective: To evaluate the impact of surgical resection and adjuvant treatment on the course of patients after malignant progression of previously treated isocitrate dehydrogenase 1 (IDH1)-mutated World Health Organization (WHO) grade II astrocytoma.

Methods: This retrospective study explored 56 patients undergoing tumor resection for malignant progression after previously treated IDH1-mutated WHO grade II astrocytoma. We analyzed survival after malignant progression, analyzed overall survival (OS), and identified prognostic factors using Kaplan-Meier estimates and log-rank test.

Results: By the time of malignant transformation, median age was 44 years, and median Karnofsky Performance Status (KPS) score was 90. Complete resection of contrast-enhancing tissue was achieved in 18 (32.1%) patients. Median survival after re-resection was 33 months (95% confidence interval [CI], 20-46); median OS was 123 months (95% CI, 77-170). Gross total tumor resection, postoperative KPS score ≥80, adjuvant radiochemotherapy, and prior radiotherapy significantly correlated with post-malignant progression survival.

Conclusions: Patients in good clinical condition with malignant progression of previously treated low-grade gliomas should receive aggressive treatment, including re-resection.
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http://dx.doi.org/10.1016/j.wneu.2017.03.123DOI Listing
July 2017

Dynamic O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography differentiates brain metastasis recurrence from radiation injury after radiotherapy.

Neuro Oncol 2017 02;19(2):281-288

Department of Neurology, University of Cologne, Cologne, Germany.

Background: The aim of this study was to investigate the potential of dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation injury after radiotherapy since contrast-enhanced MRI often remains inconclusive.

Methods: Sixty-two patients (mean age, 55 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of 18F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test.

Results: TBRs were significantly higher in recurrent metastases (n = 36) than in radiation injuries (n = 40) (TBRmax 3.3 ± 1.0 vs 2.2 ± 0.4, P < .001; TBRmean 2.2 ± 0.4 vs 1.7 ± 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001).

Conclusions: The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of 18F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from radiation-induced changes with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases.
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http://dx.doi.org/10.1093/neuonc/now149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463967PMC
February 2017

Deep brain stimulation: current applications and future prospects.

Discov Med 2015 Dec;20(112):403-11

Department of Functional Neurosurgery and Stereotaxie, Center for Neurosurgery, University Hospital Cologne, Cologne, Germany.

Deep Brain Stimulation (DBS) has proven to be an effective and minimally invasive surgical treatment for a variety of neurological and psychiatric diseases such as Parkinson's Disease, essential tremor, dystonia, Tourette's Syndrome and depression. In contrast to early surgical lesioning procedures, DBS has a considerably lower side-effect rate and is usually reversible. Common targets include nuclei involved in the basal ganglia circuitry as well as its efferent and afferent pathways such as the subthalamic nucleus (STN), the globus pallidus internus (GPi) or the ventral striatal region. Despite the increasing application of DBS, the exact mechanism of action is still matter of debates. Current trials focus on establishing alternative targets, exploring new indications as well as on capturing cortical responses during DBS in order to improve individual stimulation parameters.
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December 2015

Low dose rate brachytherapy for the treatment of brain metastases.

J Neurosurg 2015 Oct 28;123(4):1110-1. Epub 2015 Aug 28.

Department of Stereotaxy and Functional Neurosurgery, Centre of Neurosurgery, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.3171/2015.2.JNS15195DOI Listing
October 2015

Long-term Functional Recovery and Quality of Life after Surgical Treatment of Putaminal Hemorrhages.

J Stroke Cerebrovasc Dis 2015 May 21;24(5):925-9. Epub 2015 Mar 21.

Department of Neurosurgery, University of Cologne, Germany. Electronic address:

Background: To evaluate the long-term functional recovery and health-related quality of life (HRQOL) in patients after surgically treated putaminal hemorrhages. Surgery for putaminal hemorrhages remains a controversial issue. Although numerous reports describe conflictive results regarding short-term outcome of surgically treated patients, very little is known about their long-term recovery and their HRQOL.

Methods: In this monocentric, retrospective study we analyzed mortality, long-term functional outcome, activity of daily life status, and HRQOL undergoing craniotomy for hematoma evacuation between December 2004 and January 2011.

