Fully automated MR-based virtual biopsy of primary CNS lymphomas.

Background: Primary central nervous system lymphomas (PCNSL) pose a challenge as they may mimic gliomas on magnetic resonance imaging (MRI) imaging, compelling precise differentiation for appropriate treatment. This study focuses on developing an automated MRI-based workflow to distinguish between PCNSL and gliomas. Methods: MRI examinations of 240 therapy-naive patients (141 males and 99 females, mean age: 55.16 years) with cerebral gliomas and PCNSLs (216 gliomas and 24 PCNSLs), each comprising a non-contrast T1-weighted, fluid-attenuated inversion recovery (FLAIR), and contrast-enhanced T1-weighted sequence were included in the study. HD-GLIO, a pre-trained segmentation network, was used to generate segmentations automatically. To validate the segmentation efficiency, 237 manual segmentations were prepared (213 gliomas and 24 PCNSLs). Subsequently, radiomics features were extracted following feature selection and training of an XGBoost algorithm for classification. Results: The segmentation models for gliomas and PCNSLs achieved a mean Sørensen-Dice coefficient of 0.82 and 0.80 for whole tumors, respectively. Three classification models were developed in this study to differentiate gliomas from PCNSLs. The first model differentiated PCNSLs from gliomas, with an area under the curve (AUC) of 0.99 (F1-score: 0.75). The second model discriminated between high-grade gliomas and PCNSLs with an AUC of 0.91 (F1-score: 0.6), and the third model differentiated between low-grade gliomas and PCNSLs with an AUC of 0.95 (F1-score: 0.89). Conclusions: This study serves as a pilot investigation presenting an automated virtual biopsy workflow that distinguishes PCNSLs from cerebral gliomas. Prior to clinical use, it is necessary to validate the results in a prospective multicenter setting with a larger number of PCNSL patients.

Longitudinal impact of intracerebral low-grade glioma disease on health-related quality of life.

BACKGROUND: The aim of this study was to assess health-related quality of life (HRQOL) before and after treatment for intracerebral low-grade glioma. METHODS: Patients with low-grade glioma who underwent surgical tumor removal between 2012 and 2018 were eligible for this study. All individuals and their closest relatives received thorough preoperative (

KDM5B predicts temozolomide-resistant subclones in glioblastoma.

Adaptive plasticity to the standard chemotherapeutic temozolomide (TMZ) leads to glioblastoma progression. Here, we examine early stages of this process in patient-derived cellular models, exposing the human lysine-specific demethylase 5B (KDM5B) as a prospective indicator for subclonal expansion. By integration of a reporter, we show its preferential activity in rare, stem-like ALDH1A1+ cells, immediately increasing expression upon TMZ exposure. Naive, genetically unmodified KDM5Bhigh cells phosphorylate AKT (pAKT) and act as slow-cycling persisters under TMZ. Knockdown of KDM5B reverses pAKT levels, simultaneously increasing PTEN expression and TMZ sensitivity. Pharmacological inhibition of PTEN rescues the effect. Interference with KDM5B subsequent to TMZ decreases cellular vitality, and clonal tracing with DNA barcoding demonstrates high individual levels of KDM5B to predict subclonal expansion already before TMZ exposure. Thus, KDM5Bhigh treatment-naive cells preferentially contribute to the dynamics of drug resistance under TMZ. These findings may serve as a cornerstone for future biomarker-assisted clinical trials.

Entirely noninvasive outcome prediction in central nervous system lymphomas using circulating tumor DNA.

ABSTRACT: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment.

Correlation of the apparent diffusion coefficient with the standardized uptake value in meningioma of the skull plane using [68]Ga-DOTATOC PET/MRI.

PURPOSE: To evaluate a correlation between an MRI-specific marker for cellular density [apparent diffusion coefficient (ADC)] and the expression of Somatostatin Receptors (SSTR) in patients with meningioma of the skull plane and orbital space. METHODS: 68 Ga-DOTATOC PET/MR imaging was performed in 60 Patients with suspected or diagnosed meningiomas of the skull base and eye socket. Analysis of ADC values succeeded in 32 patients. ADC values (ADC mean and ADC min ) were analyzed using a polygonal region of interest. Tracer-uptake of target lesions was assessed according to corresponding maximal (SUV max ) and mean (SUV mean ) values. Correlations between assessed parameters were evaluated using the Pearson correlation coefficient. RESULTS: One out of 32 patients (3%) was diagnosed with lymphoma by histopathological examination and therefore excluded from further analysis. Median ADC mean amounted to 822 × 10 -5  mm²/s -1 (95% CI: 570-1497) and median ADC min was 493 × 10 -5 mm 2 /s -1 (95% CI: 162-783). There were no significant correlations between SUV max and ADC min (r = 0.60; P  = 0.76) or ADC mean (r = -0.52; P  = 0.79), respectively. However, Pearson's test showed a weak, inverse but insignificant correlation between ADC mean and SUV mean (r = -0.33; P  = 0.07). CONCLUSION: The presented data displays no relevant correlations between increased SSTR expression and cellularity in patients with meningioma of the skull base. SSTR-PET and DWI thus may offer complementary information on tumor characteristics of meningioma.

