Electrophysiological signatures of veridical head direction in humans.

Information about heading direction is critical for navigation as it provides the means to orient ourselves in space. However, given that veridical head-direction signals require physical rotation of the head and most human neuroimaging experiments depend upon fixing the head in position, little is known about how the human brain is tuned to such heading signals. Here we adress this by asking 52 healthy participants undergoing simultaneous electroencephalography and motion tracking recordings (split into two experiments) and 10 patients undergoing simultaneous intracranial electroencephalography and motion tracking recordings to complete a series of orientation tasks in which they made physical head rotations to target positions. We then used a series of forward encoding models and linear mixed-effects models to isolate electrophysiological activity that was specifically tuned to heading direction. We identified a robust posterior central signature that predicts changes in veridical head orientation after regressing out confounds including sensory input and muscular activity. Both source localization and intracranial analysis implicated the medial temporal lobe as the origin of this effect. Subsequent analyses disentangled head-direction signatures from signals relating to head rotation and those reflecting location-specific effects. Lastly, when directly comparing head direction and eye-gaze-related tuning, we found that the brain maintains both codes while actively navigating, with stronger tuning to head direction in the medial temporal lobe. Together, these results reveal a taxonomy of population-level head-direction signals within the human brain that is reminiscent of those reported in the single units of rodents.

Evaluation of surgical treatment strategies and outcome for cerebral arachnoid cysts in children and adults.

OBJECTIVE: The best treatment strategies for cerebral arachnoid cysts (CAC) are still up for debate. In this study, we present CAC management, outcome data, and risk factors for recurrence after surgical treatment, focusing on microscopic/endoscopic approaches as compared to minimally invasive stereotactic procedures in children and adults. METHODS: In our single-institution retrospective database, we identified all patients treated surgically for newly diagnosed CAC between 2000 and 2022. Microscopic/endoscopic surgery (ME) aimed for safe cyst wall fenestration. Stereotactic implantation of an internal shunt catheter (STX) to drain CAC into the ventricles and/or cisterns was used as an alternative procedure in patients aged ≥ 3 years. Treatment decisions in favor of ME vs. STX were made by interdisciplinary consensus. The primary study endpoint was time to CAC recurrence (TTR). Secondary endpoints were outcome metrics including clinical symptoms and MR-morphological analyses. Data analysis included subdivision of the total cohort into three distinct age groups (AG1, < 6 years; AG2, 6-18 years; AG3, ≥ 18 years). RESULTS: Sixty-two patients (median age 26.5 years, range 0-82 years) were analyzed. AG1 included 15, AG2 10, and AG3 37 patients, respectively. The main presenting symptoms were headache and vertigo. In AG1 hygromas, an increase in head circumference and thinning of cranial calvaria were most frequent. Thirty-five patients underwent ME and 27 STX, respectively; frequency did not differ between AGs. There were two (22.2%) periprocedural venous complications in infants (4- and 10-month-old) during an attempt at prepontine fenestration of a complex CAC, one with fatal outcome in a 10-month-old boy. Other complications included postoperative bleeding (2, 22.2%), CSF leaks (4, 44.4%), and meningitis (1, 11.1%). Overall, clinical improvement and significant volume reduction (p = 0.008) were seen in all other patients; this did not differ between AGs. Median follow-up for all patients was 25.4 months (range, 3.1-87.1 months). Recurrent cysts were seen in 16.1%, independent of surgical procedure used (p = 0.7). In cases of recurrence, TTR was 7.9 ± 12.7 months. Preoperative ventricular expansion (p = 0.03), paresis (p = 0.008), and age under 6 years (p = 0.03) were significant risk factors for CAC recurrence in multivariate analysis. CONCLUSIONS: In patients suffering from CAC, both ME and STX can improve clinical symptoms at low procedural risk, with equal extent of CAC volume reduction. However, in infants and young children, CAC are more often associated with severe clinical symptoms, stereotactic procedures have limited use, and microsurgery in the posterior fossa may bear the risk of severe venous bleeding.

Risk-benefit analysis of surgical treatment strategies for cystic craniopharyngioma in children and adolescents.

