Expression of Hypoxia-Inducible Factor (HIF) Is An Independent Favorable Prognostic Factor in Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP
Notice bibliographique
Résumé
Abstract HIF is a transcription factor that regulates gene expression in response to decreases in cellular oxygenation (hypoxia). Genes activated by HIF are involved in glycolysis, glucose transport, angiogenesis, cell proliferation, cell migration, cell metabolism, and cell survival. Many of these genes confer protection against the consequences of oxygen deprivation while others enhance resistance to chemotherapy or radiotherapy. Clinically, evidence of elevated HIF protein correlates with poor prognosis in lung, breast, colorectal, brain, pancreatic, ovarian, renal, and bladder cancers. Our preliminary tissue micro array (TMA) data suggested that HIF is frequently stabilized in lymphoma (BJH2008; 141:676), especially among patients with diffuse large B-cell lymphoma (DLBCL). We also found that constitutive expression of HIF-1α and/or HIF-2α is stabilized in a set of established lymphoma cell lines, underscoring the potential impact of HIF in lymphoma. To further investigate the importance of HIF, we examined TMAs for HIF-1α expression from 153 patients with DLBCL treated with CHOP or rituximab-CHOP (R-CHOP) at the BCCA between 1999–2002. Treatment was before (pre-rituximab) and after (post-rituximab) institution of a policy recommending the combination of rituximab with CHOP for all patients with newly diagnosed advanced-stage DLBCL (March 2001). Tissue sections were stained with monoclonal antibody to HIF-1α and expression (nuclear) was scored by computer (Automated Cellular Imaging System) and validated by pathology review. HIF was dichotomized as either negative (neg; no HIF staining) or positive (pos; score of 1 or greater). Of the 153 patients, 78 were consecutively treated with R-CHOP, while 75 had received CHOP. We found HIF pos expression in 63% (49/78) of patients treated with R-CHOP and 59% (44/75) treated with CHOP (p=NS). Further, based on the Hans algorithm, HIF was expressed in 62% of germinal center (GC) patients and 59% of non-GC patients (P=NS). In the R-CHOP group (see Figure 1A and 1B), the 5-year progression-free survival (PFS) was 45% for HIF neg patients vs 62% for HIF pos (log rank p=0.0187); while the 5-year overall survival (OS) was 48% for HIF neg vs 76% for HIF pos (log rank p=0.025). In patients treated with CHOP, there was no difference in outcome between HIF pos and HIF neg subsets. In multivariate analysis in the R-CHOP treated group, controlling for the International Prognostic Index (IPI), HIF pos expression remained a significant independent predictor for OS (p=0.03), while the IPI was of borderline significance (p=0.051). Comparison with other biomarkers showed that HIF did not correlate with expression of bcl-2, CD10, MUM-1, or FOXP1; while a high correlation was detected with bcl-6 and HIF (among HIF pos R-CHOP patients, 94% were bcl-6 pos and 6% were bcl-6 neg; p=0.004). We conclude that expression of HIF-1α is an important and heretofore undiscovered independent favorable prognostic factor for PFS and OS in DLBCL patients treated with R-CHOP, but not in patients treated with CHOP. These data suggest there may be an important biological interaction between CD20 monoclonal antibody-based therapy and HIF or downstream genes regulated by HIF. Further study of this observation is warranted. Figure 1. Survival according to HIF-1α status in patients treated with R-CHOP. Figure 1. Survival according to HIF-1α status in patients treated with R-CHOP.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».