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Purpose: The prognosis of relapsed primary central nervous system lymphoma remains a concern. This study aimed to compare the effects of various patient- and disease-related factors on the prognosis of relapsed primary central nervous system lymphoma (PCNSL)., Methods: We retrospectively collected real-world data from eight Finnish hospitals on 198 patients diagnosed with PCNSL between 2003 and 2020. Characteristics of the patients were available. At total of 63 patients with relapses were included after excluding seven isolated ocular relapses., Results: The median progression-free survival after relapse was 3 months. The median overall survival after the first relapse (OS2) was 4 months. Patients aged 70 or younger with good performance status who received autologous stem cell transplantation (ASCT) consolidation as second-line treatment had significantly better OS2 of 39 months (p = 0.002). OS2 for patients without ASCT consolidation remained at 3 months. Age over 70 years, poor performance status, and a first-line progression-free survival of less than 6 months negatively impacted the prognosis., Conclusion: This study confirms previous findings of poor outcomes in patients with relapsed PCNSL. Some subgroups, particularly those receiving ASCT consolidation, can achieve long-term remission with current treatment options. New treatment strategies are needed for patients ineligible for ASCT or those who do not respond to salvage induction therapies., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: There are few reports of clinical practice treatment patterns and efficacy in mantle cell lymphoma (MCL)., Materials and Methods: We retrospectively studied a large, multicenter, cohort of patients with MCL diagnosed between 2000 and 2020 in eight institutions., Results: 536 patients were registered (73% male, median of 70 years). Front-line treatment was based on high-dose cytarabine, bendamustine, and anthracyclines in 42%, 12%, and 15%, respectively. The median PFS for all patients was 45 months; 68, 34, and 30 months for those who received high-dose cytarabine-based, bendamustine-based and anthracycline-based therapy. 204 patients received second-line. Bendamustine-based treatment was the most common second-line regimen (36% of patients). The median second-line PFS (sPFS) for the entire cohort was 14 months; 19, 24, and 31 for bendamustine-, platinum-, and high-dose cytarabine-based regimens, with broad confidence intervals for these latter estimates. Patients treated with cytarabine-based therapies in the front-line and those with front-line PFS longer than 24 months had a substantially superior sPFS., Conclusion: Front-line treatment in this cohort of MCL was as expected and with a median PFS of over 3.5 years. Second-line treatment strategies were heterogeneous and the median second-line PFS was little over 1 year., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: In 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., Methods: The 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., Results: Thioredoxin-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)., Conclusions: Strong 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., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Central nervous system (CNS) relapse occurs in around 5% of diffuse large B-cell lymphoma (DLBCL) cases. No biomarkers to identify high-risk patients have been discovered. We evaluated the expression of lymphocyte-guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi-square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement (P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The cell cycle is under strict regulation by the retinoblastoma, p53 and p27 pathways, and the disruption of these pathways is an important characteristic of diffuse large B-cell lymphoma (DLBCL). In this study, we wanted to assess the function and prognostic significance of these pathways in DLBCL patients., Methods: Tissue samples from 120 DLBCL patients treated by means of R-CHOP-type chemotherapy were stained for the cell cycle-regulating proteins p16, p21, p27 and p53, and the germinal centre (GC) phenotype was determined according to Hans' algorithm. Based on the number of impaired cell cycle-regulating pathways a predictive score was obtained, covering three different prognostic groups: a 'favourable' group with damage in 0-1 of the studied pathways, a 'poor' group with damage in all three pathways and an 'intermediate' group comprising the rest of the patients., Results: The prognosis of non-GC DLBCL patients was significantly poorer vs. GC phenotype patients (P = 0.015). The prognostic score proved especially useful among non-GC phenotype patients, with 3-yrs relapse-free survival of 100% vs. 62.6% vs. 24.3% in the 'favourable-', 'intermediate-' and 'poor prognosis' groups, respectively (P = 0.003)., Conclusion: The prognosis of non-GC DLBCL patients is progressively impaired with the accumulation of damage in different cell cycle-regulating pathways., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: p53 mutations and high protein expression are associated with adverse prognosis in several lymphoma subtypes. Matrix metalloproteinase-9 (MMP-9) has also been found to correlate with poor survival in all lymphomas studied. The data concerning the clinical role of protein expression of p53 or gelatinases and their inhibitors in follicular lymphoma are rare. The purpose of this study was to evaluate the prognostic and clinical implications of the immunoreactive proteins p53, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-2 in follicular lymphoma., Methods: The material consisted of 67 patients with primarily non-transformed follicular lymphoma. Diagnostic lymph node tissue sections of patients were stained by immunohistochemical method using specific monoclonal antibodies., Results: p53 over-expression was detected in 8 (12%) out of 67 cases. p53 over-expression correlated with high grade (P = 0.011), bulky tumour (P = 0.031) and forthcoming transformation (P = 0.001). It also correlated with poor overall (P = 0.001) and cause-specific survival (P = 0.010) in multivariate analysis and had a strong inverse correlation with time to transformation (P < 0.001). MMP-2, MMP-9 and TIMP-2 expression correlated with high grade. MMP-9 positivity in centroblasts correlated with good chemotherapy response (P = 0.019), but it was not prognostic for survival. MMP-2, TIMP-1 or TIMP-2 did not associate with survival, either., Conclusions: In this study, p53 over-expression predicted both transformation to diffuse large B-cell lymphoma and poorer overall and cause-specific survival of patients with follicular lymphoma. Expression of gelatinases or their inhibitors did not have any significant correlations with prognosis, although MMP-9 predicted a good response to first-line chemotherapy.

