The aims of this multicentre retrospective study were to identify prognostic or therapeutic factors impacting on overall survival in patients with gliosarcoma. The analysis included all patients treated for gliosarcoma between 1998 and 2014 in seven French academic centres. Seventy-five patients with a median age of 60 years (range from 23 to 79 years) were treated with a combination of surgery (n = 66), radiotherapy (adjuvant for 64 patients and exclusive for 8 patients) and temozolomide based chemotherapy (n = 58). Median follow-up was 12 months (range from 2 to 71 months). Two-year overall survival (OS) and disease free survival rates were 12 % (95 % CI 4-20 %) and 2 % (95 % CI 0-6 %), respectively. The median OS was 13 months. Treatment at recurrence consisted of chemotherapy (n = 38) (bevazicumab for 18 patients, repeat temozolomide for 10 patients), salvage surgery (n = 8) and radiochemotherapy (n = 1). In univariate analysis, younger age, higher total dose of radiotherapy, longer time to recurrence and treatment at recurrence significantly increased OS. In multivariate analysis, high total dose of radiotherapy (HR = 0.97, p = 0.007) and treatment at recurrence (HR = 0.28, p < 0.001) were favourable prognostic factors of OS. Radiotherapy at a minimum dose of 54 Gy and salvage treatment increased OS of gliosarcoma. Unlike glioblastoma, in our analysis, TMZ based chemotherapy was not associated with an improvement in OS compared to patients who received radiation therapy only.
In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell–like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.
for their support in the early stages of the project. This report was a retrospective analysis of routine data, in which no personal identifiers were retained, and collected as part of clinical service provision.
The differentiation of B cells into plasmablasts (PBs) and then plasma cells (PCs) is associated with extensive cell reprogramming and new cell functions. By using specific inhibition strategies (including a novel morpholino RNA antisense approach), we found that early, sustained upregulation of the proviral integrations of Moloney virus 2 (PIM2) kinase is a pivotal event during human B-cell in vitro differentiation and then continues in mature normal and malignant PCs in the bone marrow. In particular, PIM2 sustained the G1/S transition by acting on CDC25A and p27Kip1 and hindering caspase 3–driven apoptosis through BAD phosphorylation and cytoplasmic stabilization of p21Cip1. In PCs, interleukin-6 triggered PIM2 expression, resulting in antiapoptotic effects on which malignant PCs were particularly dependent. In multiple myeloma, pan-PIM and myeloid cell leukemia-1 (MCL1) inhibitors displayed synergistic activity. Our results highlight a cell-autonomous function that links kinase activity to the newly acquired secretion ability of the PBs and the adaptability observed in both normal and malignant PCs. These findings should finally prompt the reconsideration of PIM2 as a therapeutic target in multiple myeloma.
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