Publications by authors named "Joerg C Tonn"

22 Publications

  • Page 1 of 1

F-FET PET Uptake Characteristics of Long-Term IDH-Wildtype Diffuse Glioma Survivors.

Cancers (Basel) 2021 Jun 24;13(13). Epub 2021 Jun 24.

Department of Nuclear Medicine, University Hospital, LMU Munich, 81377 Munich, Germany.

Background: IDHwt diffuse gliomas represent the tumor entity with one of the worst clinical outcomes. Only rare cases present with a long-term survival of several years. Here we aimed at comparing the uptake characteristics on dynamic F-FET PET, clinical and molecular genetic parameters of long-term survivors (LTS) versus short-term survivors (STS): Methods: Patients with de-novo IDHwt glioma (WHO grade III/IV) and F-FET PET prior to any therapy were stratified into LTS (≥36 months survival) and STS (≤15 months survival). Static and dynamic F-FET PET parameters (mean/maximal tumor-to-background ratio (TBR), biological tumor volume (BTV), minimal time-to-peak (TTP)), diameter and volume of contrast-enhancement on MRI, clinical parameters (age, sex, Karnofksy-performance-score), mode of surgery; initial treatment and molecular genetics were assessed and compared between LTS and STS.

Results: Overall, 75 IDHwt glioma patients were included (26 LTS, 49 STS). LTS were significantly younger ( < 0.001), had a higher rate of WHO grade III glioma ( = 0.032), of O(6)-Methylguanine-DNA methyltransferase () promoter methylation ( < 0.001) and missing Telomerase reverse transcriptase promoter (TERTp) mutations ( = 0.004) compared to STS. On imaging, LTS showed a smaller median BTV ( = 0.017) and a significantly longer TTP ( = 0.008) on F-FET PET than STS, while uptake intensity (TBR) did not differ. In contrast to the tumor-volume on PET, MRI-derived parameters such as tumor size as well as all other above-mentioned parameters did not differ between LTS and STS ( > 0.05 each).

Conclusion: Besides molecular genetic prognosticators, a long survival time in IDHwt glioma patients is associated with a longer TTP as well as a smaller BTV on F-FET PET at initial diagnosis. F-FET uptake intensity as well as the MRI-derived tumor size (volume and maximal diameter) do not differ in patients with long-term survival.
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http://dx.doi.org/10.3390/cancers13133163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268019PMC
June 2021

Impact of TSPO Receptor Polymorphism on [F]GE-180 Binding in Healthy Brain and Pseudo-Reference Regions of Neurooncological and Neurodegenerative Disorders.

Life (Basel) 2021 May 26;11(6). Epub 2021 May 26.

Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, 81377 Munich, Germany.

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [F]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [F]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [F]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer's disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age- and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [F]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions.
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http://dx.doi.org/10.3390/life11060484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229996PMC
May 2021

Dual PET Imaging of an H3K27M-Mutant Glioma With 18F-GE-180 and 18F-FET PET.

Clin Nucl Med 2020 Dec;45(12):992-993

Neuropathology.

A 25-year-old man presented with headache and intracranial pressure symptoms. On MRI, an intracranial lesion was detected in the right thalamus with exophytic growth into the third ventricle and inhomogeneous contrast enhancement without necrosis. Dual amino acid (F-FET) and TSPO (F-GE-180) PET imaging showed high tumor-to-background ratios in both scans and a short time-to-peak in F-FET uptake dynamics. Biopsy revealed a diffuse midline glioma, H3K27M-mutant (WHO grade IV), a novel entity in the 2016 WHO classification with poor clinical outcome. Our case shows that the highly aggressive features of this tumor entity can be visualized in vivo by both PET modalities.
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http://dx.doi.org/10.1097/RLU.0000000000003331DOI Listing
December 2020

Resting-state fMRI detects alterations in whole brain connectivity related to tumor biology in glioma patients.

Neuro Oncol 2020 09;22(9):1388-1398

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.

Background: Systemic infiltration of the brain by tumor cells is a hallmark of glioma pathogenesis which may cause disturbances in functional connectivity. We hypothesized that aggressive high-grade tumors cause more damage to functional connectivity than low-grade tumors.

Methods: We designed an imaging tool based on resting-state functional (f)MRI to individually quantify abnormality of functional connectivity and tested it in a prospective cohort of patients with newly diagnosed glioma.