Objective: Treatment strategies for craniopharyngiomas are still under debate particularly for the young population. We here present tumor control and functional outcome data after surgical treatment focusing on stereotactic and microsurgical procedures for cystic craniopharyngiomas in children and adolescents. Methods: From our prospective institutional database, we identified all consecutive patients less than 18 years of age who were surgically treated for newly-diagnosed cystic craniopharyngioma between, 2000 and, 2022. Treatment decisions in favor of stereotactic treatment (STX) or microsurgery were made interdisciplinary. STX included aspiration and/or implantation of an internal shunt catheter for permanent cyst drainage. Microsurgery aimed for safe maximal tumor resections. Study endpoints were time to tumor recurrence (TTR) and functional outcome including ophthalmological/perimetric, endocrinological, and body-mass index (BMI) data. Results: 29 patients (median age 9.9 yrs, range 4-18 years) were analyzed. According to our interdisciplinary tumor board recommendation, 9 patients underwent stereotactic treatment, 10 patients microsurgical resection, and 10 patients the combination of both. Significant volume reduction was particularly achieved in the stereotactic (p=0.0019) and combined subgroups (p<0.001). Improvement of preoperative visual deficits was always achieved independent of the applied treatment modality. Microsurgery and the combinational treatment were associated with higher rates of postoperative endocrinological dysfunction (p<0.0001) including hypothalamic obesity (median BMI increase from 17.9kg/m2 to 24.1kg/m2, p=0.019). Median follow-up for all patients was 93.9 months (range 3.2-321.5 months). Recurrent tumors were seen in 48.3% and particularly concerned patients after initial combination of surgery and STX (p=0.004). In here, TTR was 35.1 ± 46.9 months. Additional radiation therapy was found indicated in 4 patients to achieve long-lasting tumor control. Conclusion: In children and adolescents suffering from predominantly cystic craniopharyngiomas, stereotactic and microsurgical procedures can improve clinical symptoms at low procedural risk. Microsurgery, however, bears a higher risk of postoperative endocrine dysfunction. A risk-adapted surgical treatment concept may have to be applied repeatedly in order to achieve long-term tumor control even without additional irradiation.

Efficacy and safety of cysto-ventricular catheter implantation for space-occupying cysts arising from glioma and brain metastasis: a retrospective study.

BACKGROUND: Cysto-ventricular catheters (CVC) have emerged as promising treatment option for cystic craniopharyngioma and arachnoid cysts, but their effectiveness in treating cysts originating from glioma or brain metastasis (BM) remains limited. This study aimed to analyze the efficacy of CVC in patients with glioma and BM as well as procedure-associated morbidity. METHODS: This single-center retrospective study included all patients treated with CVC placement for acquired space-occupying cysts deriving from previously treated glioma or BMs between 1/2010 and 12/2021. RESULTS: A total of 57 patients with a median age of 47 years (IQR 38-63) were identified. Focal neurological deficits were the predominant symptoms in 60% of patients (n = 34), followed by cephalgia in 14% (n = 8), and epileptic seizures in 21.1% (n = 12). Accurate CVC placement was achieved in all but one case requiring revision surgery due to malposition. Three months after CVC implantation, 70% of patients showed symptomatic improvement. Multivariate logistic regression analysis identified the development of space-occupying cysts later in the course of the disease (OR 1.014; p = 0.04) and a higher reduction of cyst-volume postoperatively (OR 1.055; p = 0.05) were significant predictors of postoperative symptomatic improvement following CVC placement. Local cyst recurrence was observed in three cases during follow-up MRI after an average time of 5 months (range 3-9 months). Further complications included secondary malresorptive hydrocephalus in three cases and meningeosis neoplastica in one patient. CONCLUSIONS: Stereotactic implantation of CVC is an efficient treatment option for patients suffering from symptomatic space-occupying cysts from BMs or glioma, independently from their CNS WHO grade. However, a vigilant approach is crucial regarding potential complications and treatment failures.

Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.

Minimally invasive third ventriculostomy with stereotactic internal shunt placement for the treatment of tumor-associated noncommunicating hydrocephalus.

