In glioma patients, the differentiation between tumor progression (TP) and treatment-related changes (TRC) remains challenging. Difficulties in classifying imaging alterations may result in a delay or an unnecessary discontinuation of treatment. Positron emission tomography (PET) using O-(2-[¹⁸F]fluoroethyl-)-L-tyrosine (¹⁸F-FET) has been shown to be a useful tool for detecting TP and TRC. Methods: We retrospectively evaluated 127 consecutive patients with WHO grade II-IV glioma who underwent ¹⁸F-FET PET imaging in order to distinguish between TP and TRC. ¹⁸F-FET PET findings were verified by neuropathology (40 patients) or clinico-radiological follow-up (87 patients). Maximum tumor to brain ratios (TBRmax) of ¹⁸F-FET uptake and the slope of the time-activity curves (20-50 min post injection) were determined. Diagnostic accuracy of ¹⁸F-FET PET parameters was evaluated by Receiver-Operating-Characteristic (ROC) analysis and chi-square test. The prognostic value of ¹⁸F-FET PET was estimated using the Kaplan-Meier method. Results: TP was diagnosed in 94 patients (74%) and TRC in 33 (26%). For differentiating TP and TRC, ROC analysis yielded an optimal ¹⁸F-FET TBRmax cut-off value of 1.95 (sensitivity 70%, specificity 71%, accuracy 70%, AUC 0.75 ± 0.05). The highest accuracy was achieved by a combination of TBRmax and slope (sensitivity 86%, specificity 67%, accuracy 81%). However, accuracy was poorer when tumors harbored isocitrate dehydrogenase (IDH) mutations (91% in IDH-wildtype, 67% in IDH-mutant tumors, P < 0.001). ¹⁸F-FET PET results correlated with overall survival (P < 0.001). Conclusion: In our neuro-oncology department, diagnostic performance of ¹⁸F-FET PET was convincing but slightly inferior to that of previous reports.

(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients’ serum and CSF. (3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients. (4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.

The TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to decrease glycolysis, to activate the pentose phosphate pathway, and to provide protection against oxidative damage. Hypoxic regions are considered characteristic of glioblastoma and linked with resistance to current treatment strategies. Here, we established that LNT-229 glioma cell lines stably expressed shRNA constructs targeting TIGAR, and exposed them to hypoxia, irradiation and temozolomide. The disruption of TIGAR enhanced levels of reactive oxygen species and cell death under hypoxic conditions, as well as the effectiveness of irradiation and temozolomide. In addition, TIGAR was upregulated by HIF-1α. As a component of a complex network, TIGAR contributes to the metabolic adjustments that arise from either spontaneous or therapy-induced changes in tumor microenvironment.

In several tumor entities, transketolase-like protein 1 (TKTL1) has been suggested to promote the nonoxidative part of the pentose phosphate pathway (PPP) and thereby to contribute to a malignant phenotype. However, its role in glioma biology has only been sparsely documented. In the present in vitro study using LNT-229 glioma cells, we analyzed the impact of TKTL1 gene suppression on basic metabolic parameters and on survival following oxygen restriction and ionizing radiation. TKTL1 was induced by hypoxia and by hypoxia-inducible factor-1α (HIF-1α). Knockdown of TKTL1 via shRNA increased the cells’ demand for glucose, decreased flux through the PPP and promoted cell death under hypoxic conditions. Following irradiation, suppression of TKTL1 expression resulted in elevated levels of reactive oxygen species (ROS) and reduced clonogenic survival. In summary, our results indicate a role of TKTL1 in the adaptation of tumor cells to oxygen deprivation and in the acquisition of radioresistance. Further studies are necessary to examine whether strategies that antagonize TKTL1 function will be able to restore the sensitivity of glioma cells towards irradiation and antiangiogenic therapies in the more complex in vivo environment.

Suspected adverse reactions following chimeric antigen receptor T-cell (CAR T) treatment include more and more cases of secondary T-cell malignancies. The causality assessment of such suspected reactions challenges established evaluation practices due to (i) patient and product-specific risk factors and (ii) incomplete data available with post-marketing reports submitted to competent authorities. This is of particular relevance for gene therapy products that integrate into the host genome. We present a summary of case reports related to different CAR T products and the rationale for case causality assessment. In this context, possible pathophysiologic mechanisms and differences between CAR T products to be taken into account are discussed. The unparalleled complexity of the case follow-up and the multistep process of cancer development necessitates a case-by-case consideration. This highlights challenges in the pharmacovigilance of advanced therapy medicinal products and underlines the importance of testing for vector presence, integration location and gene expression profile for an informed case assessment of suspected secondary malignancies with the aim to obtain a better understanding of contributing factors.

Quantitative MRI allows to probe tissue properties by measuring relaxation times and may thus detect subtle changes in tissue composition. In this work we analyzed different relaxation times (T1, T2, T2* and T2′) and histological features in 321 samples that were acquired from 25 patients with newly diagnosed IDH wild-type glioma. Quantitative relaxation times before intravenous application of gadolinium-based contrast agent (GBCA), T1 relaxation time after GBCA as well as the relative difference between T1 relaxation times pre-to-post GBCA (T1rel) were compared with histopathologic features such as the presence of tumor cells, cell and vessel density, endogenous markers for hypoxia and cell proliferation. Image-guided stereotactic biopsy allowed for the attribution of each tissue specimen to its corresponding position in the respective relaxation time map. Compared to normal tissue, T1 and T2 relaxation times and T1rel were prolonged in samples containing tumor cells. The presence of vascular proliferates was associated with higher T1rel values. Immunopositivity for lactate dehydrogenase A (LDHA) involved slightly longer T1 relaxation times. However, low T2′ values, suggesting high amounts of deoxyhemoglobin, were found in samples with elevated vessel densities, but not in samples with increased immunopositivity for LDHA. Taken together, some of our observations were consistent with previous findings but the correlation of quantitative MRI and histologic parameters did not confirm all our pathophysiology-based assumptions.