Thomas Nägele

Bio: Thomas Nägele is an academic researcher from University of Tübingen. The author has contributed to research in topics: Magnetic resonance imaging & Diffusion MRI. The author has an hindex of 43, co-authored 181 publications receiving 6379 citations.

High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial

Abstract: Summary Background High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. Methods Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age ( vs ≥60 years) and institution (Berlin vs Tubingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m 2 ) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m 2 ) on days 3–5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. Findings 551 patients (median age 63 years, IQR 55–69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8–39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5–46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80–1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6–25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3–16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). Interpretation No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors. Funding German Cancer Aid.

PET/MRI: Paving the Way for the Next Generation of Clinical Multimodality Imaging Applications

Abstract: Multimodality imaging and, more specifically, the combination of PET and CT has matured into an important diagnostic tool. During the same period, concepts for PET scanners integrated into an MR tomograph have emerged. The excellent soft-tissue contrast of MRI and the multifunctional imaging options it offers, such as spectroscopy, functional MRI, and arterial spin labeling, complement the molecular information of PET. The development of a fully integrated PET/MRI system is technologically challenging. It requires not only significant modifications of the PET detector to make it compact and insensitive to magnetic fields but also a major redesign of the MRI hardware.

Awareness of the Functioning of One's Own Limbs Mediated by the Insular Cortex?

Abstract: Normally, we are aware of the current functions of our arms and legs. However, this self-evident status may change dramatically after brain damage. Some patients with "anosognosia" typically are convinced that their limbs function normally, although they have obvious motor defects after stroke. Such patients may experience their own paretic limbs as strange or as not belonging to them and may even attribute ownership to another person and try to push their paralyzed limb out of bed. These odd beliefs have been attributed to disturbances somewhere in the right hemisphere. Here, we use lesion mapping in 27 stroke patients to show that the right posterior insula is commonly damaged in patients with anosognosia for hemiplegia/hemiparesis but is significantly less involved in hemiplegic/hemiparetic patients without anosognosia. The function of the posterior insular cortex has been controversially discussed. Recent neuroimaging results in healthy subjects revealed specific involvement of this area in the subject's feeling of being versus not being involved in a movement. Our finding corresponds with this observation and suggests that the insular cortex is integral to self-awareness and to one's beliefs about the functioning of body parts.

Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients

Abstract: To avoid an unnecessary extend of surgery in primary central nervous system lymphoma (PCNSL), the diagnosis should be suspected after MRI.

Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*

Abstract: There is increasing evidence of genetic contribution to the pathogenesis of Parkinson's disease. The identification of mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene has shed new light on genetic variations responsible for autosomal dominantly inherited Parkinson's disease. In this analysis, the most comprehensive published so far, we screened a second large series comprising 53 families with Parkinson's disease for mutations in the LRRK2 gene by direct sequencing to further determine the frequency of the mutation and evaluate the clinical phenotype to establish a genotype/phenotype relation. For comparison, all novel and known mutations were investigated in a cohort of 337 patients with apparently sporadic Parkinson's disease and a cohort of 1200 control subjects using an ABI 7900 Allelic Detection system. We identified 7 more families with LRRK2 variations in the 53 families with Parkinson's disease. Four of these are novel amino acid substitutions (R793M, Q930R, S1096C, S1228T). Because of incomplete penetrance and possible phenocopies pathogenic relevance of the Q930R and S1096C mutations as well as for the previously described A3342G splice site mutation could not be established with certainty. The so far most common mutation (G2019) was not detected in our large cohort. Late onset and typical l-dopa responsive parkinsonian features were generally observed, often accompanied by impairment of executive functions and high interference values in neuropsychological testing, as well as sleeping disturbances but rare hallucinations. There were no abnormalities in electrophysiological investigations. Distinct intrafamily and interfamily differences could be observed, including the clinical presentation of diffuse Lewy body disease in one patient. The frequent finding of cerebral atrophy on MRI and less substantia nigra hyperechogenicity compared with idiopathic Parkinson's disease on transcranial ultrasound needs to be confirmed in further studies. Together with the findings obtained in 46 families in our first study, LRRK2 mutations, therefore, account for 13% of apparently autosomal dominant families in our population with varying but still generally typical clinical presentation of Parkinson's disease.

How do you feel--now? The anterior insula and human awareness.

Abstract: The anterior insular cortex (AIC) is implicated in a wide range of conditions and behaviours, from bowel distension and orgasm, to cigarette craving and maternal love, to decision making and sudden insight. Its function in the re-representation of interoception offers one possible basis for its involvement in all subjective feelings. New findings suggest a fundamental role for the AIC (and the von Economo neurons it contains) in awareness, and thus it needs to be considered as a potential neural correlate of consciousness.

2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).

Abstract: Supplementary Table 9, column 'Edoxaban', row 'eGFR category', '95 mL/min' (page 15). The cell should be coloured green instead of yellow. It should also read "60 mg"instead of "60 mg (use with caution in 'supranormal' renal function)."In the above-indicated cell, a footnote has also been added to state: "Edoxaban should be used in patients with high creatinine clearance only after a careful evaluation of the individual thromboembolic and bleeding risk."Supplementary Table 9, column 'Edoxaban', row 'Dose reduction in selected patients' (page 16). The cell should read "Edoxaban 60 mg reduced to 30 mg once daily if any of the following: creatinine clearance 15-50 mL/min, body weight <60 kg, concomitant use of dronedarone, erythromycin, ciclosporine or ketokonazole"instead of "Edoxaban 60 mg reduced to 30 mg once daily, and edoxaban 30 mg reduced to 15mg once daily, if any of the following: creatinine clearance of 30-50 mL/min, body weight <60 kg, concomitant us of verapamil or quinidine or dronedarone."

The amygdala: vigilance and emotion

Abstract: Here we provide a review of the animal and human literature concerning the role of the amygdala in fear conditioning, considering its potential influence over autonomic and hormonal changes, motor behavior and attentional processes. A stimulus that predicts an aversive outcome will change neural transmission in the amygdala to produce the somatic, autonomic and endocrine signs of fear, as well as increased attention to that stimulus. It is now clear that the amygdala is also involved in learning about positively valenced stimuli as well as spatial and motor learning and this review strives to integrate this additional information. A review of available studies examining the human amygdala covers both lesion and electrical stimulation studies as well as the most recent functional neuroimaging studies. Where appropriate, we attempt to integrate basic information on normal amygdala function with our current understanding of psychiatric disorders, including pathological anxiety.