BACKGROUND: Intracranial tumors can cause obstructive hydrocephalus (OH). Most often, symptomatic treatment is pursued through ventriculoperitoneal shunt (VS) or endoscopic third ventriculostomy (ETV). In this study, we propose stereotactic third ventriculostomy with internal shunt placement (sTVIP) as an alternative treatment option and assess its safety and efficacy. METHODS: In this single-center, retrospective analysis, clinical symptoms, procedure-related complications, and revision-free survival of all patients with OH due to tumor formations treated by sTVIP between January 2010 and December 2021 were evaluated. RESULTS: Clinical records of thirty-eight patients (11 female, 27 male) with a mean age of 40 years (range 5-88) were analyzed. OH was predominantly (in 92% of patients) caused by primary brain tumors (with exception of 3 cases with metastases). Following sTVIP, 74.2% of patients experienced symptomatic improvement. Preoperative headache was a significant predictor of postoperative symptomatic improvement (OR 26.25; 95% CI 4.1-521.1; p = 0.0036). Asymptomatic hemorrhage was detected along the stereotactic trajectory in 2 cases (5.3%). One patient required local revision due to CSF fistula (2.6%); another patient had to undergo secondary surgery to connect the catheter to a valve/abdominal catheter due to CSF malabsorption. However, in the remaining 37 patients, shunt independence was maintained during a median follow-up period of 12 months (IQR 3-32 months). No surgery-related mortality was observed. CONCLUSIONS: sTVIP led to a significant symptom control and was associated with low operative morbidity, along with a high rate of ventriculoperitoneal shunt independency during the follow-up period. Therefore, sTVIP constitutes a highly effective and minimally invasive treatment option for tumor-associated obstructive hydrocephalus, even in cases with a narrow prepontine interval.

Translocator protein (18kDA) (TSPO) marks mesenchymal glioblastoma cell populations characterized by elevated numbers of tumor-associated macrophages.

TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing.We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages.In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions.

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH-Wild-Type Glioblastoma.

The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUVmax on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O 6-alkylguanine DNA methyltransferase (MGMT) and telomerase reverse transcriptase (TERT) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUVmax was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUVmax > 2.2) was related to significantly shorter overall survival (OS; 8.3 vs. 17.8 mo, P = 0.037). Besides SUVmax, prognostic factors for OS were age (P = 0.046), MGMT promoter methylation status (P = 0.032), and T2-weighted MRI volume (P = 0.031). In the multivariate survival analysis, SUVmax in TSPO PET remained an independent prognostic factor for OS (P = 0.023), with a hazard ratio of 2.212 (95% CI, 1.115-4.386) for death in cases with a high TSPO PET signal (SUVmax > 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma.

Postoperative [68Ga]Ga-DOTA-TATE PET/CT imaging is prognostic for progression-free survival in meningioma WHO grade 1.

PURPOSE: Tumor resection represents the first-line treatment for symptomatic meningiomas, and the extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. In this preliminary study, we evaluate the prognostic relevance of postoperative PET for progression-free survival in meningiomas. METHODS: We conducted a post hoc analysis on a prospective patient cohort with resected meningioma WHO grade 1. Patients received postoperative MRI and [68Ga]Ga-DOTA-TATE PET/CT and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression. RESULTS: We included 46 patients with 49 tumors. The mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029), whereas MRI was not. 20 out of 20 patients (100%) with negative PET findings remained recurrence-free. The location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032). CONCLUSION: Our data show that [68Ga]Ga-DOTA-TATE PET/CT is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas.

Significance of molecular diagnostics for therapeutic decision-making in recurrent glioma.

Background: Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary molecular tumor board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU). Methods: We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based on next-generation sequencing results of individual patient's tumor tissue. Clinical and molecular information, previous therapy regimens, and outcome parameters were collected. Results: Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32-536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), epidermal growth factor receptor amplification (19/73; 26%), and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one-third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization. Conclusions: In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable antitumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.

Interstitial Photodynamic Therapy of Glioblastomas: A Long-Term Follow-up Analysis of Survival and Volumetric MRI Data.

