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Liquid biopsies utilizing plasma circulating tumor DNA (ctDNA) are anticipated to revolutionize decision-making in cancer care. In the field of lymphomas, ctDNA-based blood tests represent the forefront of clinically applicable tools to harness decades of genomic research for disease profiling, quantification, and detection. More recently, the discovery of nonrandom fragmentation patterns in cell-free DNA (cfDNA) has opened another avenue of liquid biopsy research beyond mutational interrogation of ctDNA. Through examination of structural features, nucleotide content, and genomic distribution of massive numbers of plasma cfDNA molecules, the study of fragmentomics aims at identifying new tools that augment existing ctDNA-based analyses and discover new ways to profile cancer from blood tests. Indeed, the characterization of aberrant lymphoma ctDNA fragment patterns and harnessing them with powerful machine-learning techniques are expected to unleash the potential of nonmutant molecules for liquid biopsy purposes. In this article, we review cfDNA fragmentomics as an emerging approach in the ctDNA research of B-cell lymphomas. We summarize the biology behind the formation of cfDNA fragment patterns and discuss the preanalytical and technical limitations faced with current methodologies. Then we go through the advances in the field of lymphomas and envision what other noninvasive tools based on fragment characteristics could be explored. Last, we place fragmentomics as one of the facets of ctDNA analyses in emerging multiview and multiomics liquid biopsies. We pay attention to the unknowns in the field of cfDNA fragmentation biology that warrant further mechanistic investigation to provide rational background for the development of these precision oncology tools and understanding of their limitations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sirpa Leppä: Abbvie: Consultancy; Bayer: Research funding*; BMS/Celgene: Research funding*; Genmab: Consultancy, research funding*; Gilead: Consultancy; Hutchmed: Research funding*; Incyte: Consultancy; Nordic Nanovector: Research Funding*; Novartis: Consultancy, honoraria, research funding*; Orion: Consultancy; Roche: Consultancy, research funding*; Sobi: Consultancy. *Not related to this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor., Material and Methods: We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment., Results: We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months., Discussion: The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.

Objectives: Testicular diffuse large B‐cell lymphoma (T‐DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor‐infiltrating lymphocytes (TILs) and PD‐1 expressing TILs associate with better survival in T‐DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival. Methods: We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T‐cells (CTLs; CD8+, OX40+, Granzyme B+, Ki‐67+, LAG‐3+, TIM‐3+, PD‐1+), CD4+ T‐cells (CD3+, CD4+, TIM‐3+, LAG‐3+), regulatory T‐cells (Tregs; CD3+, CD4+, FoxP3+), and T helper 1 cells (Th1; CD3+, CD4+, T‐bet+) in 79 T‐DLBCLs, and correlated the findings with patient demographics and outcome. Results: We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8+ TILs were Ki‐67+ and TIM‐3+ CTLs, whereas the most prominent CD4+ TILs were FoxP3+ Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T‐bet+FoxP3+ Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features. Conclusions: Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T‐DLBCL. [ABSTRACT FROM AUTHOR]

Translocations affecting both MYC and BCL2 are associated with a poor prognosis in diffuse large B-cell lymphomas. We have examined genetic aberrations combined with analyses of protein expression of respective gene products. Fluorescence in situ hybridization (FISH) for translocations of BCL2 and MYC and del17p13 was performed. Immunohistochemistry analyses included BCL2, MYC and TP53 protein expression. Sixty-seven patients with high-risk DLBCL participating in a prospective multicenter study were included. Six patients with simultaneous translocations of BCL2 and MYC had impaired overall (OS) ( p = 0.009) and progression-free survival (PFS) ( p = 0.009). Six patients with high coexpression of MYC and BCL2 proteins also had impaired OS ( p = 0.004) and PFS ( p = 0.002). Combining these groups identified nine patients with impaired OS ( p = 0.004) and PFS ( p = 0.005). Sixteen patients had double-hit translocation or protein expression and/or del17p13 and/or high TP53. This combined endpoint was associated with impaired OS ( p = 0.008) and PFS ( p = 0.036), and identified 70% of all deaths. [ABSTRACT FROM AUTHOR]

We have previously shown that expression of CD40 has a favorable prognostic impact in diffuse large B-cell lymphoma (DLBCL) after anthracycline-based chemotherapy. Here we examined the prognostic value of immunohistochemically defined CD40 expression in 95 patients with DLBCL treated with both anthracycline-based chemotherapy and rituximab. Using a 10% cut-off level, 77% of the patients had CD40-positive tumors and showed a superior overall survival ( p = 0.02 log-rank, hazard ratio 0.35, 95% CI 0.14–0.88, p = 0.03 Cox regression). When adjusted for International Prognostic Index in multivariate analysis, CD40 was not an independent prognostic factor (hazard ratio 0.39, 95% CI 0.15–1.04, p = 0.06 Cox regression). However, even after the introduction of immunochemotherapy, CD40 has a potential prognostic impact in DLBCL. Additional and larger studies are necessary, regarding the immunohistochemical robustness of CD40 and the biological mechanisms that contribute to the superior prognosis in CD40-expressing DLBCL. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK+ ALCL, 38% of ALK− ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK- ALCL (15%). Concurrent mutations were found in all subgroups except ALK+ ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30+ phenotype representing primarily ALK− ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL. [ABSTRACT FROM AUTHOR]