Rotor-based image-guided therapy of glioblastoma.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.

Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM.

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.

Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Recurrent Glioblastoma and Radiation Necrosis: A Single-Surgeon Case Series.

OBJECTIVE: To evaluate long-term clinical outcomes among patients treated with laser interstitial thermal therapy (LITT) for predicted recurrent glioblastoma (rGBM). METHODS: Patients with rGBM treated by LITT by a single surgeon (2013-2020) were evaluated for progression-free survival (PFS), overall survival (OS), and OS after LITT. RESULTS: Forty-nine patients (33 men, 16 women; mean [SD] age at diagnosis, 58.7 [12.5] years) were evaluated. Among patients with genetic data, 6 of 34 (18%) had IDH-1 R132 mutations, and 7 of 21 (33%) had MGMT methylation. Patients underwent LITT at a mean (SD) of 23.8 (23.8) months after original diagnosis. Twenty of 49 (40%) had previously undergone stereotactic radiosurgery, 37 (75%) had undergone intensity-modulated radiation therapy, and 49 (100%) had undergone chemotherapy. Patients had undergone a mean of 1.2 (0.7) previous resections before LITT. Mean preoperative enhancing and T2 FLAIR volumes were 13.1 (12.8) cm3 and 35.0 (32.8) cm3, respectively. Intraoperative biopsies confirmed rGBM in 31 patients (63%) and radiation necrosis in 18 patients (37%). Six perioperative complications occurred: 3 (6%) cases of worsening aphasia, 1 (2%) seizure, 1 (2%) epidural hematoma, and 1 (2%) intraparenchymal hemorrhage. For the rGBM group, median PFS was 2.0 (IQR, 4.0) months, median OS was 20.0 (IQR, 29.5) months, and median OS after LITT was 6.0 (IQR, 10.5) months. For the radiation necrosis group, median PFS was 4.0 (IQR, 4.5) months, median OS was 37.0 (IQR, 58.0) months, and median OS after LITT was 8.0 (IQR, 23.5) months. CONCLUSIONS: In a diverse rGBM cohort, LITT was associated with a short duration of posttreatment PFS.

A NEW HYPOTHESIS IN THE TREATMENT OF RECURRENT GLIOBLASTOMA MULTIFORME (GBM). PART 2: IS THERE AN ALTERNATIVE THERAPY OPTION IN RECURRENT GM WHEN ALL STANDARD TREATMENTS HAVE BEEN EXHAUSTED?

Glioblastoma multiforme (GBM) is the most aggressive and malignant brain tumor. The average survival time for a patient diagnosed with GBM, using standard treatment methods, is several months. Besides the routinely applied treatments such as neurosurgery, radiotherapy, and chemotherapy, progress is being made in the field of oncology, offering hope for improved treatment outcomes. New treatment methods include individualized multimodal immunotherapy (IMI) and modulated electro-hyperthermia. The coauthor of the above series of articles (parts 1 and 2) - A.Cz. presents the concept of a new, potentially breakthrough treatment option for recurrent GBM. A.Cz. was diagnosed with GBM in August 2021. Exhaustion of standard treatment methods, as well as immunotherapy and virotherapy, only provided temporary relief. Unfortunately, after a few months, the disease recurred. Having little to lose, A.Cz. accepted an ablative dose of 2960 MBq (80 mCi) of I131, based on available literature data. Three days before the administration of radioiodine therapy (RIT), A.Cz. prophylactically blocked the thyroid's ability to absorb the radioisotope. In June 2023, approximately 7 weeks after receiving single I131 dose, the MRI examination confirmed a 30% reduction in the tumor's size. Based on this, one can speculate that Iodine-131 therapy may be an alternative treatment option for GBM patients in the future. However, this hypothesis requires confirmation in further clinical studies.

Concept of a fully-implantable system to monitor tumor recurrence.

Current treatment for glioblastoma includes tumor resection followed by radiation, chemotherapy, and periodic post-operative examinations. Despite combination therapies, patients face a poor prognosis and eventual recurrence, which often occurs at the resection site. With standard MRI imaging surveillance, histologic changes may be overlooked or misinterpreted, leading to erroneous conclusions about the course of adjuvant therapy and subsequent interventions. To address these challenges, we propose an implantable system for accurate continuous recurrence monitoring that employs optical sensing of fluorescently labeled cancer cells and is implanted in the resection cavity during the final stage of tumor resection. We demonstrate the feasibility of the sensing principle using miniaturized system components, optical tissue phantoms, and porcine brain tissue in a series of experimental trials. Subsequently, the system electronics are extended to include circuitry for wireless energy transfer and power management and verified through electromagnetic field, circuit simulations and test of an evaluation board. Finally, a holistic conceptual system design is presented and visualized. This novel approach to monitor glioblastoma patients is intended to early detect recurrent cancerous tissue and enable personalization and optimization of therapy thus potentially improving overall prognosis.