Feasibility and tolerability of trofosfamide and etoposide in progressive glioblastoma.

Background: Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients. Methods: We collected clinicopathological data from adult progressive glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators' discretion balanced for tumor entity and canonical prognostic factors served as control. Results: A total of n = 22 progressive glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 vs 2.3 months, HR: 1.961, 95% CI: 0.9724-3.9560, P = .0274) and median overall survival (9.0 vs 5.7 months, HR: 4.687, 95% CI: 2.034-10.800, P = .0003) were significantly prolonged compared to the control cohort (n = 17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n = 16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n = 15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n = 11/15, 73%). Conclusions: This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients. The observed survival outcomes might suggest potential beneficial effects. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective trial.

Evaluation of [68Ga]-DOTATOC PET/MRI in Patients with Meningioma of the Subcranial and Intraorbital Space.

Meningiomas are known to express somatostatin receptor (SSTR) type 2 to a high degree. Therefore, radiolabeled somatostatin analogs, such as DOTATOC, have been introduced for PET imaging of meningiomas. However, the benefit of hybrid SSTR PET/MRI is still debated. Here, we report our experience with [68Ga]-DOTATOC PET/MRI. Methods: PET/MRI was performed in 60 patients with suspected or diagnosed meningiomas of the skull plane and eye socket. Acquired datasets were reported by 2 independent readers regarding local tumor extent and signal characteristics. Histopathologic results and follow-up imaging served as the reference standard. SUVs of target lesions were analyzed according to the corresponding maximal tracer uptake. The diagnostic accuracy of PET/MRI and conventional MRI was determined independently and compared with the reference standard. Results: In total, 60 target lesions were identified, with 54 considered to be meningiomas according to the reference standard. Sensitivity and specificity of PET/MRI versus MRI alone were 95% versus 96% and 75% versus 66%, respectively. The McNemar test was not able to distinguish any differences between PET/MRI and the reference standard or MRI and the reference standard. No differences were found between the 2 modalities with respect to local infiltration. Conclusion: SSTR PET/MRI and MRI yielded similar accuracy for the detection of meningiomas of the skull base and intraorbital space. Here, sequential low-dose SSTR PET/CT might be helpful for the planning of radioligand therapy or radiotherapy.

Location of Recurrences after Trimodality Treatment for Glioblastoma with Respect to the Delivered Radiation Dose Distribution and Its Influence on Prognosis.

BACKGROUND: While prognosis of glioblastoma after trimodality treatment is well examined, recurrence pattern with respect to the delivered dose distribution is less well described. Therefore, here we examine the gain of additional margins around the resection cavity and gross-residual-tumor. METHODS: All recurrent glioblastomas initially treated with radiochemotherapy after neurosurgery were included. The percentage overlap of the recurrence with the gross tumor volume (GTV) expanded by varying margins (10 mm to 20 mm) and with the 95% and 90% isodose was measured. Competing-risks analysis was performed in dependence on recurrence pattern. RESULTS: Expanding the margins from 10 mm to 15 mm, to 20 mm, to the 95%- and 90% isodose of the delivered dose distribution with a median margin of 27 mm did moderately increase the proportion of relative in-field recurrence volume from 64% to 68%, 70%, 88% and 88% (p < 0.0001). Overall survival of patients with in-and out-field recurrence was similar (p = 0.7053). The only prognostic factor significantly associated with out-field recurrence was multifocality of recurrence (p = 0.0037). Cumulative incidences of in-field recurrences at 24 months were 60%, 22% and 11% for recurrences located within a 10 mm margin, outside a 10 mm margin but within the 95% isodose, or outside the 95% isodose (p < 0.0001). Survival from recurrence was improved after complete resection (p = 0.0069). Integrating these data into a concurrent-risk model shows that extending margins beyond 10 mm has only small effects on survival hardly detectable by clinical trials. CONCLUSIONS: Two-thirds of recurrences were observed within a 10 mm margin around the GTV. Smaller margins reduce normal brain radiation exposure allowing for more extensive salvage radiation therapy options in case of recurrence. Prospective trials using margins smaller than 20 mm around the GTV are warranted.