BACKGROUND: The treatment of glioblastomas, the most common primary malignant brain tumors, with a devastating survival perspective, remains a major challenge in medicine. Among the recently explored therapeutic approaches, 5-aminolevulinic acid (5-ALA)-mediated interstitial photodynamic therapy (iPDT) has shown promising results. METHODS: A total of 16 patients suffering from de novo glioblastomas and undergoing iPDT as their primary treatment were retrospectively analyzed regarding survival and the characteristic tissue regions discernible in the MRI data before treatment and during follow-up. These regions were segmented at different stages and were analyzed, especially regarding their relation to survival. RESULTS: In comparison to the reference cohorts treated with other therapies, the iPDT cohort showed a significantly prolonged progression-free survival (PFS) and overall survival (OS). A total of 10 of 16 patients experienced prolonged OS (≥ 24 months). The dominant prognosis-affecting factor was the MGMT promoter methylation status (methylated: median PFS of 35.7 months and median OS of 43.9 months) (unmethylated: median PFS of 8.3 months and median OS of 15.0 months) (combined: median PFS of 16.4 months and median OS of 28.0 months). Several parameters with a known prognostic relevance to survival after standard treatment were not found to be relevant to this iPDT cohort, such as the necrosis-tumor ratio, tumor volume, and posttreatment contrast enhancement. After iPDT, a characteristic structure (iPDT remnant) appeared in the MRI data in the former tumor area. CONCLUSIONS: In this study, iPDT showed its potential as a treatment option for glioblastomas, with a large fraction of patients having prolonged OS. Parameters of prognostic relevance could be derived from the patient characteristics and MRI data, but they may partially need to be interpreted differently compared to the standard of care.

Interstitial photodynamic therapy for newly diagnosed glioblastoma.

PURPOSE: Innovative, efficient treatments are desperately needed for people with glioblastoma (GBM). METHODS: Sixteen patients (median age 65.8 years) with newly diagnosed, small-sized, not safely resectable supratentorial GBM underwent interstitial photodynamic therapy (iPDT) as upfront eradicating local therapy followed by standard chemoradiation. 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX was used as the photosensitizer. The tumors were irradiated with light at 635 nm wavelength via stereotactically implanted cylindrical diffuser fibers. Outcome after iPDT was retrospectively compared with a positively-selected in-house patient cohort (n = 110) who underwent complete tumor resection followed by chemoradiation. RESULTS: Median progression-free survival (PFS) was 16.4 months, and median overall survival (OS) was 28.0 months. Seven patients (43.8%) experienced long-term PFS > 24 months. Median follow-up was 113.9 months for the survivors. Univariate regression revealed MGMT-promoter methylation but not age as a prognostic factor for both OS (p = 0.04 and p = 0.07) and PFS (p = 0.04 and p = 0.67). Permanent iPDT-associated morbidity was seen in one iPDT patient (6.3%). Patients treated with iPDT experienced superior PFS and OS compared to patients who underwent complete tumor removal (p < 0.01 and p = 0.01, respectively). The rate of long-term PFS was higher in iPDT-treated patients (43.8% vs. 8.9%, p < 0.01). CONCLUSION: iPDT is a feasible treatment concept and might be associated with long-term PFS in a subgroup of GBM patients, potentially via induction of so far unknown immunological tumor-controlling processes.

[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

OBJECTIVES: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. METHODS: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and ß-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. RESULTS: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and ß-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. CONCLUSIONS: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

Lyme neuroborreliosis: An unusual case with extensive (peri)vasculitis of the middle cerebral artery.