Results: Thirty-four patients were analyzed (World Health Organization [WHO] grade II, n = 13; grade III, n = 6; grade IV, n = 15; mean age, 48.7 y). Connectivity abnormality could be observed not only in the lesioned brain area but also in the contralateral hemisphere with a close correlation between connectivity abnormality and aggressiveness of the tumor as indicated by WHO grade. Isocitrate dehydrogenase 1 (IDH1) mutation status was also associated with abnormal connectivity, with more alterations in IDH1 wildtype tumors independent of tumor size. Finally, deficits in neuropsychological performance were correlated with connectivity abnormality.

Conclusion: Here, we suggested an individually applicable resting-state fMRI marker in glioma patients. Analysis of the functional connectome using this marker revealed that abnormalities of functional connectivity could be detected not only adjacent to the visible lesion but also in distant brain tissue, even in the contralesional hemisphere. These changes were associated with tumor biology and cognitive function. The ability of our novel method to capture tumor effects in nonlesional brain suggests a potential clinical value for both individualizing and monitoring glioma therapy.
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http://dx.doi.org/10.1093/neuonc/noaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523460PMC
September 2020

Microscopic brain invasion in meningiomas previously classified as WHO grade I is not associated with patient outcome.

J Neurooncol 2019 Dec 11;145(3):469-477. Epub 2019 Nov 11.

Department of Neurosurgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany.

Purpose: For meningiomas, the 2016 revision of the WHO classification introduced brain invasion per se as a sufficient condition to classify as grade II. We analyzed whether meningiomas previously graded as WHO grade I differ in prognosis depending on the presence of microscopic brain invasion.

Methods: A consecutive series of patients with intracranial meningioma WHO grade I (± brain invasion) at two neurosurgical departments was analyzed retrospectively. Cox regression models on progression-free survival (PFS) and Kaplan-Meier survival estimates were performed.

Results: 875 adult patients were included. Histological diagnosis of brain invasion was confirmed in 28 patients. Median follow-up was 73 months. In univariate and multivariate models, gross total resection gained favorable prognostic influence for PFS (p < 0.001, HR: 0.237, CI 0.170-0.382). 170 patients with the brain/meningioma interface present in histopathological specimen were separately analyzed as a subgroup. Importantly, presence of brain invasion did not reach significance for PFS, even in the subgroup with available specimen of brain/meningioma interface (p = 0.787, HR: 0.852, CI 0.268-2.710 and p = 0.811, HR: 0.848, CI 0.222-3.246, respectively). Patients with and without brain invasion did not differ in terms of age, tumor location and extent of resection, but were more likely to receive radiotherapy (p = 0.03) of tumor remnants. However, subgroup analysis of non-irradiated tumors revealed no prognostic influence of brain invasion (p = 0.749, HR: 0.772, CI 0.158-3.767).

Conclusions: In this bi-institutional series, brain invasion was frequent among meningiomas WHO grade I when brain/meningioma interface was available for histology (16.5%). However, brain invasion did not impact early recurrence.
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http://dx.doi.org/10.1007/s11060-019-03312-xDOI Listing
December 2019

Imaging and diagnostic advances for intracranial meningiomas.

Neuro Oncol 2019 01;21(Suppl 1):i44-i61

Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine.
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http://dx.doi.org/10.1093/neuonc/noy143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347083PMC
January 2019

Advances in multidisciplinary therapy for meningiomas.

Neuro Oncol 2019 01;21(Suppl 1):i18-i31

Department of Neurological Surgery, University of California, San Francisco, California, USA.

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas.
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http://dx.doi.org/10.1093/neuonc/noy136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347080PMC
January 2019

Whole-Body Staging of Metastatic Atypical Meningioma Using 68Ga-DOTATATE PET/CT.

Clin Nucl Med 2019 Mar;44(3):227-228

Radiology.

A 43-year-old woman with suspected recurrence of atypical meningioma World Health Organization grade II presented extensive intracranial lesions with high Ga-DOTATATE uptake. Moreover, numerous Ga-DOTATATE-positive bone, lung, and liver lesions were seen. For final diagnosis, biopsies taken from a lung lesion revealed distant metastases of the atypical meningioma. This case underlines the high diagnostic power of Ga-DOTATATE PET/CT for the staging of meningioma even beyond cerebral or spinal lesions; in case of distant lesions in patients with known meningioma, differential diagnosis should also contain metastases despite their rare occurrence. Moreover, this case emphasizes radioligand therapy especially in metastatic meningioma.
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http://dx.doi.org/10.1097/RLU.0000000000002422DOI Listing
March 2019

TERT promoter mutation is associated with worse prognosis in WHO grade II and III meningiomas.

