Long-Term Tumor Control Following Targeted Alpha Therapy (TAT) of Low-Grade Gliomas (LGGs): A New Treatment Paradigm?

The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [213Bi]Bi/[225Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT. In two oligodendroglioma patients, TAT was applied as a second-line treatment for tumor progression, 10 years after targeted beta therapy using [90Y]Y-DOTA-substance P. The radiopharmaceutical was locally injected directly into the tumor via a stereotactic insertion of a capsule-catheter system. The activity used for radiolabeling was 2-2.5 GBq of Bismuth-213 and 17 to 35 MBq of Actinium-225, mostly applied in a single fraction. The recurrence-free survival times were in the range of 2 to 16 years (median 11 years) in low-grade astrocytoma (n = 8), in which TAT was administered following a biopsy or tumor debulking. Regarding oligodendroglioma, the recurrence-free survival time was 24 years in the first case treated, and 4 and 5 years in the two second-line cases. In conclusion, TAT leads to long-term tumor control in the majority of patients with LGG, and recurrence has so far not manifested in patients with low-grade (grade 2) astrocytomas who received TAT as a first-line therapy. We conclude that targeted alpha therapy has the potential to become a new treatment paradigm in LGG.

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.

Safety and efficacy of targeted alpha therapy with 213Bi-DOTA-substance P in recurrent glioblastoma.

Treatment options for recurrent glioblastoma multiforme (GBM) are very limited. GBM cells express high levels of the GPCR neurokinin type 1 receptor (NK-1R), and a modified substance P can be used as its ligand for the tumor cell targeting. Targeted alpha therapy with DOTA-Substance P labeled with the short range alpha emitter 213Bi allows for selective irradiation and killing of tumor cells. MATERIAL AND METHODS: Twenty patients with recurrent GBM were included into the study following a standard therapy. 1-2 intracavitary or intratumoral port-a-cath systems were stereotactically inserted. Patients were treated with 1-7 doses of 213Bi-DOTA-Substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-Substance P (68Ga-DOTA-SP) was co-injected with 213Bi-DOTA-SP to assess the biodistribution using PET/CT. Therapeutic response was monitored with performance status and MRI imaging. RESULTS: Treatment with activity up to 11.2 GBq 213Bi-DOTA-SP was well tolerated with only mild and transient adverse reactions. The median progression free survival was 2.7 months. The median overall survival from the first diagnosis was 23.6 months and median survival after recurrence was 10.9 months. The median survival time from the start of 213Bi-DOTA-SP was 7.5 months. CONCLUSIONS: Treatment of recurrent GBM with 213Bi-DOTA-SP is safe and well tolerated. The median overall survival after recurrence of 10.9 months compares favorably to the available alternative treatment options. Once the supply of high activity 225Ac/213Bi radionuclide generators is secured, targeted alpha therapy with 213Bi-DOTA-SP may evolve as a promising novel option to treat recurrent GBM.

Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue.

BACKGROUND: Glioblastoma multiforme (GBM), the most common malignant brain tumor, mainly manifests as a primary de novo and less frequently as a secondary glial neoplasm. GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. 213Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures. MATERIAL AND METHODS: Among 50 glioma patients of different subtypes that have to date been treated with targeted alpha therapy at the Medical University Warsaw, we report here the data on nine patients with secondary GBM. Following surgery, chemo- and radiotherapy, recurrent GBM was treated by intracavitary injection of 1-6 doses of 0.9-2.3 GBq 213Bi- DOTA-[Thi8,Met(O2)11]-substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-[Thi8,Met(O2)11]-substance P (68Ga-DOTA-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI. RESULTS: Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq 213Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy. CONCLUSIONS: Targeted alpha therapy of secondary GBM with 213Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM.

Quality of life in patients with brain tumors in the course of alpha therapy.