[18F]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: protocol for a prospective, multicentre PET/CT trial.

INTRODUCTION: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. METHODS AND ANALYSIS: The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. ETHICS AND DISSEMINATION: The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12619001735145.

Applying a Radiation Therapy Volume Analysis Pipeline to Determine the Utility of Spectroscopic MRI-Guided Adaptive Radiation Therapy for Glioblastoma.

Accurate radiation therapy (RT) targeting is crucial for glioblastoma treatment but may be challenging using clinical imaging alone due to the infiltrative nature of glioblastomas. Precise targeting by whole-brain spectroscopic MRI, which maps tumor metabolites including choline (Cho) and N-acetylaspartate (NAA), can quantify early treatment-induced molecular changes that other traditional modalities cannot measure. We developed a pipeline to determine how spectroscopic MRI changes during early RT are associated with patient outcomes to provide insight into the utility of adaptive RT planning. Data were obtained from a study (NCT03137888) where glioblastoma patients received high-dose RT guided by the pre-RT Cho/NAA twice normal (Cho/NAA ≥ 2x) volume, and received spectroscopic MRI scans pre- and mid-RT. Overlap statistics between pre- and mid-RT scans were used to quantify metabolic activity changes after two weeks of RT. Log-rank tests were used to quantify the relationship between imaging metrics and patient overall and progression-free survival (OS/PFS). Patients with lower Jaccard/Dice coefficients had longer PFS (p = 0.045 for both), and patients with lower Jaccard/Dice coefficients had higher OS trending towards significance (p = 0.060 for both). Cho/NAA ≥ 2x volumes changed significantly during early RT, putting healthy tissue at risk of irradiation, and warranting further study into using adaptive RT planning.

A local water molecular-heating strategy for near-infrared long-lifetime imaging-guided photothermal therapy of glioblastoma.

Owing to the strong absorption of water in the near-infrared (NIR) region near 1.0 µm, this wavelength is considered unsuitable as an imaging and analytical signal in biological environments. However, 1.0 µm NIR can be converted into heat and used as a local water-molecular heating strategy for the photothermal therapy of biological tissues. Herein, we describe a Nd-Yb co-doped nanomaterial (water-heating nanoparticles (NPs)) as strong 1.0 µm emissive NPs to target the absorption band of water. Furthermore, introducing Tm ions into the water-heating NPs improve the NIR lifetime, enabling the development of a NIR imaging-guided water-heating probe (water-heating NIR NPs). In the glioblastoma multiforme male mouse model, tumor-targeted water-heating NIR NPs reduce the tumor volume by 78.9% in the presence of high-resolution intracranial NIR long-lifetime imaging. Hence, water-heating NIR NPs can be used as a promising nanomaterial for imaging and photothermal ablation in deep-tissue-bearing tumor therapy.

Maximum Emission Peak Over 1500 nm of Organic Assembly for Blood-Brain Barrier-Crossing NIR-IIb Phototheranostics of Orthotopic Glioblastoma.

The development of blood-brain barrier (BBB)-crossing phototheranostic agents in second near-infrared window (NIR-II), especially in the range of 1500-1700 nm (NIR-IIb), affords great opportunities for glioblastoma (GBM) management. Herein, an organic assembly (denoted as LET-12) with the maximum absorption peak at 1400 nm and emission peak at 1512 nm with trailing over 1700 nm through the self-assembly of organic small molecule IR-1064 is designed and subsequently decorated with choline and acetylcholine analogs. The LET-12 can effectively cross BBB through the brain's choline-like receptors-mediated transcytosis and accumulated in tumor tissues, thus achieving fluorescence/photoacoustic (FL/PA) duplex imaging of orthotopic GBM with ≈3.0 mm depth and a superior tumor-to-normal tissue signal ratio (20.93 ± 0.59 for FL imaging and 32.63 ± 1.16 for PA imaging, respectively). Owing to its good photothermal conversion ability, the LET-12 also can serve as a photothermal conversion agent, achieving obvious tumor repression of orthotopic murine GBM model after once treatment. The findings indicate that the LET-12 holds great potential for BBB-crossing NIR-IIb phototheranostics of orthotopic GBM. This self-assembly strategy of organic small molecules opens a new avenue for the construction of NIR-IIb phototheranostics.