Objectives: Circulating gelatinases and their tissue inhibitors measured at diagnosis have been shown to exhibit prognostic relevance in several solid tumours. The clinical data concerning their role in follow-up of cancer are still very preliminary. The aim of this study was to find out whether the concentrations of these circulating markers could be used as follow-up markers predicting the risk of lymphoma relapse., Methods: Here, we investigated these circulating molecules in a large (n = 126) follow-up material of lymphoma patients and in healthy controls (n = 44). The plasma samples of patients with Hodgkin's lymphoma (n = 31), non-Hodgkin's lymphoma (n = 95), and healthy controls were analysed by enzyme-linked immunosorbent assay for matrix metalloproteinase-9 (MMP-9), proMMP-2, matrix metalloproteinase-2-tissue inhibitor of metalloproteinase-2 (MMP-2-TIMP-2) complex, TIMP-1, and TIMP-2., Results: The patients with the highest plasma levels of MMP-2-TIMP-2 complex had a 3-fold risk of relapse when compared to the patients with lower levels (P = 0.036). Plasma levels of proMMP-2 and MMP-2-TIMP-2 complex as well as the proMMP-2/TIMP-2 ratio were significantly higher in patients with active lymphoma and those in remission when compared to healthy controls. On the contrary, the values of TIMP-2 were significantly lower in lymphoma patients than in controls., Conclusions: This study shows that lymphoma patients with the highest levels of MMP-2-TIMP-2 complex are at a marked risk of relapse. Moreover, plasma levels of MMP-2-TIMP-2 complex, proMMP-2, TIMP-2, and proMMP-2/TIMP-2 ratio are at abnormal level in patients with newly diagnosed lymphoma and those in remission when compared to healthy controls. They remain abnormal even after successful lymphoma treatments.

Objectives: The influence of matrix-tumour interactions in Hodgkin's lymphoma is poorly characterised, although a large part of the tumour often consists of reactive tissue. The aim of the present study was to assess the clinicopathological role of two main inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, in Hodgkin's lymphoma., Materials and Methods: The TIMP-1 and TIMP-2 protein expressions were studied from paraffin-embedded tumour sections of 68 patients with Hodgkin's lymphoma by using immunostaining with TIMP-1 and TIMP-2-specific antibodies. The results of the stainings were compared with the clinicopathological disease characteristics., Results: A total of 33.3% of the tumour tissue sections expressed TIMP-1 and 46.8% expressed TIMP-2. The expression of the TIMP-1 protein was found to be strongly associated with the nodular sclerosis subtype (P = 0.015) and the existence of a bulky tumour (P = 0.004) in Hodgkin's lymphoma. The expression of the TIMP-2 protein, on the other hand, correlated with the occurrence of B symptoms (P = 0.032)., Conclusions: These results provide the first clinical evidence suggesting that TIMP-1 could promote growth of Hodgkin's lymphoma, and may be linked to connective tissue turnover in the nodular sclerosis subtype. However, TIMP-2 is shown to correlate with systemic symptoms.