The aim of the study was to assess subjective quality of life in patients receiving alpha therapy for malignant tumors (glioblastoma multiforme, GBM) of the brain. No significant differences in self-assessed quality of life were found between GBM patients in the course of α-therapy and healthy controls, the two groups differed only as regards somatic symptoms. Moreover, the stronger the respondents' sense of self-efficacy, the higher their subjective quality of life. The findings may have practical implications for clinical psychology, namely, it seems worthwhile to build up the patient's sense of control of his own health.

Microlesion effect as a predictor of the effectiveness of subthalamic deep brain stimulation for Parkinson's disease.

BACKGROUND: Microlesion effect (MLE) is a commonly observed phenomenon after electrode insertion into the subthalamic nucleus (STN) for deep brain stimulation (DBS). OBJECTIVES: The aim of this study was to determine the presence of the MLE in the early postoperative period and the relationship between MLE and STN DBS. METHODS: 74 patients with Parkinson's disease were included in this study. Motor symptoms were evaluated preoperatively, within 48 h after electrode implantation and at 6 months with United Parkinson's Disease Rating Scale part III (UPDRS-III). According to the improvement level with MLE, all participants were stratified into three groups: (1) less than 20%; (2) 20-40%, and (3) more than 40% in OFF medication states. The degree of improvement in UPDRS-III with DBS ON for each MLE group was assessed at the 6-month follow-up. Regression analysis was applied for the evaluation of the relationship between MLE and improvement with DBS ON. RESULTS: Mean results in UPDRS-III with the MLE in ON and OFF medication states were 22.1 ± 10.5 and 42.1 ± 14 points, respectively. At the 6-month follow-up, with active stimulation, results tended to further ameliorate to 14.6 (59.4%) points in ON and 20.8 (55.3%) in OFF. Mean improvement in MLE groups were: 33.6% group 1, 47.5% group 2 and 61.4% group 3. Regression analysis revealed a positive correlation between the MLE and results at 6 months with DBS ON. CONCLUSION: Results proved the presence of MLE in the early postoperative period. Furthermore, a positive correlation between MLE and improvement degree with active stimulation was observed.

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.

Periaqueductal/periventricular gray deep brain stimulation for the treatment of neuropathic facial pain.

Background: The Periaqueductal gray (PAG) and the periventricular gray (PVG) are the anatomical targets for deep brain stimulation (DBS) to treat severe, refractory neuropathic pain. Methods: Seven (four female and three male) patients were qualified for PAG/PVG DBS because of neuropathic facial pain. Frame-based unilateral implantations of DBS were conducted according to indirect planning of the PAG/PVG, contralateral to reported pain (3389, Activa SC 37603, Medtronic). The efficacy of PAG/PVG DBS on pain was measured with Numeric Pain Rating Scale (NRS) and Neuropathic Pain Symptom Inventory (NPSI) before surgery and 3, 12, and 24 months after surgery. Results: The mean age of the group at the implantation was 43.7 years (range: 28-62; SD: 12.13). The mean duration of pain varied from 2 to 12 years (mean: 7.3; SD: 4.11). Five patients suffered from left-sided facial pain and two suffered right-sided facial pain. The etiology of pain among four patients was connected to ischemic brain stroke and in one patient to cerebral hemorrhagic stroke. Patients did not suffer from any other chronic medical condition The beginnings of ailments among two patients were related to craniofacial injury. NRS decreased by 54% at the 3 months follow-up. The efficacy of the treatment measured with mean NRS decreased at one-year follow-up to 48% and to 45% at 24 months follow-up. The efficacy of the treatment measured with NPSI decreased from 0.27 to 0.17 at 2 years follow-up (mean reduction by 38%). The most significant improvement was recorded in the first section of NPSI (Q1: burning- reduced by 53%). The records of the last section (number five) of the NPSI (paresthesia/dysesthesia- Q11/Q12) have shown aggravation of those symptoms by 10% at the two-years follow-up. No surgery- or hardware-related complications were reported in the group. Transient adverse effects related to the stimulation were eliminated during the programming sessions. Conclusion: PAG/PVG DBS is an effective and safe method of treatment of medically refractory neuropathic facial pain. The effectiveness of the treatment tends to decrease at 2 years follow-up. The clinical symptoms which tend to respond the best is burning pain. Symptoms like paresthesia and dysesthesia might increase after DBS treatment, even without active stimulation.

