AimsOxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown.MethodsDiagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome.ResultsNuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival.ConclusionsNrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group.

Mantle cell lymphoma (MCL) is a rare peripheral B-cell lymphoma characterised by eventual relapse and progression towards a more aggressive disease biology. With the introduction of rituximab-and cytarabine-based immunochemotherapy regimens, the prognosis of the disease has changed dramatically over the last two decades. To assess the real-world survival of patients with MCL, we used a population-based cohort of 564 patients with MCL who were diagnosed and treated between 2000 and 2020. Patient data were collected from seven Finnish treatment centres and one Spanish treatment centre. For the entire patient population, we report a 2-year overall survival (OS) rate of 77%, a 5-year OS of 58%, and a 10-year OS of 32%. The estimated median OS was 80 months after diagnosis. MCL is associated with increased mortality across the entire patient population. Additionally, we assessed the survival of patients after MCL relapse with the aim of establishing a cut-off point of prognostic significance. Based on our statistical analysis of survival after the first relapse, disease progression within 24 months of the initial diagnosis should be considered as a strong indicator of poor prognosis.

ObjectiveIn diffuse large B‐cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R‐CHOP regimen.MethodsThe present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide‐containing high‐dose regimen (n = 37) and etoposide‐containing frontline treatment (n = 69, R‐CHOEP) were studied using immunohistochemical thioredoxin‐1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin.ResultsThioredoxin‐1 knockdown sensitised DLBCL cells to doxorubicin (P < .0001) but decreased etoposide‐induced cell death (P < .00001). In DLBCL patients who received etoposide‐containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5‐year overall survival (46% vs 76%, P = .026) and disease‐specific survival (68% vs 90%, P = .026).ConclusionsStrong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R‐CHOP immunochemotherapy.

DLBCL is the most common type of non-Hodgkin lymphoma with a substantial group of patients suffering a poor prognosis. Therefore more specific markers are required for better understanding of disease biology and treatment. This study demonstrates that testis-specific antioxidant enzymes TXNDC2, TXNDC3, and TXNDC6 alongside oxidative stress marker 8-OHdG are expressed in both testicular and systemic DLBCL, and their presence or absence has correlations with clinical risk factors such as the number of extranodal effusion, the appearance of B-symptoms, and treatment response. Biopsy samples were collected from 28 systemic and 21 testicular male DLBCL patients. The samples were histostained with TXNDC2, TXNDC3, TXNDC6, and 8-OHdG, then graded by a hematopathologist blinded to clinical data. Immunoelectron microscopy was used as a second method to confirm the reliability of the acquired immunohistochemistry data. The absence of nuclear TXNDC2 expression in testicular DLBCL cells correlated with worse primary treatment response, cytoplasmic TXNDC3 expression in testicular and systemic DLBCL associated with lower frequency of B-symptoms, and TXNDC6 expression in cytoplasm in systemic DLBCL had a clinical significance with higher LD levels suggesting a role in the biological nature of these lymphomas. Overall, TXNDC3 cytoplasmic expression is correlated with a more positive outcome in both testicular and systemic DLBCL, while TXNDC6 cytoplasmic expression is associated with a negative outcome in systemic DLBCL.