Results: Forty-nine consecutive patients were identified with 8 (16.3%) patients dying during acute care. Forty-one patients surviving acute phase were transferred to neurologic rehabilitation hospitals. One patient was lost to follow-up. Median follow-up was 52.9 (17-101) months. At follow-up, 24 of 40 (60%) patients still were alive with 16 of 40 (40%) patients living with major disability (modified Rankin Scale [mRS], 4 or 5). Seven patients (17.5%) showed a mRS lesser than or equal to 3 with only 3 (7.5%) of those living functionally independent (mRS, 0-2). HRQOL in survivors was reduced with a median DEMQOL/DEMQOL (a patient/caregiver reported outcome measure designed to assess health-related quality of life of people with dementia) proxy score of 92 and 93, respectively. All patients showed severe impairment in activities of daily life.

Conclusions: This is the first long-term follow-up analysis for patients with surgically treated putaminal hemorrhages. Survivors show only marginal recovery despite intensive neurologic rehabilitation; most remain dependent with a reduced HRQOL and significantly impaired activities of daily life status.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.12.001DOI Listing
May 2015

Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-L-tyrosine PET.

Eur J Nucl Med Mol Imaging 2015 Apr 20;42(5):685-95. Epub 2014 Nov 20.

Department of Neurology, University of Cologne, Cologne, Germany,

Purpose: The follow-up of glioblastoma patients after radiochemotherapy with conventional MRI can be difficult since reactive alterations to the blood-brain barrier with contrast enhancement may mimic tumour progression (i.e. pseudoprogression, PsP). The aim of this study was to assess the clinical value of O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET in the differentiation of PsP and early tumour progression (EP) after radiochemotherapy of glioblastoma.

Methods: A group of 22 glioblastoma patients with new contrast-enhancing lesions or lesions showing increased enhancement (>25 %) on standard MRI within the first 12 weeks after completion of radiochemotherapy with concomitant temozolomide (median 7 weeks) were additionally examined using amino acid PET with (18)F-FET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) were determined. (18)F-FET uptake kinetic parameters (i.e. patterns of time-activity curves, TAC) were also evaluated. Classification as PsP or EP was based on the clinical course (no treatment change at least for 6 months), follow-up MR imaging and/or histopathological findings. Imaging results were also related to overall survival (OS).

Results: PsP was confirmed in 11 of the 22 patients. In patients with PsP, (18)F-FET uptake was significantly lower than in patients with EP (TBRmax 1.9 ± 0.4 vs. 2.8 ± 0.5, TBRmean 1.8 ± 0.2 vs. 2.3 ± 0.3; both P < 0.001) and presence of MGMT promoter methylation was significantly more frequent (P = 0.05). Furthermore, a TAC type II or III was more frequently present in patients with EP (P = 0.04). Receiver operating characteristic analysis showed that the optimal (18)F-FET TBRmax cut-off value for identifying PsP was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, AUC 0.94 ± 0.06; P < 0.001). Univariate survival analysis showed that a TBRmax <2.3 predicted a significantly longer OS (median OS 23 vs. 12 months; P = 0.046).

Conclusion: (18)F-FET PET may facilitate the diagnosis of PsP following radiochemotherapy of glioblastoma.
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http://dx.doi.org/10.1007/s00259-014-2959-4DOI Listing
April 2015

Low-dose rate stereotactic iodine-125 brachytherapy for the treatment of inoperable primary and recurrent glioblastoma: single-center experience with 201 cases.

J Neurooncol 2014 Dec 24;120(3):615-23. Epub 2014 Aug 24.

Department of Stereotactic and Functional Neurosurgery, University Clinics of Cologne, Kerpener Straße 62, 50937, Cologne, Germany.

