Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P=.002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates.Peer reviewe

Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice

Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe−/−Neil3−/− mice on high-fat diet showed accelerated plaque formation as compared to Apoe−/− mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe−/−Neil3−/− mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage

Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P=.002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates

Multicolor flowcytometrisk immunfenotyping for B-cellepopulasjoner i blod- og benmargsprøver

Denne oppgaven har hatt som mål å finne egnete multicolor antistoffkombinasjoner for identifisering av B-cellepopulasjoner i blod og benmarg ved hjelp av flowcytometrisk immunfenotyping. B-cellepopulasjoner av interesse er maligne B-cellekloner ved ulike typer B-cellelymfomer, og i tillegg normale B-cellepopulasjoner i blod som undersøkes i forhold til immunsvikttilstander. Dette innebærer å velge ut passende antistoffkloner og fluorokromer som kan benyttes sammen i antistoffkombinasjoner. For å stadfeste dette er det blitt utført titrering av alle antistoffer og annen kvalitetssikring av kombinasjonene, noe som har vært vellykket med noen få unntak. I tillegg er de nye multicolor-kombinasjonene sammenlignet med gammel metode. De to metodene viser ingen signifikant forskjell fra hverandre på 5 % nivå. For å identifisere maligne B-cellekloner er det tatt utgangspunkt i europeiske retningslinjer utarbeidet av EuroFlow-konsortiumet. Fem multicolor-kombinasjoner er testet ut og tatt i bruk, og ved hjelp av avanserte analysestrategier med spesialtilpasset softwareprogram er det oppnådd å skille mellom seks ulike typer B-cellelymfomer på grunnlag av unike immunfenotypeprofiler ut fra opptil 29 parametre. Diagnose kan settes for fire av de seks B-cellelymfomene ut fra immunfenotypeprofil.Det er også blitt utarbeidet og tatt i bruk to multicolor-kombinasjoner for identifisering av B-cellepopulasjoner i perifert blod. Design av disse kombinasjonene er gjort med utgangspunkt i publikasjoner. Kombinasjonene har vist seg å være egnet for å skille mellom alle B-cellepopulasjoner som er nødvendige for klassifisering av ulike grupper immunsvikt. Det er i tillegg blitt etablert egne normalverdier for normale B-cellepopulasjoner i blod

Multicolor Panels for Flow Cytometric Immunophenotyping of B-cell Populations in Blood and Bone Marrow Samples

Denne oppgaven har hatt som mål å finne egnete multicolor antistoffkombinasjoner for identifisering av B-cellepopulasjoner i blod og benmarg ved hjelp av flowcytometrisk immunfenotyping. B-cellepopulasjoner av interesse er maligne B-cellekloner ved ulike typer B-cellelymfomer, og i tillegg normale B-cellepopulasjoner i blod som undersøkes i forhold til immunsvikttilstander. Dette innebærer å velge ut passende antistoffkloner og fluorokromer som kan benyttes sammen i antistoffkombinasjoner. For å stadfeste dette er det blitt utført titrering av alle antistoffer og annen kvalitetssikring av kombinasjonene, noe som har vært vellykket med noen få unntak. I tillegg er de nye multicolor-kombinasjonene sammenlignet med gammel metode. De to metodene viser ingen signifikant forskjell fra hverandre på 5 % nivå. For å identifisere maligne B-cellekloner er det tatt utgangspunkt i europeiske retningslinjer utarbeidet av EuroFlow-konsortiumet. Fem multicolor-kombinasjoner er testet ut og tatt i bruk, og ved hjelp av avanserte analysestrategier med spesialtilpasset softwareprogram er det oppnådd å skille mellom seks ulike typer B-cellelymfomer på grunnlag av unike immunfenotypeprofiler ut fra opptil 29 parametre. Diagnose kan settes for fire av de seks B-cellelymfomene ut fra immunfenotypeprofil.Det er også blitt utarbeidet og tatt i bruk to multicolor-kombinasjoner for identifisering av B-cellepopulasjoner i perifert blod. Design av disse kombinasjonene er gjort med utgangspunkt i publikasjoner. Kombinasjonene har vist seg å være egnet for å skille mellom alle B-cellepopulasjoner som er nødvendige for klassifisering av ulike grupper immunsvikt. Det er i tillegg blitt etablert egne normalverdier for normale B-cellepopulasjoner i blod

NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture

Myocardial infarction (MI) triggers a reparative response involving fibroblast proliferation and differentiation driving extracellular matrix modulation necessary to form a stabilizing scar. Recently, it was shown that a genetic variant of the base excision repair enzyme NEIL3 was associated with increased risk of MI in humans. Here, we report elevated myocardial NEIL3 expression in heart failure patients and marked myocardial upregulation of Neil3 after MI in mice, especially in a fibroblast-enriched cell fraction. Neil3−/− mice show increased mortality after MI caused by myocardial rupture. Genome-wide analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) reveals changes in the cardiac epigenome, including in genes related to the post-MI transcriptional response. Differentially methylated genes are enriched in pathways related to proliferation and myofibroblast differentiation. Accordingly, Neil3−/− ruptured hearts show increased proliferation of fibroblasts and myofibroblasts. We propose that NEIL3-dependent modulation of DNA methylation regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation after MI