J Neurooncol 2018 Sep 28;139(3):671-678. Epub 2018 May 28.

Department of Neurosurgery, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany.

Introduction: Transcriptional activating mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene occur at high frequency in various types of solid tumors and have also been reported for meningiomas. Especially for atypical and anaplastic meningiomas, the prognostic relevance of TERT promoter mutation is yet unclear. The present study aimed to analyze the frequency of TERT promoter mutation and define its long-term prognostic significance beyond clinical and histological factors in a cohort of meningiomas WHO grade II and III.

Methods: Patients undergoing surgical resection of aggressive meningiomas were included. Analysis for C228T and C250T mutation in the TERT promoter region was performed using PCR method. Patients were stratified into two groups (TERT mutated vs. TERT wild type). Univariate analysis was conducted using molecular and histological factors.

Results: 87 patients with atypical (N = 72) and anaplastic meningiomas (N = 15) were included in the study. TERT promoter region was found to be mutated in 4 WHO grade II and 2 WHO grade III meningiomas. TERT promoter mutation was associated with shorter progression free survival than TERT wild type meningiomas (median PFS 12.5 vs. 26 months, p = .004). In the univariate analysis, TERT promoter mutation had a strong prognostic value on overall survival (p = .009) and progression free survival.

Conclusions: Presence of TERT promoter mutation is associated with shorter progression free survival and overall survival in meningiomas WHO grade II and III. In these tumors, TERT promoter mutation should be considered as a clinically relevant prognostic factor to identify high risk patients.
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http://dx.doi.org/10.1007/s11060-018-2912-7DOI Listing
September 2018

Detection of Cerebrospinal Fluid Dissemination of Recurrent Glioblastoma Using TSPO-PET With 18F-GE-180.

Clin Nucl Med 2018 Jul;43(7):518-519

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg.

PET targeting the translocator protein (TSPO) represents an interesting approach for glioma visualization, as TSPO is highly expressed in tumor cells. We present a 32-year-old man with recurrent glioblastoma after multimodal treatment. PET with the novel TSPO ligand F-GE-180 was performed after reirradiation. Here, the previously reirradiated tumor showed a remaining circular TSPO expression. Moreover, cerebrospinal fluid dissemination was detected by a high focal uptake at the right lateral and at the fourth ventricle, whereas only a faint contrast enhancement was present in MRI. This case demonstrated the diagnostic potential of TSPO-PET for glioma imaging by visualizing even minimal disease burden.
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http://dx.doi.org/10.1097/RLU.0000000000002113DOI Listing
July 2018

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO).

Neuro Oncol 2017 02;19(2):162-174

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of Neuro-Oncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Here, we present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, we addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care.
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http://dx.doi.org/10.1093/neuonc/now241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620494PMC
February 2017

Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas.

Neuro Oncol 2016 09 21;18(9):1199-208. Epub 2016 Apr 21.

Department of Nuclear Medicine, Ludwig-Maximilians-University Munich, Munich, Germany (N.L.A.); Department of Neurology, University Hospital Zurich, Zurich, Switzerland (M.W.); Department of Neurosurgery, Ludwig-Maximilians-University Munich, Munich, Germany (B.S., J.C.T.); Institute of Neuroscience and Medicine, Research Center Juelich, Juelich, Germany (N.G.); Department of Neurology, University of Cologne, Cologne, Germany (N.G.); Department of Neuro-Oncology, University of Turin, Turin, Italy (R.S.); Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (M.M.K.); Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University of Tübingen, Tübingen, Germany (C.l.F.); Radiological Sciences, University of California Los Angeles, Los Angeles, California (W.P.); Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (I.L.); Department of Nuclear Medicine, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain (J.A.); Department of Neurology, University of Washington, Seattle, Washington (M.C.); Department of Neurological Surgery, Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio (M.A.V.); Department of Radiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (B.M.E.)

