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Intravenous valproate, levetiracetam, and fosphenytoin stopped status epilepticus that was resistant to initial treatment with lorazepam in approximately half the patients and did not differ significantly in effectiveness. Hypotension was numerically — but not significantly — more frequent with fosphenytoin.

Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4 + and CD8 + effector T cells. T cell receptor β-chain (TCRβ) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV’s mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 . Treatment of patients with advanced hepatocellular carcinoma with a personalized DNA vaccine in combination with anti-PD-1 therapy was safe and led to encouraging clinical efficacy, with immunological analyses confirming the induction of tumor antigen-specific T cell responses.

Pulmonary vein antrum isolation (PVI) as a treatment of paroxysmal atrial fibrillation (AF) is associated with a high rate of success; however, outcomes for treating persistent and long-standing persistent AF with PVI alone are substantially lower and often require multiple procedures to maintain long-term freedom from atrial arrhythmias. Foci and/or substrate outside the pulmonary veins, particularly in the left atrial appendage (LAA), has been identified as a key mechanism in the maintenance of persistent AF and long-standing persistent AF. The goals of the study are to evaluate the safety and effectiveness of the LARIAT System to percutaneously isolate and ligate the LAA and to determine if LAA ligation as adjunctive therapy to PVI improves maintenance of sinus rhythm in patients with persistent and long-standing persistent AF. The trial is a prospective, multicenter, randomized controlled study. The trial design incorporates a Bayesian adaptive design that will randomize a maximum of 600 patients with persistent or long-standing persistent AF to LAA ligation and PVI vs PVI alone in a 2:1 randomization. The primary end points include 30-day safety of the LARIAT procedure and freedom from documented AF, atrial flutter, or atrial tachycardia of more than 30 seconds at 12 months after the PVI off antiarrhythmic drugs. Key secondary outcomes include a composite of cardiovascular death and stroke, as well as quality of life. The aMAZE trial will determine if LAA ligation as adjunctive therapy to PVI increases the efficacy of maintaining sinus rhythm in patients with persistent and long-standing persistent AF.

Background Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis. Methods The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC. Discussion Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study. Conclusions The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care. Trial registration ClinicalTrials.gov Identifier NCT03903835 . Date of registration: April 4, 2019. Status: Recruiting.

WISDOM (Women Informed to Screen Depending on Measures of Risk) is a randomized trial to assess whether personalized breast cancer screening-where women are screened biannually, annually, biennially, or not at all depending on risk and age-can prevent as many advanced (stage IIB or higher) cancers as annual screening in women ages 40-74 years across 5 years of trial time. The short study time in combination with design choices of not requiring study entry and exit mammograms for all participants may introduce different sources of bias in favor of either the personalized or the annual arm. We designed a simulation model and performed 5000 virtual WISDOM trials to assess potential biases. Each virtual trial simulated 65 000 randomly assigned participants who were each assigned a risk stratum and a time to stage of at least IIB cancer sampled from an exponential distribution with the hazard rate based on the risk stratum. Results from the virtual trials were used to evaluate two candidate analysis strategies with respect to susceptibility for introducing bias: 1) difference between arms in total number of events over total trial time, and 2) difference in number of events within complete screening cycles. Based on the simulations, about 86 stage IIB or higher cancers will be detected within the trial and the total exposure time will be about 74 000 years in each arm. Potential ascertainment bias is introduced at study entry and exit. Analysis strategy 1 works better for the nonscreened stratum, whereas method 2 is considerably more unbiased for the strata of women screened biennially or every 6 months. Combining the two candidate analysis approaches gives a reasonably unbiased analysis based on the simulations and is the method we will use for the primary analysis in WISDOM. Publishing the WISDOM analysis approach provides transparency and can aid the design and analysis of other individualized screening trials.

SUMMARYConsidering and avoiding these 10 typical statistical pitfalls when submitting papers to this (or any other) journal will both improve the paper and hopefully increase the chances that it is accepted and published.

Background Bayesian predictive probabilities can be used for interim monitoring of clinical trials to estimate the probability of observing a statistically significant treatment effect if the trial were to continue to its predefined maximum sample size. Purpose We explore settings in which Bayesian predictive probabilities are advantageous for interim monitoring compared to Bayesian posterior probabilities, p-values, conditional power, or group sequential methods. Results For interim analyses that address prediction hypotheses, such as futility monitoring and efficacy monitoring with lagged outcomes, only predictive probabilities properly account for the amount of data remaining to be observed in a clinical trial and have the flexibility to incorporate additional information via auxiliary variables. Limitations Computational burdens limit the feasibility of predictive probabilities in many clinical trial settings. The specification of prior distributions brings additional challenges for regulatory approval. Conclusions The use of Bayesian predictive probabilities enables the choice of logical interim stopping rules that closely align with the clinical decision-making process.

We present a novel Bayesian adaptive comparative effectiveness trial comparing three treatments for status epilepticus that uses adaptive randomization with potential early stopping. The trial will enroll 720 unique patients in emergency departments and uses a Bayesian adaptive design. The trial design is compared to a trial without adaptive randomization and produces an efficient trial in which a higher proportion of patients are likely to be randomized to the most effective treatment arm while generally using fewer total patients and offers higher power than an analogous trial with fixed randomization when identifying a superior treatment. When one treatment is superior to the other two, the trial design provides better patient care, higher power, and a lower expected sample size.

Scientific and medical authors tend to be biased toward submitting \"statistically significant\" findings for publication. Journals show a similar bias in publishing such \"positive\" studies. The large number of publications in medical research means that, in a field obsessed with controlling Type I error rates, we have journals with an abundance of Type I errors. Failing to publish studies that do not show a treatment or exposure effect creates a literature conspicuously absent of trials necessary for unbiased meta-analyses and systematic reviews. Furthermore, by shelving or rejecting studies with nonstatistically significant outcomes, authors and editors censor the most important contributors to medical research: our consenting volunteers.