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Anaplastic lymphoma kinase–negative anaplastic large cell lymphoma (ALK– ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK– ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P = .05) but not PFS (P = .18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK– ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival (PFS) and overall survival (OS) of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. 103 patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, PFS was significantly better in the transplanted patients than in the non-transplanted group: 63% vs. 48% at 5 years (p=0.042). OS was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year OS: 70% vs. 50%, p=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged PFS (HR 0.57, 95% CI 0.35-0.93) and OS (HR 0.57, 95% CI 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.

IF 7.704 (2017)Communication donnée lors du 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Dusseldorf, Germany, du 13 au 17 octobre 2018; International audience

Oxidation of halides and thiocyanate by heme peroxidases to antimicrobial oxidants is an important cornerstone in the innate immune system of mammals. Interestingly, phylogenetic and physiological studies suggest that homologous peroxidases are already present in mycetozoan eukaryotes such as Dictyostelium discoideum. This social amoeba kills bacteria via phagocytosis for nutrient acquisition at its single-cell stage and for antibacterial defense at its multicellular stages. Here, we demonstrate that peroxidase A from D. discoideum (DdPoxA) is a stable, monomeric, glycosylated, and secreted heme peroxidase with homology to mammalian peroxidases. The first crystal structure (2.5 Å resolution) of a mycetozoan peroxidase of this superfamily shows the presence of a post-translationally-modified heme with one single covalent ester bond between the 1-methyl heme substituent and Glu-236. The metalloprotein follows the halogenation cycle, whereby compound I oxidizes iodide and thiocyanate at high rates (>108 m−1 s−1) and bromide at very low rates. It is demonstrated that DdPoxA is up-regulated and likely secreted at late multicellular development stages of D. discoideum when migrating slugs differentiate into fruiting bodies that contain persistent spores on top of a cellular stalk. Expression of DdPoxA is shown to restrict bacterial contamination of fruiting bodies. Structure and function of DdPoxA are compared with evolutionary-related mammalian peroxidases in the context of non-specific immune defense.

IF 6.671; International audience

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of neoplasms that are derived from post-thymic lymphoid cells at different stages of differentiation and with different morphological patterns, phenotypes, and clinical presentations. PTCLs are highly diverse, reflecting the diverse cells from which they can originate and are currently sub-classified using World Health Organization (WHO) 2008 criteria. Peripheral T-Cell Lymphomas account for 5%-10% of all lymphoproliferative disorders in the Western hemisphere, with an overall incidence of 0.5-2 per 100,000 individuals per year, and have a striking epidemiological distribution, with higher incidence in Asia. The clinical features of PTCL are extremely heterogeneous. PTCLs express even more clinical diversity than B-cell non-Hodgkin's lymphomas, and there is a close, though not absolute, relationship between some unusual clinical features and certain histological subtypes.Linfomas T periféricos (PTCLs) compreendem um grupo heterogêneo de neoplasias que derivam das células linfoides pós-tímicas nos diversos estágios de maturação, com diversos padrões histológicos, fenotípicos, e clínicos. PTCLs são muito diversos entre si e refletem diversas células das quais foram originadas e são atualmente subclassificadas, usando-se a classificação da Organização Mundial da Saúde (OMS) 2008, apresentada neste texto na tabela 1. PTCLs compreendem 5%-10% de todas as doenças linfoproliferativas no mundo ocidental, com uma incidência global de 0.5 a 2 a cada 100.000 pessoas por ano e têm uma distribuição epidemiológica diversa com maior incidência na Ásia. Os achados clínicos dos PTCLs são muito heterogêneos. PTCLs expressam muito maior variação de apresentações clínicas do que os linfomas B, e há uma íntima, mas não absoluta, relação entre algum achado clínico não usual e certos subtipos histológicos. O autor faz aqui uma revisão do assunto altamente contemporâneo