NIR-II Perylene Monoimide-Based Photothermal Agent with Strengthened Donor-Acceptor Conjugation for Deep Orthotopic Glioblastoma Phototheranostics.

Extensive efforts have been devoted to the design of organic photothermal agents (PTAs) that absorb in the second near-infrared (NIR-II) bio-window, which can provide deeper tissue penetration that is significant for phototheranostics of lethal brain tumors. Herein, the first example of NIR-II-absorbing small organic molecule (N1) derived from perylene monoamide (PMI) and its bio-application after nano-encapsulation of N1 to function as a nano-agent for phototheranostics of deep orthotopic glioblastoma (GBM) is reported. By adopting a dual modification strategy of introducing a donor-acceptor unit and extending π-conjugation, the obtained N1 can absorb in 1000-1400 nm region and exhibit high photothermal conversation due to the apparent intramolecular charge transfer (ICT). A choline analogue, 2-methacryloyloxyethyl phosphorylcholine, capable of interacting specifically with receptors on the surface of the blood-brain barrier (BBB), is used to fabricate the amphiphilic copolymer for the nano-encapsulation of N1. The obtained nanoparticles demonstrate efficient BBB-crossing due to the receptor-mediated transcytosis as well as the small nanoparticle size of approximately 26 nm. The prepared nanoparticles exhibit excellent photoacoustic imaging and significant growth inhibition of deep orthotopic GBM. The current study demonstrates the enormous potential of PMI-based NIR-II PTAs and provides an efficient phototheranostic paradigm for deep orthotopic GBM.

Undesired impact of iron supplement on MRI assessment of post-treatment glioblastoma.

Glioblastoma (GBM) is the most common malignant adult brain and has a poor prognosis. Routine post-treatment MRI evaluations are required to assess treatment response and disease progression. We present a case of an 83-year-old female who underwent MRI assessment of post-treatment GBM after intravenous iron replacement therapy, ferumoxytol. The brain MRI revealed unintended alteration of MRI signal characteristics from the iron containing agent which confounded diagnostic interpretation and subsequently, the treatment planning. Ferumoxytol injection prior to contrast enhanced MRI must be screened in post-treatment GBM patients to accurately evaluate tumor activity.

NIR-II absorptive dithienopyrrole-thiadiazolobenzotriazole conjugated polymer for photoacoustic imaging-guided glioblastoma multiforme photothermal therapy.

The development of new diagnostic imaging and precise treatment methods for glioblastoma multiforme (GBM) is significant to improve patients' quality of life and prolong their survival time. Herein, we proposed a photoacoustic imaging (PAI)-guided GBM high-efficient photothermal therapy (PTT) based on a second near-infrared (NIR-II) absorptive polymer (PDTP-TBZ) conjugated with intense electron donor dithienopyrrole (DTP) and strong electron acceptor thiadiazolobenzotriazole (TBZ). By nanoprecipitation, PDTP-TBZ can form into nanoparticles (PT NPs), and c(RGDfK) cyclic peptide with integrin-specific targeting was then modified on the surface of PT NPs to obtain the ability of active targeting GBM multifunctional nano-reagent (cRGD@PT NPs). Both in vitro and in vivo experiments demonstrated that cRGD@PT NPs as NIR-II GBM phototheranostic reagents can greatly improve the enrichment rate at tumor sites under PAI monitoring, and carry out precise NIR-II PTT with high effective tumor cell phototoxicity and high biological safety. Thus, cRGD@PT NPs have great potential for the future GBM phototheranostic application in clinic. STATEMENT OF SIGNIFICANCE: In this work, we successfully constructed an intense electron donor dithienopyrrole (DTP) with a strong electron acceptor thiadiazolobenzotriazole (TBZ) into a novel NIR-II optical absorptive conjugated polymer (PDTP-TBZ). Then, the c(RGDfK) cyclic peptide was modified on the surface of PT NPs to obtain multifunctional nanodiagnostic reagents (cRGD@PT NPs) that can effectively target GBM neovascularization and tumor cells. Both in vitro and in vivo experiments demonstrate that cRGD@PT NPs possess high photothermal conversion efficiency and practical photoacoustic imaging capability under 1064 nm laser irradiation. The results of this work suggested that cRGD@PT NPs have great potential in efficient NIR-II PTT guided by accurate PAI, which provide a good perspective for the treatment and diagnosis of GBM.