Treatment options for inoperable glioblastoma are limited. Low-dose-rate stereotactic iodine-125 brachytherapy (SBT) has been reported as an effective and low-risk treatment option for circumscribed low-grade gliomas and brain metastases. The present study evaluates this treatment approach for patients with inoperable glioblastoma. Between 1990 and 2012, 201 patients with histologically proven glioblastoma were treated with SBT (iodine-125 seeds; median cumulative surface dose, 60 Gy; median dose-rate, 6 cGy/h; median gross-tumor-volume, 17 ml) either as primary treatment (n = 103) or at recurrence (n = 98). In addition to SBT, 90.3 % of patients in the primary treatment group received external boost radiotherapy (median dose, 25.2 Gy). Adjuvant chemotherapy was added for 30.8 % of patients following SBT and consisted of temozolomide for the majority of cases (88.7 %). Procedure-related complications, clinical outcome, progression-free and overall survival (PFS, OS) were evaluated. Median follow-up was 9.8 months. The procedure-related mortality was zero. During follow-up, transient and permanent procedure-related morbidity was observed in 7.5 and 2.0 %, respectively. Calculated from the time of SBT, median OS and PFS rates were 10.5 and 6.2 months, with no significant differences among primary and recurrent tumors (11.1 vs.10.4 months for OS and 6.2 vs. 5.9 months for PFS). For OS, multivariate analysis revealed Karnofsky performance score, age, and adjuvant chemotherapy as independent prognostic factors (all p < 0.01). Low-dose-rate SBT is a relatively safe and potentially effective local treatment option for patients with circumscribed inoperable glioblastoma initially or at recurrence. It deserves prospective validation since it may improve the outcome for a subset of patients with inoperable GBM.
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http://dx.doi.org/10.1007/s11060-014-1595-yDOI Listing
December 2014

Role of O-(2-18F-fluoroethyl)-L-tyrosine PET as a diagnostic tool for detection of malignant progression in patients with low-grade glioma.

J Nucl Med 2013 Dec 24;54(12):2046-54. Epub 2013 Oct 24.

Institute of Neuroscience and Medicine (INM-3,-4,-5), Forschungszentrum Jülich, Jülich, Germany.

Unlabelled: In patients with low-grade glioma (LGG) of World Health Organization (WHO) grade II, early detection of progression to WHO grade III or IV is of high clinical importance because the initiation of a specific treatment depends mainly on the WHO grade. In a significant number of patients with LGG, however, information on tumor activity and malignant progression cannot be obtained on the basis of clinical or conventional MR imaging findings only. We here investigated the potential of O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET to noninvasively detect malignant progression in patients with LGG.

Methods: Twenty-seven patients (mean age ± SD, 44 ± 15 y) with histologically proven LGG (WHO grade II) were investigated longitudinally twice using dynamic (18)F-FET PET and routine MR imaging. Initially, MR imaging and PET scans were performed, and diagnosis was confirmed on the basis of biopsy. Subsequently, PET scans were obtained when clinical findings or contrast-enhanced MR imaging suggested malignant progression. Maximum and mean tumor-to-brain ratios (20-40 min after injection) (TBRmax and TBRmean, respectively) of (18)F-FET uptake as well as tracer uptake kinetics (i.e., time to peak [TTP] and patterns of the time-activity curves) were determined. The diagnostic accuracy of imaging parameters for the detection of malignant progression was evaluated by receiver-operating-characteristic analyses and by Fisher exact test for 2 × 2 contingency tables.

Results: In patients with histologically proven malignant progression toward WHO grade III or IV (n = 18), TBRmax and TBRmean increased significantly, compared with baseline (TBRmax, 3.8 ± 1.0 vs. 2.4 ± 1.0; TBRmean, 2.2 ± 0.3 vs. 1.6 ± 0.6; both P < 0.001), whereas TTP decreased significantly (median TTP, 35 vs. 23 min; P < 0.001). Furthermore, time-activity curve patterns changed significantly in 10 of 18 patients (P < 0.001). The combined analysis of (18)F-FET PET parameters (i.e., changes of TBRmax, TTP, or time-activity curve pattern) yielded a significantly higher diagnostic accuracy for the detection of malignant progression than changes of contrast enhancement in MR imaging (accuracy, 81% vs. 63%; P = 0.003).

Conclusion: Both tumor-to-brain ratio and kinetic parameters of (18)F-FET PET uptake provide valuable diagnostic information for the noninvasive detection of malignant progression of LGG. Thus, repeated (18)F-FET PET may be helpful for further treatment decisions.
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http://dx.doi.org/10.2967/jnumed.113.123836DOI Listing
December 2013

Stereotactic iodine-125 brachytherapy for the treatment of WHO grades II and III gliomas located in the central sulcus region.