Objectives: The aim of the first Nordic mantle cell lymphoma (MCL) protocol was to study the clinical significance of an augmented CHOP induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) and to examine the prognostic significance of stem cell contamination rates in newly diagnosed patients with MCL., Patients and Methods: Forty-one newly diagnosed patients below 66 yr were enrolled and given three series of an augmented CHOP regimen. Responders underwent stem cell mobilization with a fourth course of CHOP, stem cell harvest and ASCT. Stem cell purging was optional in the protocol and followed the routine of each participating centre. The number of tumour cells in the reinfused autografts was estimated by flow cytometry or quantitative PCR., Results: Induction therapy led to complete remission (CR) in 11 of 41 patients (27%), partial remission (PR) in 20 of 41 patients (49%) and no response in nine patients (22%), whereas one patient was not evaluable. Twenty-seven of the 31 responders underwent ASCT and 24 achieved or maintained a CR. The overall and failure-free 4-yr survival on intention-to-treat basis were 51% and 15%, respectively. Among the transplanted patients, a significantly increased failure-free (P<0.03) and overall survival (P=0.03) was noted among patients transplanted in CR compared with PR, respectively. By contrast, reinfusion of highly variable numbers of tumour cells with the autografts (range 0.71-80 x 10(6) tumour cells), did not affect outcome., Conclusion: In MCL, an important strategy to improve the outcome will be to intensify the induction chemotherapy.

Objectives: The present study was carried out to clarify the role of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and the extent of neovascularization in the clinicopathologic behavior of non-Hodgkin's lymphomas., Methods: Paraffin-embedded histologic sections from 57 patients with aggressive non-Hodgkin's lymphomas were stained with MMP-2, MMP-9, TIMP-1, and factor VIII antibodies to correlate the expression of these markers to the clinical disease characteristics., Results: Strong MMP-9 staining was found to be an adverse prognostic factor among patients with aggressive B-cell lymphomas, the probabilities for 5-yr disease-free survival being 73%, 63%, 50%, and 0% in patients with grades 0, 1, 2, and 3 staining, respectively. Among the patients with strong (grades 2 and 3) MMP-9 staining, however, positivity for TIMP-1 indicated a trend toward a more favorable prognosis. TIMP-1 expression also correlated with the immunoblastic and anaplastic lymphoma subtypes. The expression of the proteins for MMP-2 and factor VIII had no independent prognostic role. None of the study parameters correlated with disease stage, the occurrence of extranodal infiltrates, the occurrence of bulky tumor, or the IPI scores., Conclusions: Positivity for MMP-9 immunoreactive protein is an independent sign of an unfavorable prognosis in non-Hodgkin's lymphomas. This is not mediated through influences in tumor dissemination or neovascularization indicating it to carry other important biological functions.

This is the first study to describe the role of MMP-2 and MMP-9 in Hodgkin's disease. Strong MMP-2 expression correlated with a favorable prognosis, while MMP-9 expression showed a tendency toward an adverse outcome. MMP-9 expression correlated with B symptoms and decreased new vessel formation. MMP-2 expression was associated with the nodular sclerosis subtype, and its expression was most pronounced in the vicinity of sclerosis. Neither of the gelatinases nor the extent of neovascularization correlated with tumor stage, the occurrence of bulky disease, or extranodal infiltrates. Together, these findings imply that the adverse role of MMP-9 may be associated with the controlling of immunological processes but not the invasion probabilities or neovascularization of the tumor. The favorable prognostic value of MMP-2 is surprising in view of the role of MMPs in solid tumors. This, however, may be linked to the basic biological differences of hematological malignancies vs. other tumors.