Motor cortex stimulation in the treatment of neuropathic pain.

BACKGROUND AND PURPOSE: Despite the rapid development of neuropharmacotherapy, medical treatment of neuropathic pain (NP) still constitutes a significant socioeconomic problem. The authors herein present a group of patients treated with motor cortex stimulation (MCS) for NP of various types and aetiologies. MATERIAL AND METHODS: Our cohort included 12 female and 11 male NP patients aged 53 ± 16 treated with MCS. Eleven patients were diagnosed with neuropathic facial pain (NFP), 8 with hemi-body neuropathic pain (HNP), and 4 with deafferentation pain (DP). Prior to surgery, 16 out of 23 patients were treated with repetitive transcranial magnetic stimulation (rTMS), with a positive response in 10 cases. Pain intensity in our group was evaluated with the visual analogue scale (VAS) one month before and three months after MCS implantation. RESULTS: Improvement on the VAS was reported in the whole group of patients (p < 0.001). The best results were reported in the NFP group (p < 0.001) while the worst ones were noted in the DP group (p = 0.04). Anamnesis duration positively correlated with outcome. Infection forced the authors to permanently remove the system in one case. There were no other complications in the group. CONCLUSIONS: Minimally invasive, safe neuromodulative treatment with MCS permits neuropathic pain control with good efficacy. The type of neuropathic pain might be a prognostic factor.

Expression of glutamate carboxypeptidase II in the glial tumor recurrence evaluated in vivo using radionuclide imaging.

Glutamate carboxypeptidase II (GCP), also known as prostate specific membrane antigen (PSMA) has been found to be expressed in glioma vasculature in in-vitro studies. GCP expression can be traced with the use of [68Ga]Ga-PSMA-11 PET/CT used routinely for prostate cancer imaging. The aim of this paper was to analyze GCP expression in the recurrent glial tumors in vivo. 34 patients (pts.) aged 44.5 ± 10.3 years with suspicion of recurrence of histologically confirmed glioma grade III (6 pts.) and grade IV (28 pts.) were included in the study. All patients underwent contrast-enhanced MR and [68Ga]Ga-PSMA-11 PET/CT. No radiopharmaceutical-related adverse events were noted. PET/CT was positive in all the areas suspected for recurrence at MR in all the patients. The recurrence was confirmed by histopathological examinations or follow-up imaging in all cases. The images showed a very low background activity of the normal brain. Median maximal standard uptake value (SUVmax) of the tumors was 6.5 (range 0.9-15.6) and mean standard uptake value (SUVmean) was 3.5 (range 0.9-7.5). Target-to-background (TBR) ratios varied between 15 and 1400 with a median of 152. Target-to-liver background ratios (TLR) ranged from 0.2 to 2.6, the median TLR was 1.3. No significant difference of the measured parameters was found between the subgroups according to the glioma grade. High GCP expression in the recurrent glioma was demonstrated in-vivo with the use of [68Ga]Ga-PSMA-11 PET/CT. As the treatment options in recurrent glioma are limited, this observation may open new therapeutic perspectives with the use of radiolabeled agents targeting the GCP.

Thalamic deep brain stimulation in the treatment of essential tremor.

