Undetected pseudoprogressions in the CeTeG/NOA-09 trial: hints from postprogression survival and MRI analyses.

PURPOSE: In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO). METHODS: We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T1-enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined. RESULTS: Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T1-enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm. CONCLUSION: The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.

Long-term neurocognitive function and quality of life after multimodal therapy in adult glioma patients: a prospective long-term follow-up.

PURPOSE: Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients' neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. METHODS: Seventy-one glioma patients (WHO grade 1-4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6-11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. RESULTS: Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to < 10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean < 10 Gy showed stable or improved performance in all cognitive domains, while patients with > 50 Gy numerically deteriorated in 4/8 domains. CONCLUSIONS: Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series.

Survival, prognostic factors, hospitalization time and clinical performance status after first cerebral relapse or progression in 54 patients with primary CNS lymphoma not eligible for high dose chemotherapy: a retrospective analysis.

BACKGROUND: Treatment of relapsed or refractory primary CNS lymphoma (r/r PCNSL) is difficult, particularly in patients not eligible for high dose chemotherapy with autologous stem cell transplantation (HDC-ASCT). No standard treatment has been defined for these patients yet. METHODS: We retrospectively analyzed survival, prognostic factors, hospitalization time and Karnofsky performance score (KPS) before and after treatment in 54 r/r PCNSL patients with isolated cerebral relapse or progression (n = 23 refractory, n = 31 relapsed) not eligible for HDC-ASCT, who received heterogenous salvage treatments. RESULTS: Treatments were temozolomide (+ rituximab) (n = 21), high dose methotrexate (HD-MTX)-based therapy (n = 11), whole brain radiotherapy (WBRT)/focal radiotherapy (n = 11), other systemic treatments (n = 2) and best supportive care (BSC, n = 9). Median progression free survival (PFS) and overall survival (OS) were 2.6 months (95% CI 1.0-4.2 months) and 4.8 months (95% CI 3.3-6.3 months), respectively. Eight patients survived for ≥ 3 years (13.1%, n = 3 received temozolomide, n = 3 WBRT, n = 2 HD-MTX-based treatment). Application of any salvage treatment (vs. BSC), younger age at relapse and asymptomatic (vs. symptomatic) relapse were positive prognostic factors. No significant differences in OS were found for the different salvage treatments. Median hospitalization time for treatment was 15/13 days for temozolomide (+ rituximab)/radiotherapy compared to 55 days for HD-MTX-based therapy. Median KPS in assessable patients (n = 41) was 60 (range 30-100) before treatment and 50 (range 20-90) after treatment. In patients with response to treatment (n = 16) KPS improved from 60 (range 40-90) before treatment to 70 (range 50-90) after treatment, while patients with PD (n = 25) deteriorated from 60 (range 30-100) to 40 (range 20-70). CONCLUSION: Survival for this cohort of r/r PCNSL patients with isolated cerebral relapse or progression was poor. Considering long hospital stays associated with HD-MTX-based chemotherapy and neurotoxicity associated with WBRT, temozolomide might be worth considering with a chance of prolonged survival and avoidance of long hospitalization. Novel therapeutic agents are urgently needed to improve survival in r/r PCNSL patients.

European Association of Neuro-Oncology (EANO) guidelines for treatment of primary central nervous system lymphoma (PCNSL).

The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.

A novel serum extracellular vesicle protein signature to monitor glioblastoma tumor progression.

Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range: <.0001 to .08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44 and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making.

Pre- and postoperative self-reported and objectively assessed neurocognitive functioning in lower grade glioma patients.