Lyme disease is a tick-borne infection caused by Borrelia burgdorferi sensu latu. Neuroborreliosis is reported in approximately 10% of patients with Lyme disease. We report a patient with central nervous system (CNS) large vessel vasculitis, ischemic stroke, and tumefactive contrast-enhancing brain lesions, an unusual complication of neuroborreliosis. A 56-year-old man presented with headache and disorientation for 1 month. Magnetic resonance imaging revealed basal meningitis with rapidly progressing frontotemporoinsular edema and (peri)vasculitis. Transcranial ultrasound confirmed stenosed medial cerebral arteries. [18 F]GE-180 microglia positron emission tomography (PET) showed frontotemporoinsular signal more pronounced on the right. [18 F]FET amino acid PET demonstrated low tracer uptake, suggesting an inflammatory process. Cerebrospinal fluid (CSF) showed lymphomonocytosis (243/µl), intrathecal anti-Borrelia IgM (CSF/serum index = 15.65, normal < 1.5) and anti-Borrelia IgG (CSF/serum index = 6.5, normal < 1.5), and elevated CXCL13 (29.2 pg/ml, normal < 10 pg/ml). Main differential diagnoses of neurotuberculosis and perivascular CNS lymphoma were ruled out by biopsy and Quantiferon enzyme-linked immunosorbent assay. Ceftriaxone (28 days), cortisone, and nimodipine (3 months) led to full recovery. Neuroborreliosis is an important differential diagnosis in patients with CNS large vessel vasculitis and tumefactive contrast-enhancing brain lesions, mimicking perivascular CNS lymphoma or neurotuberculosis as main neuroradiological differential diagnoses. Vasculopathy and cerebrovascular events are rare in neuroborreliosis but should be considered, especially in endemic areas.

TSPO PET signal using [18F]GE180 is associated with survival in recurrent gliomas.

PURPOSE: Glioma patients, especially recurrent glioma, suffer from a poor prognosis. While advances to classify glioma on a molecular level improved prognostication at initial diagnosis, markers to prognosticate survival in the recurrent situation are still needed. As 18 kDa translocator protein (TSPO) was previously reported to be associated with aggressive histopathological glioma features, we correlated the TSPO positron emission tomography (PET) signal using [18F]GE180 in a large cohort of recurrent glioma patients with their clinical outcome. METHODS: In patients with [18F]GE180 PET at glioma recurrence, [18F]GE180 PET parameters (e.g., SUVmax) as well as other imaging features (e.g., MRI volume, [18F]FET PET parameters when available) were evaluated together with patient characteristics (age, sex, Karnofsky-Performance score) and neuropathological features (e.g. WHO 2021 grade, IDH-mutation status). Uni- and multivariate Cox regression and Kaplan-Meier survival analyses were performed to identify prognostic factors for post-recurrence survival (PRS) and time to treatment failure (TTF). RESULTS: Eighty-eight consecutive patients were evaluated. TSPO tracer uptake correlated with tumor grade at recurrence (p < 0.05), with no significant differences in IDH-wild-type versus IDH-mutant tumors. Within the subgroup of IDH-mutant glioma (n = 46), patients with low SUVmax (median split, ≤ 1.60) had a significantly longer PRS (median 41.6 vs. 25.3 months, p = 0.031) and TTF (32.2 vs 8.7 months, p = 0.001). Also among IDH-wild-type glioblastoma (n = 42), patients with low SUVmax (≤ 1.89) had a significantly longer PRS (median not reached vs 8.2 months, p = 0.002). SUVmax remained an independent prognostic factor for PRS in the multivariate analysis including CNS WHO 2021 grade, IDH status, and age. Tumor volume defined by [18F]FET PET or contrast-enhanced MRI correlated weakly with TSPO tracer uptake. Treatment regimen did not differ among the median split subgroups. CONCLUSION: Our data suggest that TSPO PET using [18F]GE180 can help to prognosticate recurrent glioma patients even among homogeneous molecular subgroups and may therefore serve as valuable non-invasive biomarker for individualized patient management.

Combination of pre-treatment dynamic [18F]FET PET radiomics and conventional clinical parameters for the survival stratification in patients with IDH-wildtype glioblastoma.