BACKGROUND AND PURPOSE: Quality of life can be severely impaired by essential tremor (ET) being the main cause of the patient's disability. The authors present a group of ET patients treated with deep brain stimulation of the ventral intermediate nucleus of the thalamus (Vim DBS). The aim of the study was to evaluate the efficacy and safety of Vim DBS in the treatment of ET. MATERIAL AND METHODS: Between 2006 and 2009, 8 female and 10 male ET patients were treated with Vim DBS. Mean age at implantation was 63 ± 15 years. ET lasted from 4 to 30 years (mean 12 years). Clinical condition of the group was evaluated before surgery and 3 months after implantation with spirography (spiral drawings), the modified Fahn (Tremor Rating Scale, TRS) scale, and the modified ADL (Activity of Daily Living) scale. The Vim was localized with CT and MRI. The procedures of implantation were performed under local and general anaesthesia. A bilateral procedure was performed in 11 cases and a unilateral procedure was performed in 7 cases. RESULTS: The therapeutic effect of DBS was maintained at the follow-up in the third month following surgery. Mean contralateral limb tremor reduction was 79%. Head tremor reduction was reported by 75% of patients in the bilateral Vim DBS subgroup and 50% of patients in the unilateral Vim DBS subgroup. Mean ADL score improved by 61%. CONCLUSIONS: Vim DBS is a safe and effective method of ET treatment. Vim DBS improves activities of daily living of ET patients.

Chronic bilateral pallidal stimulation in patients with generalized primary dystonia - multi-contact cathodal stimulation is superior to bipolar stimulation mode. Preliminary results.

BACKGROUND AND PURPOSE: Primary generalized dystonia (PGD) is a medically refractory progressive disease of the brain causing near total handicap of affected patients. The aim of the study was to assess the efficacy and safety of bilateral pallidal stimulation in patients with PGD. MATERIAL AND METHODS: The study population is composed of 5 patients with PGD. The formal objective assessment included the Burke-Fahn-Marsden dystonia rating scale (BFMDRS). All stereotactic procedures were performed in general anaesthesia using a Leksell G stereotactic head frame without electrophysiological guidance. Immediately after insertion of deep brain stimulation (DBS) leads, the internal pulse generators (Itrel II or Soletra) were implanted subcutaneously in the chest wall or abdominal region. RESULTS: There were no complications related to the stereotactic procedures. The hardware-related complications (two broken DBS leads) were replaced successfully. There were no infections or erosions of implanted hardware. It has been observed that in the long-term follow-up period primary set bipolar stimulation mode lost its benefit achieved previously. Various stimulation combinations were investigated. Monopolar cathodal or especially multi-contact cathodal stimulation was the most effective one. The efficacy of bilateral pallidal stimulation was proved by the objective validated BFMDRS at long-term follow-up. CONCLUSIONS: Response to DBS may improve with the number of activated cathodal contacts within the globus pallidus internus.

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.

Subthalamic deep brain stimulation for the treatment of Parkinson disease.

BACKGROUND AND PURPOSE: The role of subthalamic nucleus deep brain stimulation (STN DBS) in the treatment of Parkinson disease (PD) is well established. The authors present a group of patients diagnosed with PD who were treated with STN DBS. MATERIAL AND METHODS: Between 2008 and 2009, 32 female and 34 male patients with PD were treated with STN DBS. Mean age at implantation was 57 ± 12 years. PD lasted from 6 to 21 years (mean 10 years). Patients were qualified for the surgery according to the CAPSIT-PD criteria. The STN was identified with direct and indirect methods. Macrostimulation and microrecording for STN identification were used in all cases. A unilateral STN DBS system was implanted in two cases and bilateral implantation was performed among rest of the group. Outcome was assessed six months after implantation. Results : The mean reduction of UPDRS III score among 51 patients who underwent follow-up was 45% (5-89%). Reduction of levodopa consumption varied from 15 to 100%. Infection forced the authors to remove the DBS system in one case four months after implantation. Skin erosion above the internal pulse generator was noted in four cases. CONCLUSIONS: Cardinal symptoms of Parkinson's disease can be safely and effectively treated with STN DBS in selected group of patients.

