Transcranial magnetic stimulation as a feasible, non-invasive, neuromodulatory intervention in fetal alcohol spectrum disorders. A very first proof of concept.

INTRODUCTION: A neurobiological feature of Fetal Alcohol Spectrum Disorder (FASD) is a global decrease in neuronal connectivity, which leads to significant impairments in everyday functionality. Non-invasive repetitive transcranial magnetic stimulation (rTMS) could potentially positively influence neuronal plasticity but has not yet been studied in FASD. The present trial addresses this gap, making it the first-ever study of rTMS in FASD. MATERIALS AND METHODS: The prospective clinical trial was conducted at the LMU University Hospital Munich and enrolled eight FASD participants aged 6-16. Six sessions of 1 Hz-rTMS over the left dorsolateral prefrontal cortex were administered two times a week for three weeks consisting of 1500 pulses at 90 % of resting motor threshold in four trains of 375s. Outcome measures investigated feasibility and treatment response of rTMS on executive functions, attention/impulsivity, social-emotional regulation and quality of life (QoL) via standardized tests and the FASD parents' app. RESULTS: Adherence and retention rate were 100 %. Adverse events (AEs) were mild and self-limiting, resulting in a per-session risk of 53.3 %, with local paraesthesia accounting for 54.2 % of the AEs. There were individual relevant but no significant group-level improvements in the investigated functional cerebral domains or participants' QoL. The FASD parents' app showed no significant change in participants' daily functioning or caregivers' QoL. Caregivers' parental stress decreased significantly. CONCLUSION: FASD is a very complex disorder that is difficult to treat. In addition, comorbidities as atypical responses to pharmacotherapies are frequent. For this reason, non-invasive, innovative therapies for children with FASD have to be developed. For the first time, rTMS was shown to be safe, tolerable, and acceptable and thus well feasible in paediatric patients with FASD. Further clinical studies with larger samples are needed to identify effective stimulation protocols and to evaluate treatment response.

The phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 is effective in inhibiting regrowth of tumour cells after cytotoxic therapy.

PURPOSE: Regrowth of tumour cells between cycles of chemotherapy is a significant clinical problem. Treatment strategies where antiproliferative agents are used to inhibit tumour regrowth between chemotherapy cycles are attractive, but such strategies are difficult to test using conventional monolayer culture systems. METHODS: We used the in vitro tumour spheroid model to study regrowth of 3-D colon carcinoma tissue after cytotoxic therapy. Colon carcinoma cells with wild-type or mutant phosphatidyl inositol 3-kinase catalytic subunit (PI3KCA) or KRAS alleles were allowed to form multicellular spheroids and the effects of different pharmacological compounds were studied after sectioning and staining for relevant markers of cell proliferation and apoptosis. RESULTS: Studies using colon cancer cells with gene disruptions suggested that the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway was essential for proliferation in 3-D culture. The dual PI3K-mTOR inhibitor NVP-BEZ235, currently in clinical trials, was found to inhibit phosphorylation of the mTOR target 4EBP1 in 3-D cultured cells. The ability of NVP-BEZ235 to inhibit tumour cell proliferation and to induce apoptosis was markedly more pronounced in 3-D cultures compared to monolayer cultures. It was subsequently found that NVP-BEZ235 was effective in inhibiting regrowth of 3-D cultured cells after treatment with two cytotoxic inhibitors of the ubiquitin-proteasome system (UPS), methyl-13-hydroxy-15-oxokaurenoate (MHOK) and bortezomib (Velcade®). CONCLUSIONS: The dual PI3K-mTOR inhibitor NVP-BEZ235 was found to reduce cell proliferation and to induce apoptosis in 3-D cultured colon carcinoma cells, NVP-BEZ235 is a promising candidate for use in sequential treatment modalities together with cytotoxic drugs to reduce the cell mass of solid tumours.