Due to the tumor itself or its therapy glioma patients may complain on cognitive impairment, while validated neuropsychological testing (NPT) capturing specific neuropsychological domains does not indicate "objective" dysfunction. Little is known on the relevance of this disturbance for patients' everyday life. We aimed to address whether glioma patients treated with state-of-the-art neurosurgical techniques complain on neuropsychological impairment and whether these subjective complaints are disclosed in formal NPT. We assessed both, "objective" and "subjective" neurocognitive functioning in 13 patients with newly diagnosed WHO grade 2 and 3 gliomas, operated between 06/2018 and 12/2020. All underwent both, preoperative and follow-up NPT as well as a semi-structured interview on subjective complaints and specific questionnaires (post-therapeutic) on attention, memory and executive functioning. On group level, no significant changes between preoperative and post-therapeutic NPT occurred. On the individual level, in 3/13 patients new post-therapeutic deficits in objective NPT were detected in specific domains (verbal memory, non-verbal memory, verbal fluency). By contrast, 8/13 patients reported on "subjective" memory impairments post-therapeutically. Furthermore, on specific questionnaires cognitive and emotional executive dysfunction and increased fatigue occurred in patients relative to normative data. Although the findings have to be replicated in larger populations, a discrepancy between "subjective" and "objective" measures was evident. While subjective neurocognitive impairment may simply not represent a true dysfunction, an alternative explanation might be that established standardized NPT is not suitable to detect subtle dysfunction in this population. "Subjective" and "objective" neurocognitive functioning might represent distinct constructs, which should complement each other in patient-centered Neuro-Oncology.

Brain tumor related epilepsy: pathophysiological approaches and rational management of antiseizure medication.

BACKGROUND: Brain tumor related epilepsy (BTRE) is a common complication of cerebral tumors and its incidence is highly dependent on the type of tumor, ranging from 10-15% in brain metastases to > 80% in low grade gliomas. Clinical management is challenging and has to take into account aspects beyond the treatment of non-tumoral epilepsy. MAIN BODY: Increasing knowledge about the pathophysiology of BTRE, particularly on glutamatergic mechanisms of oncogenesis and epileptogenesis, might influence management of anti-tumor and BTRE treatment in the future. The first seizure implies the diagnosis of epilepsy in patients with brain tumors. Due to the lack of prospective randomized trials in BTRE, general recommendations for focal epilepsies currently apply concerning the initiation of antiseizure medication (ASM). Non-enzyme inducing ASM is preferable. Prospective trials are needed to evaluate, if AMPA inhibitors like perampanel possess anti-tumor effects. ASM withdrawal has to be weighed very carefully against the risk of seizure recurrence, but can be achievable in selected patients. Permission to drive is possible for some patients with BTRE under well-defined conditions, but requires thorough neurological, radiological, ophthalmological and neuropsychological examination. CONCLUSION: An evolving knowledge on pathophysiology of BTRE might influence future therapy. Randomized trials on ASM in BTRE with reliable endpoints are needed. Management of withdrawal of ASMs and permission to drive demands thorough diagnostic as well as neurooncological and epileptological expertise.

German translation and validation of the brief Epilepsy Anxiety Survey Instrument (brEASI).

