Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice.

INTRODUCTION: Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting. METHODS: Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 [pediatric], 18-64 [adults], ≥ 65 [elderly]; years of age). RESULTS: Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively). CONCLUSIONS: This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

Why intra-epidermal electrical stimulation achieves stimulation of small fibres selectively: a simulation study.

The in situ electric field in the peripheral nerve of the skin is investigated to discuss the selective stimulation of nerve fibres. Coaxial planar electrodes with and without intra-epidermal needle tip were considered as electrodes of a stimulator. From electromagnetic analysis, the tip depth of the intra-epidermal electrode should be larger than the thickness of the stratum corneum, the electrical conductivity of which is much lower than the remaining tissue. The effect of different radii of the outer ring electrode on the in situ electric field is marginal. The minimum threshold in situ electric field (rheobase) for free nerve endings is estimated to be 6.3 kV m(-1). The possible volume for electrostimulation, which can be obtained from the in situ electric field distribution, becomes deeper and narrower with increasing needle depth, suggesting that possible stimulation sites may be controlled by changing the needle depth. The injection current amplitude should be adjusted when changing the needle depth because the peak field strength also changes. This study shows that intra-epidermal electrical stimulation can achieve stimulation of small fibres selectively, because Aß-, Aδ-, and C-fibre terminals are located at different depths in the skin.

Large-scale somatotopic refinement via functional synapse elimination in the sensory thalamus of developing mice.

Functional synapse elimination and strengthening are crucial developmental processes in the formation of precise neuronal circuits in the somatosensory system, but the underlying alterations in topographical organization are not yet fully understood. To address this issue, we generated transgenic mice in which afferent fibers originating from the whisker-related brain region, called the maxillary principal trigeminal nucleus (PrV2), were selectively visualized with genetically expressed fluorescent protein. We found that functional synapse elimination drove and established large-scale somatotopic refinement even after the thalamic barreloid architecture was formed. Before functional synapse elimination, the whisker sensory thalamus was innervated by afferent fibers not only from the PrV2, but also from the brainstem nuclei representing other body parts. Most notably, only afferent fibers from PrV2 onto a whisker sensory thalamic neuron selectively survived and were strengthened, whereas other afferent fibers were preferentially eliminated via their functional synapse elimination. This large-scale somatotopic refinement was at least partially dependent on somatosensory experience. These novel results uncovered a previously unrecognized role of developmental synapse elimination in the large-scale, instead of the fine-scale, somatotopic refinement even after the initial segregation of the barreloid map.

Prognostic value of immunohistochemical profile and response to high-dose methotrexate therapy in primary CNS lymphoma.

Several biomarkers have been identified as prognostic factors in primary central nervous system lymphoma (PCNSL). However, the correlation between the histogenetic origin of PCNSL and the response to therapy is still unclear. To elucidate the utility of immunophenotypic markers in predicting clinical outcomes, we investigated 27 immunocompetent patients with PCNSL treated with high-dose methotrexate therapy. Of the 27 patients, 25 received whole-brain radiotherapy after high-dose methotrexate. Immunostaining for CD5, CD10, BCL-6, and MUM-1 was used to determine the immunophenotypic profile of diffuse large B-cell lymphoma of PCNSL. We then evaluated whether immunophenotypic markers were associated with the response to therapy or patients' survival. The response to induction high-dose methotrexate therapy was determined by magnetic resonance imaging after three courses of i.v. high-dose methotrexate. We categorized B-cell lymphomas into three known subtypes: germinal center B-cell (GCB), activated-GCB, and post-GCB subtypes according to immunohistochemical profile. All the BCL-6-positive samples were co-positive for MUM-1 and therefore classified into activated-GCB subtype. BCL-6 expression in this study was associated with poor progression-free survival (P = 0.038). No immunophenotypic markers or subtypes had a significant effect on the response to high-dose methotrexate therapy. However, the response itself was a significant predictor for both progression-free survival (P < 0.001) and overall survival (P = 0.003). Further investigation is needed to assess BCL-6 as a potential prognostic factor in PCNSL.

Serial (1)H-MRS of thalamus during deep brain stimulation of bilateral globus pallidus internus for primary generalized dystonia.

INTRODUCTION: The physiological mechanisms of deep brain stimulation (DBS) are not completely clear. Our understanding of them may be facilitated with the use of proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Serial (1)H-MRS of both thalami was performed during the course of DBS of bilateral globus pallidus internus in a patient with primary generalized dystonia. RESULTS: Two days after microelectrode implantation, a pulse frequency of 185 Hz was applied for stimulation. It resulted in relief of symptoms and a decrease of Burke-Fahn-Marsden dystonia rating scale (BFMDRS) scores, and was accompanied by a prominent increase of N-acetylaspartate (NAA)/choline-containing compounds (Cho) ratio, a mild increase of NAA/creatine (Cr) ratio, and a moderate decrease of Cho/Cr ratio. Two weeks later, for a search of the optimal stimulation mode, the pulse frequency was switched to 60 Hz, which resulted in clinical deterioration and significant increase of BFMDRS scores. At that time, all investigated (1)H-MRS-detected metabolic parameters had nearly returned to the pretreatment levels. CONCLUSION: Use of serial (1)H-MRS investigations of various brain structures during DBS in cases of movement disorders permits detailed evaluation of the treatment response, has a potential for its possible prediction, and may facilitate understanding of the physiological mechanisms of stimulation.