This guideline provides recommendations for the use of PET imaging in gliomas. The review examines established clinical benefit in glioma patients of PET using glucose ((18)F-FDG) and amino acid tracers ((11)C-MET, (18)F-FET, and (18)F-FDOPA). An increasing number of studies have been published on PET imaging in the setting of diagnosis, biopsy, and resection as well radiotherapy planning, treatment monitoring, and response assessment. Recommendations are based on evidence generated from studies which validated PET findings by histology or clinical course. This guideline emphasizes the clinical value of PET imaging with superiority of amino acid PET over glucose PET and provides a framework for the use of PET to assist in the management of patients with gliomas.
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http://dx.doi.org/10.1093/neuonc/now058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999003PMC
September 2016

Pediatric Giant Cell Glioblastoma Mimicking Hemorrhage Secondary to Ischemic Stroke.

Pediatr Neurol 2015 Nov 8;53(5):459-61. Epub 2015 Aug 8.

Department of Neuroradiology, Ludwig-Maximilians University, Munich, Germany; Institute of Clinical Radiology, Ludwig-Maximilians University, Munich, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2015.08.002DOI Listing
November 2015

Optional real-time display of intraoperative neurophysiological monitoring in the microscopic field of view: avoiding communication failures in the operating room.

Acta Neurochir (Wien) 2015 Nov 5;157(11):1843-7. Epub 2015 Aug 5.

Department of Neurosurgery, Ludwig-Maximilians-University, Marchioninistraße 15, 81377, Munich, Germany.

Background: The use of intraoperative neurophysiological monitoring (IONM) in neurosurgery has improved patient safety and outcomes. However, a pitfall in the use of IONM remains unsolved. Currently, there is no feasible way for surgeons to interpret IONM waves themselves during operations. Instead, they have to rely on verbal feedback from a neurophysiologist. This method is prone to communication failures, which can lead to delayed or false interpretation of the data. Direct visualization of IONM waves is a way to alleviate this problem and make IONM more effective.

Methods: Microscope-integrated IONM (MI-IONM) was used in 163 cranial and spinal cases. We evaluated the feasibility, system stability and how well the system integrated into the surgical workflow. We used an IONM system that was connected to a surgical microscope. All IONM modalities used at our institution could be visualized as required, superimposed on the surgical field in the eyepiece of the microscope without obstructing the surgeon's field of vision.

Results: Use of MI-IONM was safe and reliable. It furthermore provided valuable intraoperative information. The system merely required a short learning curve. Only minor system problems without impact on surgical workflow occurred. MI-IONM proved to be especially useful in surgical cases where careful monitoring of nerve function is required, e.g., cerebellopontine angle surgery. Here, direct assessment of surgical action and IONM wave change was provided to the surgeon, if necessary (on-off control).

Conclusion: MI-IONM is a useful extension of conventional IONM that provides optional real-time functional information to the surgeon on demand.
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http://dx.doi.org/10.1007/s00701-015-2518-1DOI Listing
November 2015

Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM.

Neurology 2015 Feb 21;84(7):710-9. Epub 2015 Jan 21.

From the Departments of Neurosurgery (B.S., F.W.K., J.C.T.), Nuclear Medicine (N.L.J.), Neuroradiology (J.L., H.J.), and Neuropathology (H.K., S.E.), Ludwig-Maximilians University Munich; Department of Neurosurgery (M.S.), University of Bonn; Department of Nuclear Medicine (G.P.), Katharinenhospital Stuttgart; Department of Nuclear Medicine (C.l.F.), University of Tuebingen, Germany; and Department of Neurology (M.W.), University Hospital Zurich, Switzerland.

Objective: The aim of this prospective longitudinal study was to identify static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine PET ((18)FET-PET)-derived imaging biomarkers in patients with glioblastoma (GBM).

Methods: Seventy-nine patients with newly diagnosed GBM were included; 42 patients underwent stereotactic biopsy (unresectable tumors) and 37 patients microsurgical tumor resection. All patients were scheduled to receive radiotherapy plus concomitant and adjuvant temozolomide (RCx/TMZ). (18)FET-PET evaluation using static and dynamic analysis was done before biopsy/resection, after resection, 4 to 6 weeks following RCx, and after 3 cycles of TMZ. Endpoints were survival and progression-free-survival. Prognostic factors were obtained from proportional hazards models.

Results: Biological tumor volume before RCx (BTV(preRCx)) was the most important (18)FET-PET-derived imaging biomarker and was independent of MGMT promoter methylation and clinical prognostic factors: patients with smaller BTV(preRCx) had significantly longer progression-free and overall survival (OS). (18)FET time-activity curves (TACs) before treatment and their changes after RCx were also related to outcome; patients with initially increasing TACs experienced longer OS.

