SCIDOT-15. DISRUPTING THE BLOOD-BRAIN BARRIER IN NEURO-ONCOLOGY: INNOVATIONS, ACHIEVEMENTS, AND LESSONS LEARNED FROM CLINICAL TRIALS
Bibliographic record
Abstract
Abstract BACKGROUND The blood-brain barrier (BBB) presents a formidable challenge for the development of effective therapeutics in neuro-oncology. Several strategies for the disruption of the BBB have been investigated in humans. An in-depth analysis of the concepts, design, and outcomes from these trials can provide insight into optimizing strategies for safe, selective, and efficacious BBB disruption for drug delivery. METHODS The clinicaltrials.gov database was searched on June 9th, 2019 using the term blood-brain barrier. Results were screened for studies relevant to neuro-oncology. When available, linked publications were also reviewed for supplemental information. The Pubmed database was also searched for BBB disruption strategies, to identify publications not linked to a trial registry. Details regarding patient eligibility, intervention, comparators, outcomes and other design criteria were extracted. RESULTS Among 288 registered studies, 42 were relevant to neuro-oncology. Drug-based methods predominated (33/42) but there has been a surge in device-based methods with all registrations after 2015. Mannitol was the most common drug-based method (16/33, 5 Phase II), followed by RMP-7 (8/33, 3 Phase II), Ang1005 (7/33, 4 Phase II and one pending Phase III), and Regadenoson (2/33, one Phase 0 and one Phase I). MR-guided focused ultrasound was the most common device-based method (5/9), followed by MR-guide laser ablation (2/9), Sonocloud (1/9), and transcranial magnetic stimulation (1/9). All device studies have been early phase. Most early phase studies focusing on safety and tolerability met objectives. Some Phase II studies showed preliminary efficacy but control arms were lacking. Many Phase II studies have been terminated/suspended. CONCLUSIONS Diverse BBB disruption methods have been investigated and most appear to be safe and tolerable. Advanced phase studies focusing on survival differences have been limited by heterogeneous tumors and lack of control arms. Objective establishment of BBB disruption was limited. Concerted and standardized clinical trial efforts are needed.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.009 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".