A chance to cut is a chance to cure: complete resection of an atypical neurofibroma prevents further progression to malignancy.

Plexiform neurofibromas are the hallmark of neurofibromatosis type 1 (NF1) and significantly contribute to the overall burden of disease. While surgical excision has long been the only available therapy, the MEK inhibitor (MEKi) selumetinib has been approved as a non-surgical treatment option for these tumors in 2020 (USA) and 2021 (Europe), respectively. However, selumetinib will result in tumor shrinkage only after several months of therapy and might not prevent malignant transformation of a plexiform neurofibroma that occurs with a frequency of 10-15%. Here, we demonstrate that surgical excision might be the therapy of choice in some plexiform neurofibromas despite the availability of MEKi therapy.

A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma.

PURPOSE: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. EXPERIMENTAL DESIGN: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. RESULTS: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. CONCLUSIONS: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.

Cerebral Taenia crassiceps larvae infection in a 71-year-old immunocompetent male.

We report a rare case of a cerebral infection with Taenia crassiceps tapeworm larvae in an immunocompetent 71-year-old German male. Initially, an intracerebral malignoma was suspected after the patient experienced stroke-like symptoms. After surgery, helminth larvae, later identified as T. crassiceps, were detected. Identification on the species level was possible by specific PCR and sequencing. After complete surgical removal, the patient was treated with albendazole and dexamethasone for two weeks. No residual symptoms were reported up to date.

Precision neuro-oncology: a pilot analysis of personalized treatment in recurrent glioma.

PURPOSE: When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse. METHODS: We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted. RESULTS: The investigation included 41 patients, of whom 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357). CONCLUSION: These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue.

First multicentric real-life experience with the combination of CCNU and temozolomide in newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma.

Background: The randomized phase 3 CeTeG/NOA-09 trial assessed whether CCNU plus temozolomide was superior to temozolomide alone in newly diagnosed MGMT promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months (temozolomide) to 48.1 months (CCNU plus temozolomide). In view of this encouraging data, we assessed safety and efficacy of this regimen under real-life conditions. Methods: We retrospectively collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma patients from five neuro-oncology centers in Germany. For inclusion in our analysis, treatment with CCNU and temozolomide had to be performed for at least six weeks (one course). Results: Seventy patients were included. Median progression-free survival was 14.4 months and median overall survival 33.8 months. Patients with TTFields treatment for at least 8 weeks and CCNU plus temozolomide (n = 22, 31%) had a prolonged progression-free survival compared to those with TTFields treatment for less than eight weeks (n = 48, 69%) (21.5 versus 11.2 months; P = .0105). In a multivariable Cox regression analysis, TTFields treatment for eight weeks or longer together with CCNU plus temozolomide and a Karnofsky performance score ≥ 90% were independent prognostic factors for progression-free and overall survival. Pseudoprogression occurred in n = 16 (33%) of investigated n = 49 (70%) patients. In n = 31 (44%) patients high-grade hematotoxicity was observed. Conclusions: The results from this multicentric trial indicate that-under real-life conditions-toxicity and survival estimates are comparable to the CeTeG/NOA-09 trial. TTFields therapy for at least eight weeks in combination with this regimen was independently associated with prolonged survival.

Prevalence and predictors of neurological manifestations in systemic AL amyloidosis.

INTRODUCTION: Immunoglobulin light chain (AL) amyloidosis is a life-threatening systemic disease due to plasma cell dyscrasias, which is characterized by amyloid deposition in various tissues. Neurological manifestations, in particular peripheral nervous system involvement, play a major role for quality of life and treatment decisions as frequently potentially neurotoxic drugs are used. METHODS: We retrospectively investigated the prevalence of neurological manifestations, its risk factors and prognostic value in 155 consecutive patients with AL amyloidosis in a single German tertiary center between 2010 and 2021. Multiple logistic regression was performed to identify predictors of amyloid neuropathy and the impact of peripheral neuropathy on patient survival was assessed by Cox proportional hazard regression analysis. RESULTS: Nearly half of patients showed at least one of four neurological manifestations of AL amyloidosis which were frequent in our study: peripheral neuropathy (36.8%), carpal tunnel syndrome (12.9%), lumbar spinal stenosis (7.1%), and amyloid myopathy (3.9%). Male sex (OR 2.943, CI 1.152-8.139, p = 0.029) and cardiac involvement (OR 6.186, CI 1.449-43.38, p = 0.028) were independent predictors of peripheral neuropathy which was closely related to autonomic dysfunction in patients with AL amyloidosis. Peripheral neuropathy had no impact on survival (HR 0.952, CI 0.517-1.754, p = 0.876). CONCLUSIONS: Neurological involvement is common in systemic AL amyloidosis. Treatment decisions should take into account peripheral neuropathy, in particular in male patients with amyloid cardiomyopathy, but also amyloid myopathy that seems to be not as rare as previously suggested.