Conclusion: BTV(preRCx) and TAC represent important (18)FET-PET-derived imaging biomarkers in GBM. Increasing TACs are associated with prolonged OS. The BTV(preRCx) is a strong prognostic factor for progression-free survival and OS independent of the mode of surgery. Our data furthermore suggest that patients harboring resectable GBM might benefit from maximal PET-guided tumor resection.
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http://dx.doi.org/10.1212/WNL.0000000000001262DOI Listing
February 2015

PET imaging for brain tumor diagnostics.

Curr Opin Neurol 2014 Dec;27(6):683-8

aDepartment of Neurosurgery bDepartment of Nuclear Medicine, University Hospital, Ludwig Maximilians University, Munich, Germany.

Purpose Of Review: Brain tumors differ in histology, biology, prognosis and treatment options. Although structural magnetic resonance is still the gold standard for morphological tumor characterization, molecular imaging has gained an increasing importance in assessment of tumor activity and malignancy.

Recent Findings: Amino acid PET is frequently used for surgery and biopsy planning as well as therapy monitoring in suspected primary brain tumors as well as metastatic lesions, whereas 18F-fluorodeoxyglucose (18F-FDG) remains the tracer of choice for evaluation of patients with primary central nervous system lymphoma. Application of somatostatin receptor ligands has improved tumor delineation in skull base meningioma and concurrently opened up new treatment possibilities in recurrent or surgically not assessable tumors.Recent development focuses on the implementation of hybrid PET/MRI as well as on the development of new tracers targeting tumor hypoxia, enzymes involved in neoplastic metabolic pathways and the combination of PET tracers with therapeutic agents.

Summary: Implementation of molecular imaging in the clinical routine continues to improve management in patients with brain tumors. However, more prospective large sample studies are needed to validate the additional informative value of PET.
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http://dx.doi.org/10.1097/WCO.0000000000000143DOI Listing
December 2014

Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy.

Int J Cancer 2014 May;134(10):2437-47

The epidermal growth factor receptor vIII mutant (EGFRvIII) is found in ~50% of all EGFR-amplified glioblastomas and constitutes a tumor-specific therapeutic target. To assess molecular testing approaches and the prognostic role of EGFRvIII in patients treated according to current standards of care, we compared different EGFRvIII detection methods and correlated EGFRvIII status with outcome in a prospective patient cohort of the German Glioma Network. In total, 184 newly diagnosed glioblastoma patients were investigated for EGFR amplification and for expression of EGFR and EGFRvIII by immunohistochemistry. Further, the EGFRvIII status was additionally studied by multiplex ligation-dependent probe amplification (MLPA) analysis and reverse transcription-PCR (RT-PCR). Immunohistochemistry demonstrated EGFRvIII in 34 of 184 patients (18%). RT-PCR or MLPA analysis detected four additional EGFRvIII-positive patients. Overall, RT-PCR and immunohistochemistry were more sensitive for EGFRvIII detection than MLPA. EGFRvIII status was not associated with progression-free and overall survival. EGFRvIII also had no prognostic significance in the subgroup of patients who were free from progression after concomitant radiochemotherapy and thus would be eligible for the ongoing ACT IV EGFRvIII vaccination trial. Age, extent of resection and O⁶-methylguanine DNA methyltransferase (MGMT) promoter methylation status appeared to be less prognostic in EGFRvIII-positive patients. Thus, EGFRvIII positivity is not a major negative prognostic factor in glioblastoma patients treated according to current standards of care. Data from phase II EGFRvIII-targeted vaccination trials compare favorably with the present contemporary results, supporting the further exploration of EGVRvIII vaccination in newly diagnosed glioblastoma.
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http://dx.doi.org/10.1002/ijc.28576DOI Listing
May 2014

Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice.

Neuro Oncol 2012 Sep;14 Suppl 4:iv100-8

Department of Neurology, University Hospital Zurich and Center for Neurosciences, University of Zurich, Zurich, Switzerland.