BACKGROUND: Anxiety disorders remain undiagnosed in routine clinical practice in up to two thirds of affected patients with epilepsy despite their significant impact on medical and psychosocial outcomes. The study objective was to translate and validate the German 8-item "brief Epilepsy Anxiety Survey Instrument" (brEASI) to facilitate effective screening for the presence of anxiety disorders in German-speaking patients. METHODS: After expert translation into German, the brEASI was completed by consecutive adult inpatients with epilepsy hospitalized for seizures at an academic reference epilepsy center. Patients also completed the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), the Generalized Anxiety Disorder scale (GAD-7) for external validity, and underwent a standardized interview (Mini-DIPS-OA) as a gold standard to determine the presence of an ICD-10 anxiety disorder (generalized anxiety disorder (GAD), panic disorder, agoraphobia, and social phobia). Receiver operating characteristics (ROC) were calculated to determine the diagnostic accuracy of the brEASI, including the associated area under the curve (AUC) statistics to determine the potential of the brEASI to identify ICD-10 anxiety disorders diagnosed by interview. For comparative purposes, these analyses were also conducted for the GAD-7. RESULTS: Of 80 recruited adult inpatients with epilepsy, 18 (23 %) were found to have a current anxiety disorder through standardized interview. In this study, both brEASI and GAD-7 showed a better diagnostic performance at a cutoff of >5 than at the previously reported cutoff values of >6 and >9, respectively. The AUC of the German brEASI was outstanding (AUC = 0.90, 95 % confidence interval (CI) = 0.82-0.96) for detecting all anxiety disorders and excellent for detecting non-GAD disorders (AUC = 0.85, CI = 0.76-0.92) at a cutoff of >5. At this optimal cutoff of >5 the brEASI demonstrated better sensitivity and specificity (89 % and 84 %) for identifying anxiety disorders than the GAD-7 (83 % and 74 %). The final German version of the brEASI is free to download at https://www.v-neuro.de/veroeffentlichungen/. CONCLUSION: The German version of the brEASI represents a valid and reliable epilepsy-specific anxiety screening instrument. A positive screening result should be followed by further diagnostic procedures. Appropriate therapeutic steps should be initiated if the presence of an anxiety disorder or other psychiatric disorders is confirmed.

Outcome and prognostic factors of very old patients with primary CNS lymphoma: a retrospective analysis of patients ≥80 years treated with high-dose methotrexate-based chemotherapy.

Although >10% of primary CNS lymphoma (PCNSL) patients are ≥80 years, data on this population are limited. We analyzed 19 consecutive octogenarians with PCNSL treated with high-dose methotrexate (HD-MTX)-based chemotherapy at our institution concerning outcome, prognostic factors and living conditions at six-month follow-up for 11 patients alive and in remission. Seven patients received intracerebroventricular (ICV) treatment additional to systemic therapy. Median follow-up was 27.3 months. Median overall survival was 16.3 months. Positive prognosticators of survival were application of ICV treatment (p = 0.033) and female gender (p = 0.015). All 11 patients alive and in remission at 6-month follow-up were living at home with a median Karnofsky performance score of 60 (range 50-90) and a median instrumental activities of daily living score of 3 (range 1-8). HD-MTX-based polychemotherapy including ICV treatment was feasible in this population, patients in remission needed moderate support in everyday live.

Mid-term treatment-related cognitive sequelae in glioma patients.

PURPOSE: Cognitive functioning represents an essential determinant of quality of life. Since significant advances in neuro-oncological treatment have led to prolonged survival it is important to reliably identify possible treatment-related neurocognitive dysfunction in brain tumor patients. Therefore, the present study specifically evaluates the effects of standard treatment modalities on neurocognitive functions in glioma patients within two years after surgery. METHODS: Eighty-six patients with World Health Organization (WHO) grade 1-4 gliomas were treated between 2004 and 2012 and prospectively followed within the German Glioma Network. They received serial neuropsychological assessment of attention, memory and executive functions using the computer-based test battery NeuroCog FX. As the primary outcome the extent of change in cognitive performance over time was compared between patients who received radiotherapy, chemotherapy or combined radio-chemotherapy and patients without any adjuvant therapy. Additionally, the effect of irradiation and chemotherapy was assessed in subgroup analyses. Furthermore, the potential impact of the extent of tumor resection and histopathological characteristics on cognitive functioning were referred to as secondary outcomes. RESULTS: After a median of 16.8 (range 5.9-31.1) months between post-surgery baseline neuropsychological assessment and follow-up assessment, all treatment groups showed numerical and often even statistically significant improvement in all cognitive domains. The extent of change in cognitive functioning showed no difference between treatment groups. Concerning figural memory only, irradiated patients showed less improvement than non-irradiated patients (p = 0.029, η2 = 0.06). Resected patients, yet not patients with biopsy, showed improvement in all cognitive domains. Compared to patients with astrocytomas, patients with oligodendrogliomas revealed a greater potential to improve in attentional and executive functions. However, the heterogeneity of the patient group and the potentially selected cohort may confound results. CONCLUSION: Within a two-year post-surgery interval, radiotherapy, chemotherapy or their combination as standard treatment did not have a detrimental effect on cognitive functions in WHO grade 1-4 glioma patients. Cognitive performance in patients with adjuvant treatment was comparable to that of patients without.

