ImportanceGlioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.ObjectiveTo investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.Design, Setting, and ParticipantsThis phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.InterventionsThe active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.Main Outcomes and MeasuresThe primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.ResultsA total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).Conclusions and RelevanceIn this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.Trial RegistrationClinicalTrials.gov Identifier: NCT00045968
Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).
Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.
A sol-gel method is used to introduce fluorescent silica shells with tunable thickness on the spherical carbonyl iron particles (CIP) by a combined hydrolysis and condensation of tetraethyl orthosilicate (TEOS). Both gelatin B and 3-aminopropyltriethoxysilane (APTES) are used as primers to render the metal particle surface compatible with TEOS. The silica shell is formed through the hydrolysis and condensation of TEOS on the primer-treated CIP and the shell thickness can be controlled by varying the ratio of chemicals, such as TEOS and ammonia. The silica shell on the particle surface is confirmed by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA) and transmission electron microscopy (TEM). The magnetic and anti-corrosive properties of the CIP and CIP-silica particles have been evaluated. A conformal coating shell is confirmed surrounding the CIP against their etching/dissolution by protons. Polyurethane composites filled with CIP and CIPsilica particles are fabricated with a surface initiated polymerization (SIP) method. A salt fog industrial-level test indicates an improved anti-corrosive behavior of the CIP-silica/PU composites than that of the CIP/PU composites. Both CIP-silica particles and CIP-silica/PU composites exhibit better thermal stability and antioxidation capability than their CIP and CIP/PU counterparts, respectively due to the stronger barrier effect of the noble silica shell. The insulating silica shell decreases the efficiency of the electron transportation among the particles and thus leads to a higher resistivity in the composites.
Experiments confirm that small amounts of noise help a nanotube transistor detect noisy subthreshold electrical signals. Gaussian, uniform, and impulsive (Cauchy) noise produced this feedforward stochastic-resonance effect by increasing both the nanotube system's mutual information and its input−output correlation. The noise corrupted a synchronous Bernoulli or random digital sequence that fed into the thresholdlike nanotube transistor and produced a Bernoulli sequence. Both Shannon's mutual information and correlation measured the performance gain by comparing the input and output sequences. This nanotube SR effect was robust: it persisted even when infinite-variance Cauchy noise corrupted the signal stream. Such noise-enhanced signal processing at the nanolevel promises applications to signal detection in wideband communication systems and biological and artificial neural networks.
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