Histological subtyping and grading by malignancy are the cornerstones of the World Health Organization (WHO) classification of tumors of the central nervous system. They shall provide clinicians with guidance as to the course of disease to be expected and the choices of treatment to be made. Nonetheless, patients with histologically identical tumors may have very different outcomes, notably in patients with astrocytic and oligodendroglial gliomas of WHO grades II and III. In gliomas of adulthood, 3 molecular markers have undergone extensive studies in recent years: 1p/19q chromosomal codeletion, O(6)-methylguanine methyltransferase (MGMT) promoter methylation, and mutations of isocitrate dehydrogenase (IDH) 1 and 2. However, the assessment of these molecular markers has so far not been implemented in clinical routine because of the lack of therapeutic implications. In fact, these markers were considered to be prognostic irrespective of whether patients were receiving radiotherapy (RT), chemotherapy, or both (1p/19q, IDH1/2), or of limited value because testing is too complex and no chemotherapy alternative to temozolomide was available (MGMT). In 2012, this situation has changed: long-term follow-up of the Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951 trials demonstrated an overall survival benefit from the addition to RT of chemotherapy with procarbazine/CCNU/vincristine confined to patients with anaplastic oligodendroglial tumors with (vs without) 1p/19q codeletion. Furthermore, in elderly glioblastoma patients, the NOA-08 and the Nordic trial of RT alone versus temozolomide alone demonstrated a profound impact of MGMT promoter methylation on outcome by therapy and thus established MGMT as a predictive biomarker in this patient population. These recent results call for the routine implementation of 1p/19q and MGMT testing at least in subpopulations of malignant glioma patients and represent an encouraging step toward the development of personalized therapeutic approaches in neuro-oncology.
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http://dx.doi.org/10.1093/neuonc/nos206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480248PMC
September 2012

Varicella zoster virus infection of malignant glioma cell cultures: a new candidate for oncolytic virotherapy?

Anticancer Res 2012 Apr;32(4):1137-44

Department of Neurosurgery, Hospital of the University of Munich, Grosshadern, Munich, Germany.

Background: Glioblastoma multiforme is a highly aggressive tumor with a median survival of 14 months despite all standard therapies. Focusing on alternative treatment strategies, we evaluated the oncolytic potential of varicella zoster virus (VZV) in malignant glioma cell cultures.

Materials And Methods: Replication of wildtype and mutant VZV was comparatively analyzed in glioma cell lines (U87, U251 and U373) and in primary malignant glioma cells (n=10) in vitro by infectious foci assay, immunofluorescence microscopy and western blot analysis. Additionally, the tumor-targeting potential of VZV-infected human mesenchymal stem cells was evaluated.

Results: VZV replicated efficiently in all the glioma cells studied here followed by rapid oncolysis in vitro. The attenuated vaccine VZV mutant rOKA/ORF63rev[T171] exhibited most efficient replication. Human mesenchymal stem cells were found suitable for targeting VZV to sites of tumor growth.

Conclusion: VZV exhibits an intrinsic oncolytic potential in malignant glioma cell cultures and might be a novel candidate for virotherapy in glioblastoma multiforme.
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April 2012

O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation.

PLoS One 2011 Feb 18;6(2):e17156. Epub 2011 Feb 18.

Department of Anaesthesiology, Ludwig Maximilians University, Munich, Germany.

Background: We analyzed prospectively whether MGMT (O(6)-methylguanine-DNA methyltransferase) mRNA expression gains prognostic/predictive impact independent of MGMT promoter methylation in malignant glioma patients undergoing radiotherapy with concomitant and adjuvant temozolomide or temozolomide alone. As DNA-methyltransferases (DNMTs) are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells, we analyzed further, whether MGMT promoter methylation is associated with upregulation of DNMT expression.

Methodology/principal Findings: ADULT PATIENTS WITH A HISTOLOGICALLY PROVEN MALIGNANT ASTROCYTOMA (GLIOBLASTOMA: N = 53, anaplastic astrocytoma: N = 10) were included. MGMT promoter methylation was determined by methylation-specific PCR (MSP) and sequencing analysis. Expression of MGMT and DNMTs mRNA were analysed by real-time qPCR. Prognostic factors were obtained from proportional hazards models. Correlation between MGMT mRNA expression and MGMT methylation status was validated using data from the Cancer Genome Atlas (TCGA) database (N = 229 glioblastomas). Low MGMT mRNA expression was strongly predictive for prolonged time to progression, treatment response, and length of survival in univariate and multivariate models (p<0.0001); the degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status (p<0.0001); however, discordant findings were seen in 12 glioblastoma patients: Patients with methylated tumors with high MGMT mRNA expression (N = 6) did significantly worse than those with low transcriptional activity (p<0.01). Conversely, unmethylated tumors with low MGMT mRNA expression (N = 6) did better than their counterparts. A nearly identical frequency of concordant and discordant findings was obtained by analyzing the TCGA database (p<0.0001). Expression of DNMT1 and DNMT3b was strongly upregulated in tumor tissue, but not correlated with MGMT promoter methylation and MGMT mRNA expression.

