Surgical ischemia and detection of clear cell renal cell carcinoma biomarkers.
Bibliographic record
Abstract
e15571 Background: To discover biomarkers of progression in patients with localized clear cell renal cell carcinoma (ccRCC), we sought to screen targeted protein and mRNA biomarkers from patient tumor specimens. We first addressed pre-analytic biases of tumor heterogeneity and “cold” ischemia, by comparing biomarkers in pre-operative vs. postoperative tumor samples. Methods: Within matched patients we collected, (1) preoperative diagnostic needle core biopsies for comparison to postoperative nephrectomy ccRCC samples (1st cohort), and, (2) intra-operative pre-ischemic biopsies for comparison to postoperative samples (2ndcohort). Protein biomarkers were screened with the MD Anderson reverse phase protein array (RPPA) and RNA using a custom NanoString signature codeset previously validated to predict prognosis in ccRCC. Results: Striking differences in protein and mRNA detection were observed between diagnostic biopsies and postoperative samples in the 1st cohort but the times to surgery was variable, and only a single technical replicate was available per patient per time point. In the 2ndcohort however, there were equally profound global differences in RNA and protein detection between the pre-ischemic and postoperative samples, across triplicate and physically separate samples. Concordant with previous studies, there was little additional change in biomarker detection in postoperative samples up to 2 hours after surgical extirpation. Phosphoproteins showed greater lability than total protein levels. Even in this limited biomarker set, several pathways were identified as significantly influenced, including the MAPK, mTOR-PI3K and EGFR pathways. Conclusions: We demonstrate for the first time in human cancers that perioperative “warm” ischemia has a broad and profound influence on protein and mRNA biomarker detection, which is far greater than post-operative “cold” ischemia. Assessment of clinically relevant biomarkers may therefore be distorted by perioperative ischemia, and high-throughput analyses using post-operative ccRCC specimens should be interpreted with caution. Validation of these findings in a larger patient cohort, and in other tumor types is urgently warranted.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| 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".