Surgery of Motor Eloquent Glioblastoma Guided by TMS-Informed Tractography: Driving Resection Completeness Towards Prolonged Survival.

Background: Surgical treatment of patients with glioblastoma affecting motor eloquent brain regions remains critically discussed given the risk-benefit dilemma of prolonging survival at the cost of motor-functional damage. Tractography informed by navigated transcranial magnetic stimulation (nTMS-informed tractography, TIT) provides a rather robust estimate of the individual location of the corticospinal tract (CST), a highly vulnerable structure with poor functional reorganisation potential. We hypothesised that by a more comprehensive, individualised surgical decision-making using TIT, tumours in close relationship to the CST can be resected with at least equal probability of gross total resection (GTR) than less eloquently located tumours without causing significantly more gross motor function harm. Moreover, we explored whether the completeness of TIT-aided resection translates to longer survival. Methods: A total of 61 patients (median age 63 years, m = 34) with primary glioblastoma neighbouring or involving the CST were operated on between 2010 and 2015. TIT was performed to inform surgical planning in 35 of the patients (group T; vs. 26 control patients). To achieve largely unconfounded group comparisons for each co-primary outcome (i.e., gross-motor functional worsening, GTR, survival), (i) uni- and multivariate regression analyses were performed to identify features of optimal outcome prediction; (ii), optimal propensity score matching (PSM) was applied to balance those features pairwise across groups, followed by (iii) pairwise group comparison. Results: Patients in group T featured a significantly higher lesion-CST overlap compared to controls (8.7 ± 10.7% vs. 3.8 ± 5.7%; p = 0.022). The frequency of gross motor worsening was higher in group T, albeit non-significant (n = 5/35 vs. n = 0/26; p = 0.108). PSM-based paired-sample comparison, controlling for the confounders of preoperative tumour volume and vicinity to the delicate vasculature of the insula, showed higher GTR rates in group T (77% vs. 69%; p = 0.025), particularly in patients with a priori intended GTR (87% vs. 78%; p = 0.003). This translates into a prolonged PFS in the same PSM subgroup (8.9 vs. 5.8 months; p = 0.03), with GTR representing the strongest predictor of PFS (p = 0.001) and OS (p = 0.0003) overall. Conclusion: The benefit of TIT-aided GTR appears to overcome the drawbacks of potentially elevated motor functional risk in motor eloquent tumour localisation, leading to prolonged survival of patients with primary glioblastoma close to the CST.

A New Subform? Fast-Progressing, Severe Neurological Deterioration Caused by Spinal Epidural Lipomatosis.

Spinal epidural lipomatosis (SEL) is a rare condition caused by hypertrophic growth of epidural fat. The prevalence of SEL in the Western world is approximately 1 in 40 patients and is likely to increase due to current medical and socio-economic developments. Rarely, SEL can lead to rapid severe neurological deterioration. The pathophysiology, optimal treatment, and outcome of these patients remain unclear. This study aims to widen current knowledge about this "SEL subform" and to improve its clinical management. A systematic literature review according to the PRISMA guidelines using PubMed, Scopus, Web of Science, and Cochrane Library was used to identify publications before 7 November 2021 reporting on acute/rapidly progressing, severe SEL. The final analysis comprised 12 patients with acute, severe SEL. The majority of the patients were male (9/12) and multimorbid (10/12). SEL mainly affected the thoracic part of the spinal cord (11/12), extending a median number of 7 spinal levels (range: 4-19). Surgery was the only chosen therapy (11/12), except for one critically ill patient. Regarding the outcome, half of the patients regained independence (6/11; = modified McCormick Scale ≤ II). Acute, severe SEL is a rare condition, mainly affecting multimorbid patients. The prognosis is poor in nearly 50% of the patients, even with maximum therapy. Further research is needed to stratify patients for conservative or surgical treatment.

Tumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression.

