Dose escalation study of targeted alpha therapy with [225Ac]Ac-DOTA-substance P in recurrence glioblastoma - safety and efficacy.

Glioblastoma is the most common and malignant primary brain tumour, with a poor prognosis. Introduction of new treatment options is critically important. The study aimed to assess the appropriateness of escalation doses and toxicity of [225Ac]Ac-DOTA-SP therapy. MATERIAL AND METHODS: A total of 21 patients (age of 43.0 ± 9.5 years), with histologically confirmed recurrent or conversion glioblastoma grade 4 following a standard therapy, have been included in the study. One to 2 intracavitary port-a-cath systems were stereotactically inserted. Patients were treated with escalation dose protocol with 10, 20 and 30 MBq per cycle totally 1-6 doses of [225Ac]Ac-DOTA-SP in 2-month intervals. Therapeutic response was monitored by clinical performance status and MRI imaging. RESULTS: Treatment was well tolerated with mostly mild temporary adverse effects (oedema, epileptic seizures, aphasia, hemiparesis) mainly in the group of patients treated with 30 MBq of [225Ac]Ac-DOTA-SP. Only one patient treated with 30 MBq revealed thrombopenia grade 3. There was no other grade 3 and 4 toxicity related to [225Ac]Ac-DOTA-treatment in all groups. The median overall survival time from the primary diagnosis (OS-d) was 35.0 months and from the diagnosis of the recurrence/conversion (OS-r/c) was 13.2 months. From the start of treatment with [225Ac]Ac-DOTA-SP, the median PFS was 2.4 months, and the OS-t was 9.0 months. There were no statistically significant differences between the investigated dose escalation groups. CONCLUSIONS: Treatment of recurrent glioblastoma with [225Ac]Ac-DOTA-SP is safe and well tolerated up to 30 MBq per cycle. The escalation dose protocol showed good tolerability. Only mild temporary adverse effects were observed. No remarkable haematological, kidney and liver toxicity was seen.

Quantitative SPECT/CT imaging of actinium-225 for targeted alpha therapy of glioblastomas.

BACKGROUND: A new, alternative option for patients with recurrent glioblastoma is targeted alpha therapy (TAT), in the form of a local administration of substance P (neurokinin type 1 receptor ligand, NK-1) labelled with 225Ac. The purpose of the study was to confirm the feasibility of quantitative SPECT imaging of 225Ac, in a model reproducing specific conditions of TAT. In particular, to present the SPECT calibration methodology used, as well as the results of validation measurements and their accuracy. Additionally, to discuss the specific problems related to high noise in the presented case. MATERIALS AND METHODS: All SPECT/CT scans were conducted using the Symbia T6 equipped with HE collimators, and acquired with multiple energy windows (three main windows: 440 keV, 218 keV, and 78 keV, with three lower scatter energy windows). A Jaszczak phantom with fillable cylindrical sources of various sizes was used to investigate quantitative SPECT/CT imaging characteristics. The planar sensitivity of the camera, an imaging calibration factor, and recovery coefficients were determined. Additionally, the 3D printed model of the glioblastoma tumour was developed and imaged to evaluate the accuracy of the proposed protocol. RESULTS: Using the imaging calibration factor and recovery coefficients obtained with the Jaszczak phantom, we were able to quantify the activity in a 3D-printed model of a glioblastoma tumour with uncertainty of no more than 10% and satisfying accuracy. CONCLUSIONS: It is feasible to perform quantitative 225Ac SPECT/CT imaging. However, there are still many more challenges that should be considered for further research on this topic (among others: accurate determination of ICF in the case of high background noise, better method of background estimation for recovery coefficient calculations, other methods for scatter correction than the dual-energy window scatter-compensation method used in this study).

Locoregional Treatment of Glioblastoma With Targeted α Therapy: [ 213 Bi]Bi-DOTA-Substance P Versus [ 225 Ac]Ac-DOTA-Substance P-Analysis of Influence Parameters.

BACKGROUND: Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [ 213 Bi]Bi-DOTA-substance P (SP) and [ 225 Ac]Ac-DOTA-SP. METHODS: Treatment was performed as salvage therapy in patients with recurrent primary and secondary GB. [ 213 Bi]Bi-DOTA-SP with injected activity 1.85 GBq per cycle was used in 20 primary (48.2 ± 11.8 years old) and in 9 secondary (38.8 ± 10.8 years old) GB patients and [ 225 Ac]Ac-DOTA-SP in 15 primary (45.1 ± 9.9 years old) and in 6 secondary (37.8 ± 6.4 years old) GB patients with a dose escalation scheme (10, 20, and 30 MBq). RESULTS: Local treatment with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP was well tolerated with only few adverse effects. There was no statistically significant difference between [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP groups in survival parameters. For primary GB, survival parameters of patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows(in months): progression-free survival time, 2.7 versus 2.4; OS-d (overall survival from time of diagnosis to death from any cause), 23.6 versus 21.0; OS-t (overall survival from the start of treatment to death from any cause), 7.5 versus 5.0; and OS-r (overall survival from recurrence in primary tumors to death from any cause), 10.9 versus 12.0. Survival parameters of secondary GB patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows (in months): progression-free survival time, 5.8 versus 2.4; OS-d, 52.3 versus 65.0; OS-t, 16.4 versus 16.0; and OS-c (overall survival from conversion into secondary GB multiforme to death from any cause), 18.4 versus 36.0. CONCLUSIONS: The similarity results of 213 Bi or 225 Ac may suggest that the local treatment of brain tumors can be greatly simplified. The experience to date shows that local radioisotope treatment of brain tumors requires further dosimetry studies, taking into account the complexity of biological processes.