Detection of glioblastoma multiforme using quantitative molecular magnetic resonance imaging based on 5-aminolevulinic acid: in vitro and in vivo studies.

OBJECTIVES: We demonstrated a novel metabolic method based on sequential administration of 5-aminolevulinic acid (ALA) and iron supplement, and ferric ammonium citrate (FAC), for glioblastoma multiforme (GBM) detection using R2' and quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: Intra-cellular iron accumulation in glioblastoma cells treated with ALA and/or FAC was measured. Cell phantoms containing glioblastoma cells and Wistar rats bearing C6 glioblastoma were imaged using a 3 T MRI scanner after sequential administration of ALA and FAC. The relaxivity and QSM analysis were performed on the images. RESULTS: The intra-cellular iron deposition was significantly higher in the glioma cells with sequential treatment of ALA and FAC for 6 h compared to those treated with the controls. The relaxivity and magnetic susceptibility values of the glioblastoma cells and rat brain tumors treated with ALA + FAC (115 ± 5 s-1 for R2', and 0.1 ± 0.02 ppm for magnetic susceptibility) were significantly higher than those treated with the controls (55 ± 18 (FAC), 45 ± 15 (ALA) s-1 for R2', p < 0.05, and 0.03 ± 0.03 (FAC), 0.02 ± 0.02 (ALA) ppm for magnetic susceptibility, p < 0.05). DISCUSSION: Sequential administration of ALA and iron supplements increases the iron deposition in glioblastoma cells, enabling clinical 3 T MRI to detect GBM using R2' or QSM.

Neodymium (3+)-Coordinated Black Phosphorus Quantum Dots with Retrievable NIR/X-Ray Optoelectronic Switching Effect for Anti-Glioblastoma.

Heteroatom interaction of atomically thin nanomaterials enables the improvement of electronic transfer, band structure, and optical properties. Black phosphorus quantum dots (BP QDs) are considered to be candidate diagnostic and/or therapeutic agents due to their innate biocompatibility and exceptional photochemical effects. However, BP QDs are not competitive regarding second near-infrared (NIR-II) window medical diagnosis and X-ray induced phototherapy. Here, an Nd3+ ion coordinated BP QD (BPNd) is synthesized with the aim to sufficiently improve its performances in NIR-II fluorescence imaging and X-ray induced photodynamic therapy, benefitting from the retrievable NIR/X-ray optoelectronic switching effects between BP QD and Nd3+ ion. Given its ultrasmall size and efficient cargo loading capacity, BPNd can easily cross the blood-brain barrier to precisely monitor the growth of glioblastoma through intracranial NIR-II fluorescence imaging and impede its progression by specific X-ray induced, synergistic photodynamic chemotherapy.

The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns.

PURPOSE: Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. METHODS AND MATERIALS: Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. RESULTS: Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. CONCLUSIONS: There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.

PET/MR in recurrent glioblastoma patients treated with regorafenib: [18F]FET and DWI-ADC for response assessment and survival prediction.

OBJECTIVE: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. Diffusion-weighted imaging and O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in diffusion-weighted imaging/apparent diffusion coefficient (ADC) and [18F]FET PET-derived parameters in patients who underwent PET/MR at both baseline and after starting regorafenib. METHODS: We retrospectively reviewed 16 consecutive GBM patients who underwent [18F]FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze four SD patients who underwent a third PET/MR after another four cycles of regorafenib. [18F]FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and after treatment. Several metrics were then derived and compared. Log-rank test was applied for overall survival analysis. RESULTS: Percentage difference in FET volumes correlates with the corresponding percentage difference in ADC (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Kaplan-Meier analysis, performed to compare the performance in overall survival prediction, revealed that the percentage variations of FET- and ADC-derived metrics performed at least as well as RANO criteria (p = 0.02, p = 0.024 and p = 0.04 respectively) and in some cases even better. TBR Max and TBR mean are not able to accurately predict overall survival. CONCLUSION: In recurrent glioblastoma patients treated with regorafenib, [18F]FET and ADC metrics, are able to predict overall survival and being obtained from completely different measures as compared to RANO, could serve as semi-quantitative independent biomarkers of response to treatment. ADVANCES IN KNOWLEDGE: Simultaneous evaluation of [18F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival.

Diffuse midline gliomas, H3 K27M-mutant are associated with less peritumoral edema and contrast enhancement in comparison to glioblastomas, H3 K27M-wildtype of midline structures.

