impact in DLBCL. [14][15][16][17] Of the macrophages, classically activated M1 type TAM have been described as "good", acting to prevent the growth of tumor tissue, whereas the alternative M2 type TAM may have an opposite effect promoting angiogenesis and tumor development. [18][19][20] Importantly, however, studies in follicular lymphoma have demonstrated that the prognostic significance of the tumor microenvironment and especially macrophages is highly dependent on a given therapy. [21][22][23] In the present study, we investigated how the combination of rituximab with chemotherapy influences non-malignant inflammatory cell-associated clinical outcome in DLBCL. Among all studied markers for macrophages, dendritic, and lymphoid cells, we found that pretreatment gene expression of a macrophage marker CD68 and immunohistochemically defined CD68+ TAM content had a positive prognostic impact on the survival of DLBCL patients treated with chemoimmunotherapy, whereas in patients treated without rituximab, CD68 + TAM content was associated with a poor outcome. Methods Patients and samplesThe screening cohort consisted of prospectively collected DLBCL patients who were less than 65 years old and had primary high-risk (age-adjusted IPI score 2-3) disease. They were treated in the Nordic phase II NLG-LBC-04 protocol with dose-dense chemoimmunotherapy followed by systemic central nervous system prophylaxis. 24 The patients in this correlative study represent a subset of patients in the main clinical trial and were selected on the basis of DLBCL histology, the availability of fresh frozen tissue for RNA extraction and exon arrays (gene expression cohort; n=38) and formalin-fixed, paraffin-embedded lymphoma tissue containing adequate material for the preparation of tissue microarrays (TMA; immunohistochemistry cohort; n=59), and the patients' consent to correlative studies. Details of the screening cohort are provided in Table 1, the Online Supplementary Material and Online Supplementary Table S1.The clinical protocol and sampling were approved by Institutional Review Boards, National Medical Agencies and Ethics Committees in Denmark, Finland, Norway and Sweden, and the trial was registered at ClinicalTrials.gov, number NCT01502982.To validate the findings, three independent retrospective series of chemoimmunotherapy-treated DLBCL patients were used. In order to confirm gene expression data, we used RNA sequencing data from 92 patients generated by the Cancer Genome Characterization Initiative (CGCI; dbGaP database applied study accession: phs000532.v3.p1) 25,26 and oligonucleotide-based microarray data from 233 DLBCL patients generated by the Lymphoma/Leukemia Molecular Profiling Project (LLMPP; GEO dataset: GSE10846).10 Both cohorts are subsets of the original study populations treated with a R-CHOP-like regimen based on the availability of complete expression data and clinical information (Online Supplementary Table S2).In order to confirm the immunohistochemical data, an independent population-based series of ...
Inadequate molecular and clinical stratification of the patients with high-risk diffuse large B-cell lymphoma (DLBCL) is a clinical challenge hampering the establishment of personalized therapeutic options. We studied the translational significance of liquid biopsy in a uniformly treated trial cohort. Pretreatment circulating tumor DNA (ctDNA) revealed hidden clinical and biological heterogeneity, and high ctDNA burden determined increased risk of relapse and death independently of conventional risk factors. Genomic dissection of pretreatment ctDNA revealed translationally relevant phenotypic, molecular, and prognostic information that extended beyond diagnostic tissue biopsies. During therapy, chemorefractory lymphomas exhibited diverging ctDNA kinetics, whereas end-of-therapy negativity for minimal residual disease characterized cured patients and resolved clinical enigmas, including false residual PET positivity. Furthermore, we discovered fragmentation disparities in the cell-free DNA that characterize lymphoma-derived ctDNA and, as a proof-of-concept for their clinical application, utilized machine learning to show that end-of-therapy fragmentation patterns predict outcome. Altogether, we have discovered novel molecular determinants in the liquid biopsy that can non-invasively guide treatment decisions.
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.
Two escBEACOPP plus six sBEACOPP is efficacious in advanced-stage high-risk HL. We document a high incidence of aseptic bone necrosis, possibly related to prednisolone.
In a relatively large cohort of patients with DLBCL analyzed by chromosome banding, loss of 17p was the only chromosomal abnormality associated with inferior survival in uni- and multivariate analysis.
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