Integrating precision medicine through evaluation of cell of origin in treatment planning for diffuse large B-cell lymphoma

Precision medicine is modernizing strategies for clinical study design to help improve diagnoses guiding individualized treatment based on genetic or phenotypic characteristics that discriminate between patients with similar clinical presentations. Methodology to personalize treatment choices is being increasingly employed in clinical trials, yielding favorable correlations with improved response rates and survival. In patients with diffuse large B-cell lymphoma (DLBCL), disease characteristics and outcomes may vary widely, underscoring the importance of patient classification through identification of sensitive prognostic features. The discovery of distinct DLBCL molecular subtypes based on cell of origin (COO) is redefining the prognosis and treatment of this heterogeneous cancer. Owing to significant molecular and clinical differences between activated B-cell-like (ABC)- and germinal center B-cell-like (GCB)-DLBCL subtypes, COO identification offers opportunities to optimize treatment selection. Widespread adoption of COO classification would greatly improve treatment and prognosis; however, limitations in interlaboratory concordance between immunohistochemistry techniques, cost, and availability of gene expression profiling tools undermine universal integration in the clinical setting. With advanced methodology to determine COO in a real-world clinical setting, therapies targeted to specific subtypes are under development. The focus here is to review applications of precision medicine exemplified by COO determination in DLBCL patients

Developing benign Ni/g-C3N4 catalysts for CO2 hydrogenation: Activity and toxicity study

This research discusses the CO2 valorization via hydrogenation over the non-noble metal dusters of Ni and Cu supported on graphitic carbon nitride (g-C3N4). The Ni and Cu catalysts were characterized by conventional techniques including XRD, AFM, ATR, Raman imaging, and TPR and were tested via the hydrogenation of CO2 at 1 bar. The transition-metal-based catalyst designed with atom-economy principles presents stable activity and good conversions for the studied processes. At 1 bar, the rise in operating temperature during CO2 hydrogenation increases the CO(2 )conversion and the selectivity for CO and decreases the selectivity for methanol on Cu/CN catalysts. For the Ni/CN catalyst, the selectivity to light hydrocarbons, such as CH4, also increased with rising temperature. At 623 K, the conversion attained ca. 20%, with CH4 being the primary product of the reaction (CH4 yield >80%). Above 700 K, the Ni/CN activity increases, reaching almost equilibrium values, although the Ni loading in Ni/CN is lower by more than 90% compared to the reference NiREF catalyst. The presented data offer a better understanding of the effect of the transition metals' small metal cluster and their coordination and stabilization within g-C3N4, contributing to the rational hybrid catalyst design with a less-toxic impact on the environment and health. Bare g-C3N4 is shown as a good support candidate for atom-economy-designed catalysts for hydrogenation application. In addition, cytotoxicity to the keratinocyte human HaCaT cell line revealed that low concentrations of catalysts particles (to 6.25 mu g mL(-1)) did not cause degenerative changes.Web of Scienc

AUGMENT : a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma

PURPOSE Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab. METHODS A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review. RESULTS A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively. CONCLUSION Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile

High-Grade B-cell Lymphoma, Not Otherwise Specified: A Multi-Institutional Retrospective Study

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ( double hit ). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase \u3e3 × upper limit of normal, and a dual-expressor immunophenotype. Age \u3e60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS

Selective Induction of DNA Repair Pathways in Human B Cells Activated by CD4+ T Cells

Greater than 75% of all hematologic malignancies derive from germinal center (GC) or post-GC B cells, suggesting that the GC reaction predisposes B cells to tumorigenesis. Because GC B cells acquire expression of the highly mutagenic enzyme activation-induced cytidine deaminase (AID), GC B cells may require additional DNA repair capacity. The goal of this study was to investigate whether normal human B cells acquire enhanced expression of DNA repair factors upon AID induction. We first demonstrated that several DNA mismatch repair, homologous recombination, base excision repair, and ATR signaling genes were overexpressed in GC B cells relative to naïve and memory B cells, reflecting activation of a process we have termed somatic hyperrepair (SHR). Using an in vitro system, we next characterized activation signals required to induce AID expression and SHR. Although AID expression was induced by a variety of polyclonal activators, SHR induction strictly required signals provided by contact with activated CD4+ T cells, and B cells activated in this manner displayed reduced levels of DNA damage-induced apoptosis. We further show the induction of SHR is independent of AID expression, as GC B cells from AID -/- mice retained heightened expression of SHR proteins. In consideration of the critical role that CD4+ T cells play in inducing the SHR process, our data suggest a novel role for CD4+ T cells in the tumor suppression of GC/post-GC B cells

Impact of the Coulomb field on charged-pion spectra in few-GeV heavy-ion collisions

In nuclear collisions the incident protons generate a Coulomb field which acts on produced charged particles. The impact of these interactions on charged-pion transverse-mass and rapidity spectra, as well as on pion–pion momentum correlations is investigated in Au + Au collisions at $\sqrt{^{S}NN}$ = 2.4 GeV. We show that the low-m$_{t}$ region (m$_{t}$ < 0.2 GeV / c$^{2}$) can be well described with a Coulomb-modified Boltzmann distribution that also takes changes of the Coulomb field during the expansion of the fireball into account. The observed centrality dependence of the fitted mean Coulomb potential energy deviates strongly from a $A_{part}^{2/3}$ scaling, indicating that, next to the fireball, the non-interacting charged spectators have to be taken into account. For the most central collisions, the Coulomb modifications of the HBT source radii are found to be consistent with the potential extracted from the single-pion transverse-mass distributions. This finding suggests that the region of homogeneity obtained from two-pion correlations coincides with the region in which the pions freeze-out. Using the inferred mean-square radius of the charge distribution at freeze-out, we have deduced a baryon density, in fair agreement with values obtained from statistical hadronization model fits to the particle yields

Diffuse large B-Cell lymphoma: from novel molecular classifications to tailored targeted therapies

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease comprising multiple genetic subtypes that translates and impacts clinical outcomes after standard chemoimmunotherapy. Our initial understanding of the complex biological subtypes of DLBCL began with the identification of cell of origin (COO), and now has evolved to include even more specific subtypes defined by genetic signatures and mutations. These newer classifications lend themselves to the application of precision-based medicine, allowing us to tailor new treatment platforms that target specific oncogenic drivers in order to improve DLBCL outcomes. Essential to this is the development of genetic assays and tools that are reliable and readily available to assist in the application of these molecular classifications to real-world use. In this review, we discuss the history of DLBCL classification systems and their implication on clinical investigation as well as novel therapeutic options in DLBCL