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B Introduction: b Individualized, PET2-guided first-line treatment of patients with advanced-stage classical Hodgkin Lymphoma (AS-cHL) with eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). This mature and unparalleled PFS rate suggests that individualized treatment with PET2-directed BrECADD is currently the most effective therapy for adult patients with AS-cHL. BRECADD IS NON-INFERIOR TO EBEACOPP IN PATIENTS WITH ADVANCED STAGE CLASSICAL HODGKIN LYMPHOMA: EFFICACY RESULTS OF THE GHSG PHASE III HD21 TRIAL. [Extracted from the article]

B Introduction: b Most recent phase III trials investigating single targeted treatment additions to R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL) failed, at least in part, due to the high heterogeneity of this disease. Based on 34 patients completing all treatment cycles, the median follow-up is 11.5 months and the CT-based overall response rate is 44% (15 CR, 19 PR - with no mandatory PET/CT certainly underestimating metabolic CR). B Methods: b 37 IPI >=2 newly diagnosed DLBCL patients 61-80 years of age were enrolled in the ImbruVeRCHOP multi-center IIS (EudraCT number 2015-003429-32, ClinicalTrials.gov identifier NCT03129828). [Extracted from the article]

At FU12, grade 2 or higher PNP was reported for 17 (2.7%) patients following eBEACOPP and for 12 (1.9%) patients following BrECADD; however, no or only grade 1 PNP was reported for most patients in both treatment groups with 97.3% for eBEACOPP and 98.1% for BrECADD. B Introduction: b The HD21 trial compares BrECADD with eBEACOPP for the first-line treatment of advanced stage classical Hodgkin Lymphoma (AS-cHL). FSH levels at FU12 were available for 597 patients and were higher for patients who received eBEACOPP (mean FSH 29.4 and 31.8 after 4 and 6 cycles, respectively) compared to BrECADD (mean FSH 18.3 and 20.5 after 4 and 6 cycles, respectively. [Extracted from the article]

B Introduction: b Persisting cancer related fatigue (CRF) has impact on health related quality of life (HRQoL) and social re-integration of patients with Hodgkin lymphoma (HL). Impact of PET-2 guided treatment de-escalation on time-to-recovery from cancer-related fatigue in advanced stage Hodgkin Lymphoma: results from the GHSG HD18 study The GHSG HD18 trial established treatment PET-2 guided de-escalation of treatment for advanced-stage HL as new standard. [Extracted from the article]

The article presents a study on the provision of IL-15 cytokine system of growth and survival signals in Hodgkin lymphoma (HL) and the enhancement of inflammatory phenotype of Hodgkin and multinucleated Reed-Sternberg (HRS) cells. It cites the attraction of inflammatory cells by cytokines and chemokines secreted by the malignant cell population. The screening of microarray gene expression profiles of HRS and B non-Hodgkin cell lines to identify factors in the formation of the HL is outlined.

Background Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group with Sézary syndrome (SS) as one of the most aggressive variants. Recently, we identified a loss of E2A as a recurrent event in SS, which enhanced proliferation via upregulation of the proto-oncogene MYC. MYC-induced transformation usually requires deleterious alterations of key apoptotic genes including p53; however, p53 functionality and mutation status in SS are unclear. Objectives We investigated functionality of p53 signalling by pharmacological treatment with the MDM2 antagonist nutlin-3, which might result in p53 activation. Furthermore, we analysed the TP53 mutation status in CTCL cell lines and highly purified tumour cells from patients with SS by mRNA and DNA sequencing. Methods We analysed the apoptosis induction due to nutlin-3 treatment in various SS cell lines and primary patient samples by annexin V/propidium iodide staining. Induction of p53 target genes was analysed by immunoblotting, and TP53 was sequenced at the mRNA and DNA level. Results We identified various TP53 mutations and an impaired p53 signalling in the vast majority of the investigated cell lines and primary SS cells. Conclusions In accordance with the importance of MYC deregulation in SS, p53 signalling is frequently nonfunctional in SS. However, although most likely ineffective as exclusive treatment in SS, it remains possible that pharmacological p53 activation could be beneficial in combination with other approaches including classical chemotherapeutics. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a paradigm for a malignant disease that exploits external stimuli of the microenvironment for growth and survival. A thorough understanding of the complex interactions between malignant plasma cells and their surrounding requires a detailed analysis of the transcriptional response of myeloma cells to environmental signals. We determined the changes in gene expression induced by interleukin (IL)-6, tumor necrosis factor-α, IL-21 or co-culture with bone marrow stromal cells in myeloma cell lines. Among a limited set of genes that were consistently activated in response to growth factors, a prominent transcriptional target of cytokine-induced signaling in myeloma cells was the gene encoding the serine/threonine kinase serum/glucocorticoid-regulated kinase 1 (SGK1), which is a down-stream effector of PI3-kinase. We could demonstrate a rapid, strong and sustained induction of SGK1 in the cell lines INA-6, ANBL-6, IH-1, OH-2 and MM.1S as well as in primary myeloma cells. Pharmacologic inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway abolished STAT3 phosphorylation and SGK1 induction. In addition, small hairpin RNA (shRNA)-mediated knock-down of STAT3 reduced basal and induced SGK1 levels. Furthermore, downregulation of SGK1 by shRNAs resulted in decreased proliferation of myeloma cell lines and reduced cell numbers. On the molecular level, this was reflected by the induction of cell cycle inhibitory genes, for example, CDKNA1/p21, whereas positively acting factors such as CDK6 and RBL2/p130 were downregulated. Our results indicate that SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their malignant growth. [ABSTRACT FROM AUTHOR]

Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including classical Hodgkin lymphoma (cHL) cells, relative to normal B cells. Inhibition of MAML-protein activity by a dominant negative form of MAML or by small hairpin RNAs targeting MAML2 in cHL cells resulted in downregulation of the NOTCH target genes HES7 and HEY1, which we identified as overexpressed in cHL cells, and in reduced proliferation. Furthermore, a NOTCH gene-expression signature in cHL cells confirmed their cell-autonomous NOTCH activity. Finally, in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro. These data strongly suggest direct targeting of the NTC as treatment strategy for NOTCH-dependent malignancies. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Cotransplantation of mesenchymal cells and a higher relapse rate: a role for HLA-G molecules?" published online on June 5, 2008 is presented.

Plasticity of committed mouse B cells has been demonstrated by inactivation of the B-cell commitment transcription factor PAX5, resulting in loss of the B-cell phenotype and differentiation into various hematopoietic lineages. Furthermore, mature mouse B cells could be reprogrammed into macrophages by overexpression of myeloid-specific transcription factors. Here, we report that aberrant activity of the transmembrane receptor, Notch1, interferes with the B-lymphoid phenotype of mature human germinal center-derived B cells in Hodgkin lymphoma, so called Hodgkin and Reed-Sternberg cells. They have lost the B-cell phenotype despite their mature B-cell origin. Notch1 remodels the B-cell transcription factor network by antagonizing the key transcription factors E2A and early B-cell factor (EBF). Through this mechanism, B lineage-specific genes were suppressed and B lineage-inappropriate genes were induced. We provide evidence that absence of the Notch inhibitor Deltex1 contributes to deregulated Notch activity in Hodgkin and Reed-Sternberg cells. These data suggest that Notch activation interferes with dedifferentiation of neoplastic B cells in Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]