PURPOSE: The aim of this study was to build and evaluate a prediction model which incorporates clinical parameters and radiomic features extracted from static as well as dynamic [18F]FET PET for the survival stratification in patients with newly diagnosed IDH-wildtype glioblastoma. METHODS: A total of 141 patients with newly diagnosed IDH-wildtype glioblastoma and dynamic [18F]FET PET prior to surgical intervention were included. Patients with a survival time ≤ 12 months were classified as short-term survivors. First order, shape, and texture radiomic features were extracted from pre-treatment static (tumor-to-background ratio; TBR) and dynamic (time-to-peak; TTP) images, respectively, and randomly divided into a training (n = 99) and a testing cohort (n = 42). After feature normalization, recursive feature elimination was applied for feature selection using 5-fold cross-validation on the training cohort, and a machine learning model was constructed to compare radiomic models and combined clinical-radiomic models with selected radiomic features and clinical parameters. The area under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive values were calculated to assess the predictive performance for identifying short-term survivors in both the training and testing cohort. RESULTS: A combined clinical-radiomic model comprising six clinical parameters and six selected dynamic radiomic features achieved highest predictability of short-term survival with an AUC of 0.74 (95% confidence interval, 0.60-0.88) in the independent testing cohort. CONCLUSIONS: This study successfully built and evaluated prediction models using [18F]FET PET-based radiomic features and clinical parameters for the individualized assessment of short-term survival in patients with a newly diagnosed IDH-wildtype glioblastoma. The combination of both clinical parameters and dynamic [18F]FET PET-based radiomic features reached highest accuracy in identifying patients at risk. Although the achieved accuracy level remained moderate, our data shows that the integration of dynamic [18F]FET PET radiomic data into clinical prediction models may improve patient stratification beyond established prognostic markers.

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model.

Introduction: The 18 kDa translocator protein (TSPO) receives growing interest as a biomarker in glioblastoma. Mouse models can serve as an important tool for the investigation of biomarkers in glioblastoma, but several glioblastoma models indicated only low TSPO-PET signals in contrast to high TSPO-PET signals of human glioblastoma. Thus, we aimed to investigate TSPO-PET imaging in the syngeneic immunocompetent SB28 mouse model, which is thought to closely represent the tumor microenvironment (TME) of human glioblastoma. Methods: Dynamic TSPO-PET/CT imaging was performed for 60 min after injection of 13.6 ± 4.2 MBq [18F]GE-180. Contrast enhanced CT (ceCT) was acquired prior to PET and served for assessment of tumor volumes and attenuation correction. SB28 and sham mice were imaged at an early (week-1; n = 6 SB28, n = 6 sham) and a late time-point (week-3; n = 8 SB28, n = 9 sham) after inoculation. Standard of truth ex vivo tumor volumes were obtained for SB28 mice at the late time-point. Tracer kinetics were analyzed for the lesion site and the carotid arteries to establish an image derived input function (IDIF). TSPO-PET and ceCT lesion volumes were compared with ex vivo volumes by calculation of root-mean-square-errors (RMSE). Volumes of distribution (VTmax/mean) in the lesion were calculated using carotid IDIF and standardized uptake values (SUVmax/mean) were obtained for a 40-60 min time frame. Results: Higher uptake rate constants (K1) were observed for week-1 SB28 tumor lesions when compared to week-3 SB28 tumor lesions. Highest agreement between TSPO-PET lesion volumes and ex vivo tumor volumes was achieved with a 50% maximum threshold (RMSE-VT: 39.7%; RMSE-SUV: 34.4%), similar to the agreement of ceCT tumor volumes (RMSE: 30.1%). Lesions of SB28 mice had higher PET signal when compared to sham mice at week-1 (VTmax 6.6 ± 2.9 vs. 3.9 ± 0.8, p = 0.035; SUVmax 2.3 ± 0.5 vs. 1.2 ± 0.1, p < 0.001) and PET signals remained at a similar level at week-3 (VTmax 5.0 ± 1.6 vs. 2.7 ± 0.8, p = 0.029; SUVmax 1.9 ± 0.5 vs. 1.2 ± 0.2, p = 0.0012). VTmax correlated with SUVmax (R 2 = 0.532, p < 0.001). Conclusion: TSPO-PET imaging of immunocompetent SB28 mice facilitates early detection of tumor signals over sham lesions. SB28 tumors mirror high TSPO-PET signals of human glioblastoma and could serve as a valuable translational model to study TSPO as an imaging biomarker.

Limited efficacy of temozolomide alone for astrocytoma, IDH-mutant, CNS WHO grades 2 or 3.