Point-of-Care Testing Using a Neuropsychology Pocketcard Set: A Preliminary Validation Study.

Neurocognitive screening instruments usually require printed sheets and additional accessories, and can be unsuitable for low-threshold use during ward rounds or emergency workup, especially in patients with motor impairments. Here, we test the utility of a newly developed neuropsychology pocketcard set for point-of-care testing. For aphasia and neglect assessment, modified versions of the Language Screening Test and the Bells Test were validated on 63 and 60 acute stroke unit patients, respectively, against expert clinical evaluation and the original pen-and-paper Bells Test. The pocketcard aphasia test achieved an excellent area under the curve (AUC) of 0.94 (95% CI: 0.88−1, p < 0.001). Using an optimal cut-off of ≥2 mistakes, sensitivity was 91% and specificity was 81%. The pocketcard Bells Task, measured against the clinical neglect diagnosis, achieved higher sensitivity (89%) and specificity (88%) than the original paper-based instrument (78% and 75%, respectively). Separately, executive function tests (modified versions of the Trail Making Test [TMT] A and B, custom Stroop color naming task, vigilance 'A' Montreal Cognitive Assessment item) were validated on 44 inpatients with epilepsy against the EpiTrack® test battery. Pocketcard TMT performance was significantly correlated with the original EpiTrack® versions (A: r = 0.64, p < 0.001; B: r = 0.75, p < 0.001). AUCs for the custom Stroop task, TMT A and TMT B for discriminating between normal and pathological EpiTrack® scores were acceptable, excellent and outstanding, respectively. Quick point-of-care testing using a pocketcard set is feasible and yields diagnostically valid information.

Prognostic impact of obesity in newly-diagnosed glioblastoma: a secondary analysis of CeTeG/NOA-09 and GLARIUS.

PURPOSE: The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy. METHODS: The impact of obesity (BMI ≥ 30 kg/m2) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan-Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables. RESULTS: Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7-30.8) vs. 43.2 (32.5-54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8-18.9) vs 17.6 (14.7-20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53-4.31), p < 0.001) adjusted for age, sex, extent of resection, baseline steroids, Karnofsky performance score, and treatment arm. CONCLUSION: Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients.

High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Relapsed or Refractory Primary CNS Lymphoma: A Retrospective Monocentric Analysis of Long-Term Outcome, Prognostic Factors, and Toxicity.

High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is reportedly an effective treatment strategy in relapsed or refractory primary CNS lymphoma (r/r PCNSL); however, only selected patients are eligible for this treatment. We retrospectively analyzed outcome, prognostic factors, and toxicity in 59 patients with r/r PCNSL planned to receive HCT-ASCT at our institution between January 2005 and December 2021 (n = 33 < 65 years; n = 26 ≥ 65 years). Median follow-up was 65 months (95% CI 21−109). Median age was 63 years (range 29−76), median Karnofsky performance score (KPS) was 80 (range 30−100). In the entire cohort of 59 patients, median overall survival (OS) was 14 months (95% CI 0−37). In 50/59 (84.7%) patients who completed HCT-ASCT, median progression free survival (PFS) was 12 months (95% CI 3−21) and median OS 30 months (95% CI 0−87). 1-year, 2-year, and 5-year OS rates of 61.2%, 52.3% and 47.1%, respectively, were observed. Six patients (10.2%) died related to treatment (1 during induction treatment, 5 post HCT-ASCT). Age was not prognostic. On univariate analysis, KPS ≥ 80 (p = 0.019) and complete or partial remission before HCT-ASCT (p = 0.026) were positive prognosticators of OS; on multivariate analysis, KPS (p = 0.043) and male gender (p = 0.039) had an impact on OS. The 5-year OS rate in patients with progressive or stable disease after induction treatment was 32.7%. In summary, HCT-ASCT was effective and feasible in this cohort of r/r PCNSL patients. Clinical state, remission status before HCT-ASCT, and gender influenced survival, whereas age did not influence outcome in this study.

