Utility of 3D multimodality imaging in the implantation of intracranial electrodes in epilepsy.

OBJECTIVE: We present a single-center prospective study, validating the use of 3D multimodality imaging (3 DMMI) in patients undergoing intracranial electroencephalography (IC-EEG). METHODS: IC-EEG implantation preparation entails first designing of the overall strategy of implantation (strategy) and second the precise details of implantation (planning). For each case, the multidisciplinary team made decisions on strategy and planning before the disclosure of multimodal brain imaging models. Any changes to decisions, following disclosure of the multimodal models, were recorded. RESULTS: Disclosure of 3 DMMI led to a change in strategy in 15 (34%) of 44 individuals. The changes included addition and subtraction of electrodes, addition of grids, and going directly to resection. For the detailed surgical planning, 3 DMMI led to a change in 35 (81%) of 43 individuals. Twenty-five (100%) of 25 patients undergoing stereo-EEG (SEEG) underwent a change in electrode placement, with 158 (75%) of 212 electrode trajectories being altered. SIGNIFICANCE: The use of 3 DMMI makes substantial changes in clinical decision making.

Advancing novel therapies for neurodegeneration through an innovative model for industry-academia collaborations: A decade of the Eisai-UCL experience.

External innovation initiatives in the pharmaceutical industry have become an integral part of research and development. Collaborations have been built to enhance innovation, mitigate risk, and share cost, especially for neurodegenerative diseases, a therapeutic area that has suffered from high attrition rates. This article outlines the Eisai-University College London (UCL) Drug Discovery and Development Collaboration as a case study of how to implement a productive industry-academic partnership. In the first 10 years, seven projects have been established and the first project, a novel anti-tau antibody for Alzheimer's disease, has entered clinical trials, providing early validation of this collaboration model.

Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial.

Background A substantial and unmet clinical need exists for pharmacological treatment of cannabis use disorders. Cannabidiol could offer a novel treatment, but it is unclear which doses might be efficacious or safe. Therefore, we aimed to identify efficacious doses and eliminate inefficacious doses in a phase 2a trial using an adaptive Bayesian design. METHODS: We did a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial at the Clinical Psychopharmacology Unit (University College London, London, UK). We used an adaptive Bayesian dose-finding design to identify efficacious or inefficacious doses at a-priori interim and final analysis stages. Participants meeting cannabis use disorder criteria from DSM-5 were randomly assigned (1:1:1:1) in the first stage of the trial to 4-week treatment with three different doses of oral cannabidiol (200 mg, 400 mg, or 800 mg) or with matched placebo during a cessation attempt by use of a double-blinded block randomisation sequence. All participants received a brief psychological intervention of motivational interviewing. For the second stage of the trial, new participants were randomly assigned to placebo or doses deemed efficacious in the interim analysis. The primary objective was to identify the most efficacious dose of cannabidiol for reducing cannabis use. The primary endpoints were lower urinary 11-nor-9-carboxy-δ-9-tetrahydrocannabinol (THC-COOH):creatinine ratio, increased days per week with abstinence from cannabis during treatment, or both, evidenced by posterior probabilities that cannabidiol is better than placebo exceeding 0·9. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT02044809) and the EU Clinical Trials Register (2013-000361-36). FINDINGS: Between May 28, 2014, and Aug 12, 2015 (first stage), 48 participants were randomly assigned to placebo (n=12) and to cannabidiol 200 mg (n=12), 400 mg (n=12), and 800 mg (n=12). At interim analysis, cannabidiol 200 mg was eliminated from the trial as an inefficacious dose. Between May 24, 2016, and Jan 12, 2017 (second stage), randomisation continued and an additional 34 participants were allocated (1:1:1) to cannabidiol 400 mg (n=12), cannabidiol 800 mg (n=11), and placebo (n=11). At final analysis, cannabidiol 400 mg and 800 mg exceeded primary endpoint criteria (0·9) for both primary outcomes. For urinary THC-COOH:creatinine ratio, the probability of being the most efficacious dose compared with placebo given the observed data was 0·9995 for cannabidiol 400 mg and 0·9965 for cannabidiol 800 mg. For days with abstinence from cannabis, the probability of being the most efficacious dose compared with placebo given the observed data was 0·9966 for cannabidiol 400 mg and 0·9247 for cannabidiol 800 mg. Compared with placebo, cannabidiol 400 mg decreased THC-COOH:creatinine ratio by -94·21 ng/mL (95% interval estimate -161·83 to -35·56) and increased abstinence from cannabis by 0·48 days per week (0·15 to 0·82). Compared with placebo, cannabidiol 800 mg decreased THC-COOH:creatinine ratio by -72·02 ng/mL (-135·47 to -19·52) and increased abstinence from cannabis by 0·27 days per week (-0·09 to 0·64). Cannabidiol was well tolerated, with no severe adverse events recorded, and 77 (94%) of 82 participants completed treatment. INTERPRETATION: In the first randomised clinical trial of cannabidiol for cannabis use disorder, cannabidiol 400 mg and 800 mg were safe and more efficacious than placebo at reducing cannabis use. FUNDING: Medical Research Council.

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer.

UNLABELLED: Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized (131)I-labeled anti-carcinoembryonic antigen antibody ((131)I-huA5B7), with cetuximab in colorectal cancer (CRC). METHODS: Three human CRC cell lines--SW1222, LoVo, and LS174T--were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of (131)I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis. RESULTS: Selective tumor targeting was achieved with (131)I-huA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair. CONCLUSION: Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen-expressing malignancies could also benefit from this approach.

A novel method for implementation of frameless StereoEEG in epilepsy surgery.

BACKGROUND: Stereoelectroencephalography (SEEG) is an invasive diagnostic procedure in epilepsy surgery that is usually implemented with frame-based methods. OBJECTIVE: To describe a new technique of frameless SEEG and report a prospective case series at a single center. METHODS: Image integration and planning of electrode trajectories were performed preoperatively on specialized software and exported to a Medtronic S7 StealthStation. Trajectories were implemented by frameless stereotaxy using percutaneous drilling and bolt insertion. RESULTS: Twenty-two patients went this technique, with the insertion of 187 intracerebral electrodes. Of 187 electrodes, 175 accurately reached their neurophysiological target, as measured by postoperative computed tomography reconstruction and multimodal image integration with preoperative magnetic resonance imaging. Four electrodes failed to hit their target due to extradural deflection, and 3 were subsequently resited satisfactorily. Eight electrodes were off target by a mean of 3.6 mm (range, 0.9-6.8 mm) due to a combination of errors in bolt trajectory implementation and bending of the electrode. There was 1 postoperative hemorrhage that was clinically asymptomatic and no postoperative infections. Sixteen patients were offered definitive cortical resections, and 6 patients were excluded from resective surgery. CONCLUSION: Frameless SEEG is a novel and safe method for implementing SEEG and is easily translated into clinical practice.