PURPOSE: The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH)-mutant astrocytomas has not been conclusively determined. Radiotherapy might be superior to temozolomide. Recent studies have linked temozolomide with induction of hypermutation and poor clinical course in some IDH-mutant gliomas. METHODS: In this retrospective study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 and diagnosed between 2001 and 2019 were included. Patients initially monitored by wait-and-scan strategies or treated with radiotherapy or temozolomide alone were studied. Patient data were correlated with outcome. Matched pair and subgroup analyses were conducted. RESULTS: Radiotherapy was associated with longer progression-free survival than temozolomide (6.2 vs 3.4 years, p = 0.02) and wait-and-scan strategies (6.2 vs 4 years, p = 0.03). Patients treated with radiotherapy lived longer than patients treated with temozolomide (14.4 vs 10.7 years, p = 0.02). Survival was longer in the wait-and-scan cohort than in the temozolomide cohort (not reached vs 10.7 years, p < 0.01). Patients from the wait-and-scan cohort receiving temozolomide at first progression had significantly shorter survival times than patients treated with any other therapy at first progression (p < 0.01). Post-surgical T2 tumor volume, contrast enhancement on MRI and WHO grade were associated with overall survival in univariate analyses (p < 0.01). CONCLUSION: The results suggest superiority of radiotherapy over temozolomide and wait-and-scan strategies regarding progression-free survival and superiority of radiotherapy over temozolomide regarding overall survival. Our results are consistent with the notion that early temozolomide might compromise outcome in some patients.

Diagnostic Yield and Complication Rate of Stereotactic Biopsies in Precision Medicine of Gliomas.

Background: An integrated diagnosis consisting of histology and molecular markers is the basis of the current WHO classification system of gliomas. In patients with suspected newly diagnosed or recurrent glioma, stereotactic biopsy is an alternative in cases in which microsurgical resection is deemed to not be safely feasible or indicated. In this retrospective study, we aimed to analyze both the diagnostic yield and the safety of a standardized biopsy technique. Material and Methods: The institutional database was screened for frame-based biopsy procedures (January 2016 until March 2021). Only patients with a suspected diagnosis of glioma based on imaging were included. All tumors were classified according to the current WHO grading system. The clinical parameters, procedural complications, histology, and molecular signature of the tissues obtained were assessed. Results: Between January 2016 and March 2021, 1,214 patients underwent a stereotactic biopsy: 617 (50.8%) for a newly diagnosed lesion and 597 (49.2%) for a suspected recurrence. The median age was 56.9 years (range 5 months-94.4 years). Magnetic resonance imaging (MRI)-guidance was used in 99.3% of cases and additional positron emission tomography (PET)-guidance in 34.3% of cases. In total, stereotactic serial biopsy provided an integrated diagnosis in 96.3% of all procedures. The most frequent diagnoses were isocitrate dehydrogenase (IDH) wildtype glioblastoma (n = 596; 49.2%), oligodendroglioma grade 2 (n = 109; 9%), astrocytoma grade 3 (n = 108; 8.9%), oligodendroglioma grade 3 (n = 76; 6.3%), and astrocytoma grade 2 (n = 66; 5.4%). A detailed determination was successful for IDH 1/2 mutation in 99.4% of cases, for 1p/19q codeletion in 97.4% of cases, for TERT mutation in 98.9% of cases, and for MGMT promoter methylation in 99.1% of cases. Next-generation sequencing was evaluable in 64/67 (95.5%) of cases and DNA methylome analysis in 41/44 (93.2%) of cases. Thirteen (1.1%) cases showed glial tumors that could not be further specified. Seventy-three tumors were different non-glioma entities, e.g., of infectious or inflammatory nature. Seventy-five out of 597 suspected recurrences turned out to be post-therapeutic changes only. The rate of post-procedural complications with clinical symptoms of the Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher was 1.2% in overall patients and 2.6% in the subgroup of brainstem biopsies. There was no fatal outcome in the entire series. Conclusion: Image-guided stereotactic serial biopsy enables obtaining reliable histopathological and molecular diagnoses with a very low complication rate even in tumors with critical localization. Thus, in patients not undergoing microsurgical resection, this is a valuable tool for precision medicine of patients with glioma.