Sociocognitive Functioning and Psychosocial Burden in Patients with Brain Tumors.

Brain tumors may represent devastating diseases and neuro-oncological research in the past solely focused on development of better treatments to achieve disease control. The efficacy of tumor-directed treatment was evaluated by progression-free and overall survival. However, as neuro-oncological treatment became more effective, preservation and improvement of quality of life (QoL) was noticed to represent an important additional outcome measure. The need to balance between aggressive tumor-directed treatment and preservation of QoL was increasingly acknowledged in brain tumor patients. QoL is comprised by many determinants; one of those may have been rather neglected so far: social cognition. Since diagnosis and treatment of brain tumors represent demanding life situations, patients may experience increased psychosocial burden and the negative consequences of illness on well-being may be buffered by intact social relationships. These skills to build and maintain supportive social relationships essentially depend on the ability to empathize with others and to recognize and appropriately address social conflicts, i.e., "sociocognitive functioning". Therefore, sociocognitive functions may influence QoL and treatment outcome. In this article, we review the literature on psychosocial burden and sociocognitive functioning in adult brain tumor patients.

Cortical thickness in default mode network hubs correlates with clinical features of dissociative seizures.

BACKGROUND: Dissociative seizures (DS) are a common subtype of functional neurological disorder (FND) with an incompletely understood pathophysiology. Here, gray matter variations and their relationship to clinical features were investigated. METHODS: Forty-eight patients with DS without neurological comorbidities and 43 matched clinical control patients with syncope with structural brain MRIs were identified retrospectively. FreeSurfer-based cortical thickness and FSL FIRST-based subcortical volumes were used for quantitative analyses, and all findings were age and sex adjusted, and corrected for multiple comparisons. RESULTS: Groups were not statistically different in cortical thickness or subcortical volumes. For patients with DS, illness duration was inversely correlated with cortical thickness of left-sided anterior and posterior cortical midline structures (perigenual/dorsal anterior cingulate cortex, superior parietal cortex, precuneus), and clusters at the left temporoparietal junction (supramarginal gyrus, postcentral gyrus, superior temporal gyrus), left postcentral gyrus, and right pericalcarine cortex. Dissociative seizure duration was inversely correlated with cortical thickness in the left perigenual anterior cingulate cortex, superior/middle frontal gyri, precentral gyrus and lateral occipital cortex, along with the right isthmus-cingulate and posterior-cingulate, middle temporal gyrus, and precuneus. Seizure frequency did not show any significant correlations. CONCLUSIONS: In patients with DS, illness duration inversely correlated with cortical thickness of left-sided default mode network cortical hubs, while seizure duration correlated with left frontopolar and right posteromedial areas, among others. Etiological factors contributing to neuroanatomical variations in areas related to self-referential processing in patients with DS require more research inquiry.

Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial.