Thalamic deep brain stimulation for tremor among multiple sclerosis patients.

BACKGROUND AND PURPOSE: Disabling tremor might be the main cause of disability of multiple sclerosis (MS) patients. Neuromodulation with deep brain stimulation of the thalamic nucleus ventralis intermedius (Vim DBS) is a well accepted method of neurosurgical treatment of tremor related to essential tremor or Parkinson disease. Vim DBS is not widely used to control MS tremor. MATERIAL AND METHODS: Five MS patients with tremor (3 females and 2 males) were treated with Vim DBS. Age at implantation was 37 ± 5 years. MS lasted from 5 to 12 years (mean 6) and tremor was the main cause of disability of those patients from 2 to 5 years (mean 3) before surgery. Clinical condition of the group was evaluated with spirography, the modified Fahn scale and the modified Activity of Daily Living (ADL) scale. Evaluations were performed before surgery and 3 months after surgery. MRI exclusion criteria were the presence of a thalamic hyperintense signal in T2-weight-ed images or ventricular enlargement. The procedures of implantation were performed under local and general anaesthesia. RESULTS: Intensity of contralateral limb tremor during intraoperative macrostimulation was reduced in the whole group. The therapeutic effect of DBS was maintained at three-month follow-up. Mean contralateral limb tremor reduction was 40%. Mean ADL score improved by 18%. No mortality or morbidity was reported in the group. CONCLUSIONS: The study confirms the value and safety of Vim DBS for treatment of MS-related tremor. Further study on a larger population and introduction of a qualification protocol might increase efficacy of the treatment.

Bilateral subthalamic nucleus stimulation in the treatment of advanced Parkinson's disease. Five years' personal experience.

BACKGROUND AND PURPOSE: The objective of the study was to assess bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with advanced Parkinson disease (PD). MATERIAL AND METHODS: The study population included 5 patients with bilateral STN DBS who completed a 5-year postoperative follow-up period. In all patients electrodes (Model 3387 or 3389) were stereotactically bilaterally inserted into the STN using a Leksell stereotactic G frame. The clinical rating tests included Unified Parkinson's Disease Rating Scale (UPDRS) and two motor-timed tests derived from CAPIT (rapid movements between two points and stand-walk-sit test). All patients were assessed in off and on condition before implantation and 1, 3 and 5 years in medication on and off condition and stimulation on condition and stimulation off condition. To compare preoperative to postoperative UPDRS scores, only mean values and standard deviations are presented because of the small study population. RESULTS: The stimulation effect was noted in the off state, resulting in a 59% improvement in motor scores of UPDRS at 5-year follow-up, when compared to preoperative scores. In the on state the stimulation improved motor scores by 17%. At 5-year follow-up, reduction of daily levodopa dose was 50%. CONCLUSIONS: Bilateral STN DBS is an effective and safe treatment for patients with advanced PD. Bilateral STN DBS contributes to improvement of parkinsonian symptoms in the off state and levodopa-induced dyskinesia. This can be correlated with a 50% reduction of daily levodopa dose 5 years postoperatively.

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.

225Ac- and 213Bi-Substance P Analogues for Glioma Therapy.