Neuropsychological assessment of language functions during functional magnetic resonance imaging: development of new tasks. Preliminary report.

BACKGROUND AND PURPOSE: Due to the complex and extended cerebral organization of language functions, the brain regions crucial for speech and language, i.e. eloquent areas, have to be affected by neurooncological surgery. One of the techniques that may be helpful in pre-operative planning of the extent of tumour removal and estimating possible complications seems to be functional magnetic resonance imaging (fMRI). The aim of the study was to develop valid procedures for neuropsychological assessment of various language functions visualisable by fMRI in healthy individuals. MATERIAL AND METHODS: In this fMRI study, 10 healthy (with no CNS pathology), right-handed volunteers aged 25-35 were examined using four tasks designed to measure different language functions, and one for short-term memory assessment. A 1.5-T MRI scanner performing ultrafast functional (EPI) sequences with 4-mm slice thickness and 1-mm interslice gap was used to detect the BOLD response to stimuli present-ed in a block design (30-second alternating blocks of activity and rest). The analyses used the SPM software running in a MATLAB environment, and the obtained data were interpreted by means of colour-coded maps superimposed on structural brain scans. RESULTS: For each of the tasks developed for particular language functions, a different area of increased neuronal activity was found. CONCLUSIONS: The differential localization of function-related neuronal activity seems interesting and the research worth continuing, since verbal communication failure may result from impairment of any of various language functions, and studies reported in the literature seem to focus on verbal expression only.

68Ga-Prostate-Specific Membrane Antigen-11 PET/CT: A New Imaging Option for Recurrent Glioblastoma Multiforme?

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and most aggressive primary tumor of the brain. After initial therapy and total resection of GBM, 80% to 90% of recurrences occur at the surgical margins. Currently, limited data are available in the literature on the possible use of Ga-prostate-specific membrane antigen (PSMA-11) for diagnosis of recurrence in GBM patients. The aim was to assess the feasibility and potential of Ga-PSMA-11 PET/CT as a diagnostic procedure in patients with histologically confirmed of GBM and suspected recurrent disease on MRI. RESULTS: No radiopharmaceutical-related adverse events were noted. Characterization of recurrent disease with MRI included T2-weighted fast spin-echo images, fluid-attenuated inversion recovery and diffusion-weighted imaging sequences, and gadolinium enhanced T1-weighted images. Visual interpretation of PET showed increased accumulation of Ga-PSMA-11 in recurrent lesion detected by T1 contrast enhanced and diffusion-weighted imaging images in all patients with a median SUVmax of the tumor of 6.5 and an SUVmean of 3.5. The median tumor-to-background brain ratio and tumor-to-liver ratio obtained from Ga-PSMA-11 PET/CT were 96.7 and 0.8, respectively. CONCLUSIONS: The extremely low background uptake in normal brain tissue and consequently high tumor-to-brain ratio make Ga-PSMA-11 PET/CT highly promising for diagnosis of recurrent disease in GBM patients. Although PSMA expression in recurrent GBM also opens a potential way for targeted peptide therapy with α/ß-emitters as well as for prediction of treatment with antiangiogenic agents, the low tumor-to-liver ratio observed in the majority of patients in this study suggests a limited role of radiolabeled PSMA ligands for targeted radionuclide therapy of recurrent GBM.

The neural correlates of specific executive dysfunctions in Parkinson's disease.

Several functional neuroimaging studies in patients with Parkinson's disease (PD) have suggested that changes in the fronto-parietal-striatal networks are associated with deficits in executive functioning. However, executive functions (EF) are multifaceted and include three dissociable components: working memory, response inhibition, and task-switching. This study investigated which component of executive functioning is most strongly associated with fronto-parietal-striatal efficiency in PD. PD patients (with and without executive dysfunction), and age-matched healthy subjects, completed a battery of cognitive tests previously shown to discriminate among the three EF components. Principal component analysis conducted on the selected cognitive test variables yielded three expected EF components. The component scores were used in regression analysis to assess the relationship between the EF efficiency and blood oxygenation level-dependent (BOLD) signal related to performing the n-back, an experimental task that draws upon multiple components of executive functioning: working memory, response inhibition, and task-switching. We found distinct neural correlates of specific executive dysfunctions in patients with PD. However, all of them seem to be associated with fronto-parietal-striatal efficiency.