Brain tumors are typically immunosuppressive and refractory to immunotherapies for reasons that remain poorly understood. The unbiased profiling of immune cell types in the tumor microenvironment may reveal immunologic networks affecting therapy and course of disease. Here we identify and validate the presence of hematopoietic stem and progenitor cells (HSPCs) within glioblastoma tissues. Furthermore, we demonstrate a positive link of tumor-associated HSPCs with malignant and immunosuppressive phenotypes. Compared to the medullary hematopoietic compartment, tumor-associated HSPCs contain a higher fraction of immunophenotypically and transcriptomically immature, CD38- cells, such as hematopoietic stem cells and multipotent progenitors, express genes related to glioblastoma progression and display signatures of active cell cycle phases. When cultured ex vivo, tumor-associated HSPCs form myeloid colonies, suggesting potential in situ myelopoiesis. In experimental models, HSPCs promote tumor cell proliferation, expression of the immune checkpoint PD-L1 and secretion of tumor promoting cytokines such as IL-6, IL-8 and CCL2, indicating concomitant support of both malignancy and immunosuppression. In patients, the amount of tumor-associated HSPCs in tumor tissues is prognostic for patient survival and correlates with immunosuppressive phenotypes. These findings identify an important element in the complex landscape of glioblastoma that may serve as a target for brain tumor immunotherapies.

Prediction of survival in patients with IDH-wildtype astrocytic gliomas using dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine PET.

PURPOSE: Integrated histomolecular diagnostics of gliomas according to the World Health Organization (WHO) classification of 2016 has refined diagnostic accuracy and prediction of prognosis. This study aimed at exploring the prognostic value of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in newly diagnosed, histomolecularly classified astrocytic gliomas of WHO grades III or IV. METHODS: Before initiation of treatment, dynamic FET PET imaging was performed in patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA). Static FET PET parameters such as maximum and mean tumour/brain ratios (TBRmax/mean), the metabolic tumour volume (MTV) as well as the dynamic FET PET parameters time-to-peak (TTP) and slope, were obtained. The predictive ability of FET PET parameters was evaluated concerning the progression-free and overall survival (PFS, OS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate Kaplan-Meier and multivariate Cox regression survival analyses were performed to assess the predictive power of these parameters for survival. RESULTS: Sixty patients (45 GBM and 15 AA patients) of two university centres were retrospectively identified. Patients with isocitrate dehydrogenase (IDH)-mutant or O6-methylguanine-DNA-methyltransferase (MGMT) promoter-methylated tumours had a significantly longer PFS and OS (both P < 0.001). Furthermore, ROC analysis of IDH-wildtype glioma patients (n = 45) revealed that a TTP > 25 min (AUC, 0.90; sensitivity, 90%; specificity, 87%; P < 0.001) was highly prognostic for longer PFS (13 vs. 7 months; P = 0.005) and OS (29 vs. 12 months; P < 0.001). In contrast, at a lower level of significance, TBRmax, TBRmean, and MTV were only prognostic for longer OS (P = 0.004, P = 0.038, and P = 0.048, respectively). Besides complete resection and a methylated MGMT promoter, TTP remained significant in multivariate survival analysis (all P ≤ 0.02), indicating an independent predictor for OS. CONCLUSIONS: Our data suggest that dynamic FET PET allows the identification of patients with longer OS among patients with newly diagnosed IDH-wildtype GBM and AA.

Tumour Treating Fields (TTFields) in combination with lomustine and temozolomide in patients with newly diagnosed glioblastoma.

PURPOSE: In the EF-14 trial for newly diagnosed glioblastoma (ndGBM) patients addition of Tumour Treating Fields (TTFields) to temozolomide treatment resulted in a significantly improved overall survival (OS). In the NOA-09/CeTeG trial, combination of lomustine and temozolomide was superior to temozolomide monotherapy in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylated (MGMTm) ndGBM. We evaluated combination of these two treatment modalities in patients with MGMTm ndGBM. There have been so far no data on the combination of these two efficient regimens. METHODS: This bicentric retrospective analysis investigated 16 patients. Parameters evaluated included safety outcome as measured by Common Toxicity Criteria for Adverse Events (CTCAE), clinical outcomes, and compliance to treatment. RESULTS: Hematologic adverse events CTCAE ≥ 3 were observed in seven, hepatotoxic adverse events of CTCAE ≥ 3 in four patients. Mild to moderate skin toxicity was detected in six patients. At data cutoff, patients demonstrated a median progression-free survival (PFS) of 20 months. The usage rate of TTFields showed a high median adherence (83%) to the therapy. CONCLUSIONS: This analysis provides first indication that the combination of TTFields/lomustine/temozolomide is safe and feasible. The observed survival outcomes might suggest potential beneficial effects.