Within the last decades, there has been no major improvement in treatment of patients with glioma, especially with glioblastoma multiforme (GBM) which is related to specific features of this tumor type, such as heterogeneity at the macroscopic, microscopic and genetic level, the infiltrative nature of tumors and the obstacle of the brain-blood barrier which limits the accessability of most drugs. The current standard of care is surgical resection, followed by radio- and chemotherapy. After first-line treatment of the primary lesion, tumor recurrence is diagnosed in virtually all GBM patients. Treatment of tumor recurrence represents a challenging clinical task. Surgical resection to relief symptoms of mass effect and/or salvage chemotherapy are often considered as last therapeutic option. A new treatment option is urgently needed. Targeted alpha therapy with an intratumoral injection of 213Bi-DOTA-Substance P (SP) or 225Ac-DOTAGA-Substance P has been introduced into the therapeutic armamentarium of recurrent GBM. There are many advantages of using SP such as very high prevalence of increased NK-1 expression in GBM cells, regardless of the degree of malignancy, and expression of the NK-1 receptor system not only on the membrane of cancer cells but also strong expression of NK1 receptors within the tumor neovasculature suggesting concomitant targeting of vascular and neoplastic structures. Radioisotopes with different physical properties, mainly beta-emitting metallic radionuclides, were implemented for brain tumor treatment. Based on their radiophysical properties, however, alpha emitters exhibit more promising properties. In investigator-initiated phase I and II studies, targeted alpha therapy using Bi-213/Ac-225 radiolabeled Substance P for malignant gliomas compare favorably with standard therapy, with the limitation that no large controlled series have so far been generated. Further development should focus on the improvement of the biological and chemical properties of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within growth and infiltrative zone of these glial neoplasms.

A patient with parkinsonism related to Gaucher's disease type I successfully treated by unilateral pallidotomy - a 3-year follow-up.

Gaucher's disease is the most common hereditary lysosomal storage disorder and presents with a wide clinical spectrum including parkinsonism. We present a patient first diagnosed with idiopathic Parkinson's disease at the age of 38 due to left-sided bradykinesia and rigidity. But thereafter the diagnosis of Gaucher's disease type I according to clinical pictures and clinical genetic testing was made. Despite the optimal enzyme replacement therapy, the parkinsonian symptoms worsened. He was referred for consideration for surgical treatment of his severe parkinsonism. At the age of 54 he underwent right-sided posteroventrolateral pallidotomy. The surgery was uneventful and he immediately improved. On the last examination performed 3 years later, he had mild parkinsonism and was independent in all activities of daily living. This case demonstrates a benefit of surgical treatment for genetically proven Gaucher's disease type I.

Subthalamic and pallidal oscillatory activity in patients with Neurodegeneration with Brain Iron Accumulation type I (NBIA-I).

OBJECTIVES: Neurodegeneration with Brain Iron Accumulation type I (NBIA-I) is a rare hereditary neurodegenerative disorder with pallidal degeneration leading to disabling generalized dystonia and parkinsonism. Pallidal or subthalamic deep brain stimulation can partially alleviate motor symptoms. Disease-specific patterns of abnormally enhanced oscillatory neuronal activity recorded from the basal ganglia have been described in patients with movement disorders undergoing deep brain stimulation (DBS). Here we studied oscillatory activity recorded from the internal globus pallidus (GPi) and the subthalamic nucleus (STN) to characterize neuronal activity patterns in NBIA-I. METHODS: We recorded local field potentials (LFP) from DBS electrodes in 6 juvenile patients with NBIA-I who underwent functional neurosurgery. Four patients were implanted in the STN and two patients in the GPi. Recordings were performed during wakeful rest. An FFT-based approach was used to analyze the power spectrum in the target area. RESULTS: In all patients we found distinct peaks in the low frequency (7-12 Hz) and in 5 out 6 also in the beta frequency range (15-30 Hz) with the largest beta peak in the patient that presented with the most prominent bradykinesia. No distinct peaks occurred in the gamma frequency range (35-100 Hz). The oscillatory pattern did not differ between STN and GPi. CONCLUSIONS: Here we show for the first time the oscillatory activity pattern in the STN and the GPi in juvenile patients with dystonia plus syndrome due to NBIA-I. The low frequency peak we found is in line with previous studies in patients with isolated idiopathic dystonia. In our cohort, the pallidal beta band activity may be related to more severe motor slowing in dystonia plus syndrome such as NBIA-I. SIGNIFICANCE: Our results further support the link between hyperkinetic motor symptoms such as dystonia and enhanced basal ganglia low frequency activity irrespective of the underlying etiology of dystonia.