Background: The International Peripheral T-cell Lymphoma Project was organized to better understand the T-cell and natural killer (NK) cell lymphomas, and our task is to present the clinicopathologic correlations and therapeutic results for adult T-cell leukemia/lymphoma (ATL). Patients and methods: Among 1153 patients with T-cell or NK cell lymphomas, 126 patients (9.6%) with ATL were represented in this project. All were categorized as aggressive ATL, i.e. acute or lymphoma type, and 87% fell into the lymphoma type. Results: The median age was 62 years and the male to female ratio was 1.2 : 1. Significant prognostic factors for overall survival (OS) by univariate analysis were the presence of B symptoms (P = 0.018), platelet count

Purpose Peripheral T-cell lymphoma (PTCL) and natural killer/T-cell lymphoma (NKTCL) are rare and heterogeneous forms of non-Hodgkin's lymphoma (NHL) that, in general, are associated with a poor clinical outcome. Patients and Methods A cohort of 1,314 cases of PTCL and NKTCL was organized from 22 centers worldwide, consisting of patients with previously untreated PTCL or NKTCL who were diagnosed between 1990 and 2002. Tissue biopsies, immunophenotypic markers, molecular genetic studies, and clinical information from consecutive patients at each site were reviewed by panels of four expert hematopathologists and classified according to the WHO classification. Results A diagnosis of PTCL or NKTCL was confirmed in 1,153 (87.8%) of the cases. The most common subtypes were PTCL not otherwise specified (NOS; 25.9%), angioimmunoblastic type (18.5%), NKTCL (10.4%), and adult T-cell leukemia/lymphoma (ATLL; 9.6%). Misclassification occurred in 10.4% of the cases including Hodgkin's lymphoma (3%), B-cell lymphoma (1.4%), unclassifiable lymphoma (2.8%), or a diagnosis other than lymphoma (2.3%). We found marked variation in the frequency of the various subtypes by geographic region. The use of an anthracycline-containing regimen was not associated with an improved outcome in PTCL-NOS or angioimmunoblastic type, but was associated with an improved outcome in anaplastic large-cell lymphoma, ALK positive. Conclusion The WHO classification is useful for defining subtypes of PTCL and NKTCL. However, expert hematopathology review is important for accurate diagnosis. The clinical outcome for patients with most of these lymphoma subtypes is poor with standard therapies, and novel agents and new modalities are needed to improve survival.

To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years ( P = .0002), equal to or more than 2 extranodal sites ( P = .0002), lactic dehydrogenase (LDH) value at normal levels or above ( P < .0001), performance status (PS) equal to or more than 2 ( P ≤ .0001), stage III or higher ( P = .0001), and bone marrow involvement ( P = .0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P < .0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P < .0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P < .0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P = .026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4, 3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively ( P ≤ .0001; log-rank, 66.79).

Catalase-peroxidases are the only heme peroxidases with substantial hydrogen peroxide dismutation activity. In order to understand the role of the redox chemistry in their bifunctional activity, catalatically-active and inactive mutant proteins have been probed in spectroelectrochemical experiments. In detail, wildtype KatG from Synechocystis has been compared with variants with (i) disrupted KatG-typical adduct (Trp122-Tyr249-Met275), (ii) mutation of the catalytic distal His123-Arg119 pair, and (iii) altered accessibility to the heme cavity (Asp152, Ser335) and modified charge at the substrate channel entrance (Glu253). A valuable insight into the mechanism of reduction potential (E degrees') modulation in KatG has been obtained from the parameterization of the corresponding enthalpic and entropic components, determined from the analysis of the temperature dependence of E degrees'. Moreover, model structures of ferric and ferrous Synechocystis KatG have been computed and used as reference to analyze and discuss the experimental data. The results, discussed by reference to published resonance Raman data on the strength of the proximal iron-imidazole bond and catalytic properties, demonstrate that E degrees' of the Fe(III)/Fe(II) couple is not strongly correlated with the bifunctional activity. Besides the importance of an intact Trp-Tyr-Met adduct, it is the architecture of the long and constricted main channel that distinguishes KatGs from monofunctional peroxidases. An ordered matrix of oriented water dipoles is important for H2O2 oxidation. Its disruption results in modification of enthalpic and entropic contributions to E degrees' that reflect reduction-induced changes in polarity, electrostatics, continuity and accessibility of solvent to the metal center as well as alterations in solvent reorganization. (C) 2010 Elsevier Inc. All rights reserved.