PURPOSE: The entity 'diffuse midline glioma, H3 K27M-mutant (DMG)' was introduced in the revised 4th edition of the 2016 WHO classification of brain tumors. However, there are only a few reports on magnetic resonance imaging (MRI) of these tumors. Thus, we conducted a retrospective survey focused on MRI features of DMG compared to midline glioblastomas H3 K27M-wildtype (mGBM-H3wt). METHODS: We identified 24 DMG cases and 19 mGBM-H3wt patients as controls. After being retrospectively evaluated for microscopic evidence of microvascular proliferations (MVP) and tumor necrosis by two experienced neuropathologists to identify the defining histological criteria of mGBM-H3wt, the samples were further analyzed by two experienced readers regarding imaging features such as shape, peritumoral edema and contrast enhancement. RESULTS: The DMG were found in the thalamus in 37.5% of cases (controls 63%), in the brainstem in 50% (vs. 32%) and spinal cord in 12.5% (vs. 5%). In MRI and considering MVP, DMG were found to be by far less likely to develop peritumoral edema (OR: 0.13; 95%-CL: 0.02-0.62) (p = 0.010). They, similarly, were associated with a significantly lower probability of developing strong contrast enhancement compared to mGBM-H3wt (OR: 0.10; 95%-CL: 0.02-0.47) (P = 0.003). CONCLUSION: Despite having highly variable imaging features, DMG exhibited markedly less edema and lower contrast enhancement in MRI compared to mGBM-H3wt. Of these features, the enhancement level was associated with evidence of MVP.

Anti-PD-1 Immunotherapy in Preclinical GL261 Glioblastoma: Influence of Therapeutic Parameters and Non-Invasive Response Biomarker Assessment with MRSI-Based Approaches.

Glioblastomas (GBs) are malignant brain tumours with poor prognosis even after aggressive therapy. Programmed cell death-1 (PD-1) immune checkpoint blockade is a promising strategy in many types of cancer, but its therapeutic effects in GB remain low and associated with immune infiltration. Previous work suggests that oscillations of magnetic resonance spectroscopic imaging (MRSI)-based response pattern with chemotherapy could act as a biomarker of efficient immune system attack onto GBs. The presence of such oscillations with other monotherapies such as anti-PD-1 would reinforce its monitoring potential. Here, we confirm that the oscillatory behaviour of the response biomarker is also detected in mice treated with anti PD-1 immunotherapy both in combination with temozolomide and as monotherapy. This indicates that the spectral pattern changes observed during therapy response are shared by different therapeutic strategies, provided the host immune system is elicited and able to productively attack tumour cells. Moreover, the participation of the immune system in response is also supported by the rate of cured animals observed with different therapeutic strategies (in the range of 50-100% depending on the treatment), which also held long-term immune memory against tumour cells re-challenge. Taken together, our findings open the way for a translational use of the MRSI-based biomarker in patient-tailored GB therapy, including immunotherapy, for which reliable non-invasive biomarkers are still missing.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Therapeutic Efficiency of Multiple Applications of Magnetic Hyperthermia Technique in Glioblastoma Using Aminosilane Coated Iron Oxide Nanoparticles: In Vitro and In Vivo Study.

Magnetic hyperthermia (MHT) has been shown as a promising alternative therapy for glioblastoma (GBM) treatment. This study consists of three parts: The first part evaluates the heating potential of aminosilane-coated superparamagnetic iron oxide nanoparticles (SPIONa). The second and third parts comprise the evaluation of MHT multiple applications in GBM model, either in vitro or in vivo. The obtained heating curves of SPIONa (100 nm, +20 mV) and their specific absorption rates (SAR) stablished the best therapeutic conditions for frequencies (309 kHz and 557 kHz) and magnetic field (300 Gauss), which were stablished based on three in vitro MHT application in C6 GBM cell line. The bioluminescence (BLI) signal decayed in all applications and parameters tested and 309 kHz with 300 Gauss have shown to provide the best therapeutic effect. These parameters were also established for three MHT applications in vivo, in which the decay of BLI signal correlates with reduced tumor and also with decreased tumor glucose uptake assessed by positron emission tomography (PET) images. The behavior assessment showed a slight improvement after each MHT therapy, but after three applications the motor function displayed a relevant and progressive improvement until the latest evaluation. Thus, MHT multiple applications allowed an almost total regression of the GBM tumor in vivo. However, futher evaluations after the therapy acute phase are necessary to follow the evolution or tumor total regression. BLI, positron emission tomography (PET), and spontaneous locomotion evaluation techniques were effective in longitudinally monitoring the therapeutic effects of the MHT technique.