BACKGROUND: Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGMT-methylated glioblastoma is not standardized and may consist of re-resection, re-irradiation, and chemotherapy with temozolomide (TMZ), lomustine (CCNU), or a combination thereof. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID) and registered in the USA, sensitizes glioblastoma cells to temozolomide-induced toxicity via inhibition of gap junction-mediated intercellular cytosolic traffic and demolishment of tumor microtube (TM)-based network morphology. METHODS: In this study, combined MFA/TMZ therapy will be administered (orally) in patients with first relapse of MGMT-methylated glioblastoma. A phase I component (6-12 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II component (2 × 30 patients) with progression-free survival as the primary endpoint. DISCUSSION: This study is set up to assess toxicity and first indications of efficacy of MFA repurposed in the setting of a very difficult-to-treat recurrent tumor. The trial is a logical next step after the identification of the role of resistance-providing TMs in glioblastoma, and results will be crucial for further trials targeting TMs. In case of favorable results, MFA may constitute the first clinically feasible TM-targeted drug and therefore might bridge the idea of a TM-targeted therapeutic approach from basic insights into clinical reality. TRIAL REGISTRATION: EudraCT 2021-000708-39 . Registered on 08 February 2021.

Diagnostic challenges in patients with temporal lobe seizures and features of autoimmune limbic encephalitis.

BACKGROUND AND PURPOSE: Consensus criteria for autoimmune limbic encephalitis (ALE) allow for a diagnosis even without neuronal antibodies (Abs), but it remains unclear which clinical features should prompt neuronal Ab screening in temporal lobe epilepsy patients. The aim of the study was to investigate whether patients with temporal lobe seizures associated with additional symptoms or signs of limbic involvement may harbor neuronal Abs, and which clinical features should prompt neuronal Ab screening in these patients. METHODS: We identified 47 patients from a tertiary epilepsy center with mediotemporal lobe seizures and additional features suggestive of limbic involvement, including either memory deficits, psychiatric symptoms, mediotemporal magnetic resonance imaging (MRI) hyperintensities or inflammatory cerebrospinal fluid (CSF). Neuronal Ab testing was carried out at two independent reference laboratories (Bielefeld-Bethel, Germany, and Barcelona, Spain). All brain MRI scans were assessed by two reviewers independently. RESULTS: Temporal lobe seizures were accompanied by memory deficits in 35/46 (76%), psychiatric symptoms in 27/42 (64%), and both in 19/42 patients (45%). Limbic T2/fluid-attenuated inversion recovery signal hyperintensities were found in 26/46 patients (57%; unilateral: n = 22, bilateral: n = 4). Standard CSF studies were abnormal in 2/37 patients (5%). Neuronal Abs were confirmed in serum and/or CSF in 8/47 patients (17%) and were directed against neuronal cell-surface targets (leucine-rich glioma inactivated protein 1: n = 1, contactin-associated protein-2: n = 1, undetermined target: n = 3) or glutamic acid decarboxylase in its 65-kD isoform (n = 3, all with high titers). Compared to Ab-negative patients, those who harbored neuronal Abs were more likely to have uni- or bilateral mediotemporal MRI changes (8/8, 100% vs. 18/38, 47%; p = 0.01, Fisher's exact test). CONCLUSIONS: In patients with temporal lobe seizures and additional limbic signs, 17% had neuronal Abs affirming ALE diagnosis. Mediotemporal MRI changes were found in all Ab-positive cases and had a positive likelihood ratio of 2.11 (95% confidence interval 1.51-2.95).

[Development and content validation of a questionnaire for functional movement disorders]. / Entwicklung und inhaltliche Validierung eines Fragebogens für funktionelle Bewegungsstörungen.

From shell shock tremors to TikTok tics, functional movement disorders have long been assumed to be motor expressions of emotional turmoil. However, psychodynamic explanations are increasingly complemented by neurophysiological findings, meaning that specialized physiotherapy is gaining in importance alongside psychotherapy. Still, there is no disease-specific outcome measure that adequately assesses patient-relevant aspects of this heterogeneous condition. Such a questionnaire was developed and its content was validated in a multistage development process. The relevance and comprehensibility of the items were first evaluated by a panel of experts and then by affected patients, and questions and possible response categories were adjusted accordingly. The resultant revised questionnaire yields good content-related validity and thus allows, for the first time, a quantification of the subjective complaints and implications associated with functional movement disorders. The next step will be a multicenter study to analyze the psychometric properties and factorial structure of this new instrument.