Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia
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Bibliographic record
Abstract
PURPOSE: Despite its clinical success, methotrexate (MTX) therapy is associated with toxicities such as seizures, the pathogenesis of which remains unclear. It has been suggested that hyperhomocysteinemia is caused by MTX and is responsible for its neurotoxic effects. The purposes of this study were to explore whether hyperhomocysteinemia was related to MTX administration and toxicity and whether homocysteine or MTX toxicity differed by methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier (RFC) genetic polymorphisms. PATIENTS AND METHODS: We studied 53 children with newly diagnosed acute lymphoblastic leukemia who were consecutively treated on a single clinical protocol that included two courses of high-dose MTX (high-dose methotrexate [HDMTX]; 2.5 or 5.0 g/m2 per day) as consolidation therapy. RESULTS: The study participants' median plasma homocysteine concentrations at 23 and 44 hours after HDMTX (9.00 micromol/L and 10.12 micromol/L, respectively) were greater than the concentrations immediately before HDMTX (5.77 micromol/L, P <.0001 for both comparisons). Seven days after HDMTX treatment, their plasma concentration returned to baseline. Nine patients experienced seizures, and five patients experienced thrombosis during the first 15 months of therapy, with a tendency for there to be higher plasma homocysteine in patients with seizures across all time points (P =.063) but not in patients with thrombosis (P =.59). We observed no significant differences in plasma or cerebrospinal fluid homocysteine levels or in toxicity based on the MTHFR 677C/T or RFC 80G/A genotypes. CONCLUSION: We conclude that homocysteine was transiently elevated after HDMTX and may be related to seizure risk in children with leukemia.
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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 | 0.003 | 0.004 |
| 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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it