Conclusions/significance: MGMT mRNA expression plays a direct role for mediating tumor sensitivity to alkylating agents. Discordant findings indicate methylation-independent pathways of MGMT expression regulation. DNMT1 and DNMT3b are likely to be involved in CGI methylation. However, their exact role yet has to be defined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017156PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041820PMC
February 2011

A transmedullary approach to occlusion of a ventral perimedullary arteriovenous fistula of the thoracic spinal cord.

Neurosurgery 2010 Mar;66(3):611-5; discussion 615

Department of Neurosurgery, Georg-August-University, Göttingen, Germany.

Objective: A spinal perimedullary arteriovenous fistula (PMAVF) is a direct fistula of one or more spinal arteries into the perimedullary venous network with reversed venous flow and subsequent venous congestion of the spinal cord. The therapeutic goal of surgery is to normalize the venous drainage by obliterating the fistula. Strictly ventral lesions typically require an anterior approach to ensure adequate exposure of the fistula as well and the preservation of the physiological blood supply to the spinal cord.

Clinical Presentation: We present a case of a ventral PMAVF at the level of T10 with feeders from the anterior spinal artery, caudally draining veins on the ventral spinal cord, and a dilated transmedullary vein filling cranially draining veins on the dorsal aspect of the spinal cord.

Technique: The dilated transmedullary vein was approached by a laminectomy. The vein was coagulated, and the gliotic channel was used to approach the ventral fistula site from the dorsal surface of the spinal cord. Complete obliteration of the fistula was achieved, and the preoperative neurological deficit improved.

Conclusion: We conclude that transmedullarly draining veins offers a possible dorsal approach for the occlusion of some ventral PMAVFs, thus avoiding more complex anterior approaches to the ventral spinal cord.
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http://dx.doi.org/10.1227/01.NEU.0000365365.10977.48DOI Listing
March 2010

Serial O-(2-[(18)F]fluoroethyl)-L: -tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma.

Eur J Nucl Med Mol Imaging 2006 Jul 21;33(7):792-800. Epub 2006 Mar 21.

Department of Nuclear Medicine, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.

Purpose: Intracavitary radioimmunotherapy (RIT) offers an effective adjuvant therapeutic approach in patients with malignant gliomas. Since differentiation between recurrence and reactive changes following RIT has a critical impact on patient management, the aim of this study was to analyse the value of serial O-(2-[(18)F]fluoroethyl)-L: -tyrosine (FET) PET scans in monitoring the effects of this locoregional treatment.

Methods: Following conventional therapy, 24 glioma patients (5 WHO III, 19 WHO IV) underwent one to five RIT cycles with either (131)I-labelled (n=19) or (188)Re-labelled (n=5) anti-tenascin antibodies. Patients were monitored with serial FET PET scans (2-12 scans). For semiquantitative evaluation, maximal tumoural uptake (TU(max)) was evaluated and the ratio to background (BG) was calculated. Results of PET were correlated with histopathological findings (n=9) and long-term clinical follow-up for up to 87 months.

Results: In seven tumour-free patients, PET revealed slightly increasing but homogeneous FET uptake surrounding the resection cavity with a peak up to 18 months following RIT (TU(max)/BG 2.07+/-0.25) but stable or decreasing values during further follow-up (last follow-up: TU(max)/BG 1.63+/-0.22). Seventeen patients developed regrowth of residual tumour/tumour recurrence showing additional nodular FET uptake (TU(max)/BG 2.79+/-0.53). A threshold value of 2.4 (TU(max)/BG) allowed best differentiation between recurrence and reactive changes (sensitivity 82%, specificity 100%).

Conclusion: FET PET is a sensitive tool for monitoring the effects of locoregional RIT. Homogeneous, slightly increasing FET uptake around the tumour cavity with a peak up to 18 months after RIT, followed by stable or decreasing uptake, points to benign, therapy-related changes. In contrast, nodular uptake is a reliable indicator of recurrence.
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http://dx.doi.org/10.1007/s00259-005-0053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1998889PMC
July 2006
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