Neuro Oncol 2013 Dec 17;15(12):1721-31. Epub 2013 Sep 17.

Corresponding Author: Maximilian I. Ruge, MD, Department of Stereotactic and Functional Neurosurgery, University Clinics of Cologne, Kerpener Straße 62, 50937 Cologne, Germany.

Background: Resection of gliomas located in eloquent brain areas remains a neurosurgical challenge. The reported incidence of transient or permanent neurological deficits after microsurgery in eloquent brain ranges 20%-100%, or 0%-47% among contemporary neurosurgical series. The aim of this study was to assess the feasibility of stereotactic brachytherapy (SBT) as a local treatment alternative to microsurgical resection for patients with gliomas in highly eloquent areas, located in the central sulcus region (CSR).

Method: Between 1997 and 2010, 60 patients with World Health Organization (WHO) grades II and III gliomas located in the CSR were treated with SBT (iodine-125 seeds; cumulative therapeutic dose, 50-65 Gy). Following SBT, WHO grade III glioma patients additionally received percutaneous radiotherapy (median boost dose, 25.2 Gy). We evaluated procedure-related complications, clinical outcome, and progression-free survival.

Results: Procedure-related mortality was zero. Within 30 days of SBT, 3 patients (5%) had transient neurological deficits, and 8 patients (13%) had temporarily increased seizure activity. One patient (1.6%) deteriorated permanently. Space-occupying cysts (6 patients) and radiation necrosis (1 patient) developed after a median of 38 months and required surgical intervention. Seizure activity, rated 12 months following SBT, decreased in 82% of patients (Engel classes I-III). Median progression-free survivals were 62.2 ± 19.7 months (grade II gliomas) and 26.1 ± 17.9 months (grade III gliomas).

Conclusions: Compared with microsurgical resection, SBT harbors a low risk of procedural complications, is minimally invasive, and seems to be an effective local treatment option for patients with inoperable, eloquent WHO grade II and III gliomas in the CSR. However, the value of SBT for treating gliomas still needs to be determined in prospective, randomized studies.
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http://dx.doi.org/10.1093/neuonc/not126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829594PMC
December 2013

Differentiation of local tumor recurrence from radiation-induced changes after stereotactic radiosurgery for treatment of brain metastasis: case report and review of the literature.

Radiat Oncol 2013 Mar 6;8:52. Epub 2013 Mar 6.

Department for Stereotaxy and Functional Neurosurgery, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.

Background: Structural follow-up magnetic resonance imaging (MRI) after stereotactic radiosurgery (SRS) for brain metastases frequently displays local changes in the area of applied irradiation, which are often difficult to interpret (e.g., local tumor recurrence, radiation-induced changes). The use of stereotactic biopsy for histological assessment of these changes has a high diagnostic accuracy and can be considered as method of choice. In order to solve this relevant clinical problem non-invasively, advanced MRI techniques and amino acid positron-emission-tomography (PET) are increasingly used.

Case Presentation: We report the long-term follow-up of a patient who had been treated with linear accelerator based SRS for cerebral metastases of a lung cancer. Fifty-eight months after SRS, the differentiation of local recurrent brain metastasis from radiation-induced changes using structural MRI was difficult. For further differentiation, perfusion-weighted MRI (PWI), proton magnetic resonance spectroscopy (MRS), and (11)C-methyl-L-methionine (MET) PET was performed. Due to artifacts and technical limitations, PWI MRI and MRS findings were not conclusive. In contrast, MET PET findings were suggestive for radiation-induced changes. Finally, a stereotactic biopsy for histological assessment of these changes demonstrated clearly a radiation-induced necrosis and the absence of vital tumor.

Conclusion: The use of stereotactic biopsy for histological assessment of indistinguishable lesions on structural MRI after SRS for treatment of brain metastasis represents a highly reliable method to differentiate local tumor recurrence from radiation-induced changes. In this field, results of studies with both advanced MRI techniques and amino acid PET suggest encouraging results. However, artifacts and technical limitations (e.g., lesion size) are still a problem and comparative studies are needed to investigate the relationship, diagnostic performance, and complementary character of advanced MRI techniques and amino acid PET.
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http://dx.doi.org/10.1186/1748-717X-8-52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608155PMC
March 2013