Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.

In previous studies, a below-average, average, or above-average intelligence quotient (IQ) in children with SMA was detected but, aside from a severe physical disability, the cognitive performance of adult SMA patients has not yet been evaluated. The intelligence test used in this study, the Wechsler Adult Intelligence Scale, fourth edition (WAIS-IV), was used to measure major intelligence components of adult SMA patients. The WAIS-IV determines four index scores representing verbal comprehension, perceptual reasoning, working memory, and processing speed. Due to time-dependent demands on motor function, the processing speed index score was excluded. IQ index scores of 33 adult SMA patients did not differ from IQ index scores of the normal population. In SMA type-3 patients, the index scores for verbal comprehension, perceptual reasoning, and working memory did not differ from the normal population but showed a trend of IQ scores towards lower points. Patients with SMA type 2 had lower IQ index scores for working memory (90.33 ± 12.95; p = 0.012) and perceptual reasoning (90.73 ± 12.58; p = 0.013) than the normal population. This study provided further evidence that SMA is a multi-systemic disease and may refute the widespread hypothesis that SMA patients might improve their cognitive skills to compensate for their physical impairment.

Background: Patients with primary brain tumors face profound disease- and treatment-related immunosuppression, placing them at high risk for severe infections. Their capacity to mount protective immune responses to vaccination, particularly to repeated antigen exposures such as COVID-19 boosters, remains critically under-defined, leading to uncertainty in clinical practice. Methods: In this prospective cohort study, we analyzed humoral responses to seasonal COVID-19 (mRNA-based) and influenza vaccination in 17 patients with primary brain tumors (recruited from an initial cohort of 37) who received a booster shot, and 19 healthy controls. Serum samples were collected before (T1) and 30 ± 2 days after (T2) vaccination to quantify SARS-CoV-2 anti-Spike (S) IgG and anti-Influenza IgG titers. Results: Despite ongoing chemotherapy in 47% of patients, baseline anti-S antibody titers were comparable between groups. Following the booster, median anti-S titers increased significantly and to a similar magnitude in both patients (from 5030 to 18,500 BAU/mL; IQR: 13,885–24,420) and controls (from 4429 to 20,200 BAU/mL; IQR: 11,075–26,680; p = 0.6137, Mann–Whitney U test). Only two heavily pre-treated patients showed no booster response. All participants showed sero-positivity to Anti-Influenza IgG at baseline. For the primary brain tumor cohort, a significant increase for anti-Influenza IgG at T2 was observed (p = 0.0002). Mean antibody titers did not differ between both cohorts. Conclusions: Our findings provide evidence that patients with primary brain tumors can mount robust recall immunity to mRNA vaccines, addressing clinical uncertainty about booster efficacy in this population. These data provide a strong rationale for prioritizing booster vaccinations in this vulnerable population and argue for the inclusion of these patients in future pivotal vaccine trials.

Background: Tumor Treating Fields improve survival when started after chemoradiotherapy in newly diagnosed glioblastoma, but the safety and feasibility of initiating treatment before and during radiotherapy remain uncertain. Methods: PriCoTTF is a prospective, open-label, nonrandomized, multicenter phase I/II trial. Arm A enrolled adults aged 18 to 70 years with newly diagnosed IDH-wildtype glioblastoma or gliosarcoma, Karnofsky Performance Status of at least 60, and planned focal radiotherapy to 60 Gy in 30 fractions. TTFields at 200 kHz were initiated 2 to 4 weeks after surgery and 1 to 2 weeks before radiotherapy. The primary endpoint was protocol-defined treatment-limiting toxicity from TTFields initiation through 4 weeks after radiotherapy. Results: Twenty evaluable patients comprised the Arm A feasibility cohort. No protocol-defined treatment-limiting toxicities occurred (0 of 20 patients; exact 95% CI, 0.0%-16.8%). Grade 3 or higher adverse events occurred in 12 patients (60%), predominantly hematologic toxicity attributable to chemoradiotherapy; lymphopenia occurred in 6 patients (30%). Median usage through visit 4 was 76.5%, and median time to first attainment of at least 75% daily use was 2 days. Median progression-free survival was 6.9 months (95% CI, 2.7–14.0), and median overall survival was 18.0 months (95% CI, 12.1–19.9). Conclusions: Initiation of TTFields before and during radiotherapy was feasible and was not associated with protocol-defined treatment-limiting toxicity in the Arm A cohort. Because the TLT definition was narrow and efficacy analyses were exploratory and exposure-conditioned, these findings should be interpreted as feasibility data rather than evidence of improved tumor control or survival. The results support randomized evaluation of earlier TTFields integration in newly diagnosed glioblastoma. Trial registration: German Clinical Trials Register DRKS00016667, registered 26 February 2019.