MAPK and mTOR Inhibition Improves Childhood RASopathy-Associated Hypertrophic Cardiomyopathy
Bibliographic record
Abstract
All articles of this category Background: To evaluate the benefit of mutation-specific small molecule inhibitors of target of rapamycin (mTORi) or MAPK kinase (MEKi) in RAS-CM patients with severe pediatric-onset cardiomyopathy associated with distinct germline mutations in RAS/mitogen-activated protein kinase (MAPK) pathway (RAS-CM). Method: Retrospective case–control analysis on 33 children with progressive RAS-CM receiving off-label or compassionate use mTORi and/or MEKi in addition to standard therapies (“treatment group”) and 40 age-, gender-, genotype- and disease-matched natural history patients (“control group”) in 21 European, North American, and British centers. Results: Over a follow-up period of 3,200 patient-months, 67% of critically ill patients presenting in severe heart failure survived in the treatment versus none in the control group ( p = 0.013). Transplant-free survival without undergoing surgical outflow tract resection was 79% in the treatment compared to 20% in the controls ( p < 0.001). From baseline to last follow-up time point, there was a greater decrease in heart failure classification and myocardial wall thickness Z-score measured on echocardiography in treatment compared to control cases (median [IQR] change in Ross classification −2 [−2; −1] vs. −1 [−1.5; −0.5], p = 0.024; and in myocardial wall thickness −1.2 [−2.5; −0.1] vs. −0.7 [−0.9; 0.5], p = 0.027). Skin and mucous membranes were the most common organs affected by side effects, requiring cessation or reduction of therapy in 27% of patients. No life-threatening adverse events related to mTORi or MEKi were observed. Conclusion: Selected RASopathy patients may benefit from novel mechanism-informed therapeutics targeting the RAS/MAPK pathway. Clinical trials are needed to substantiate the findings reported in this retrospective case-control analysis. Publication History Article published online: 28 January 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".