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Nodal peripheral T-cell lymphomas (nPTCL) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in clinical practice. Accurate biomarkers to define the different subtypes of nPTCL and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA-3 gene expression, and its capability to discriminate the different subtypes of nPTCL.We retrospectively assessed GATA-3 gene expression by quantitative real time PCR (qRT-PCR) from neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE) of 80 patients with nPTCL that were admitted in a single cancer treatment center from 2000 to 2017.Median age was 49 years-old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years, 36.3% were classified as PTCL, NOS, 31.2% as ALK-negative ALCL, 21.2% as ALK-positive ALCL and 11.3% as AITL. The majority of cases had advanced stage cancer (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA-3 gene expression level was 0.49 (range 0 - 7.07) in all cohort, with 0.11 for ALK-positive ALCL, 0.46 for ALK-negative ALCL, 0.86 for PTCL, NOS and 0.67 for AITL. The difference of GATA-3 gene expression among distinct variants of nPTCL was statistically significant (p 0.001). GATA-3 gene expression levels ≥ 0.71 discriminate PTCL, NOS from ALK-negative ALCL and AITL with sensitivity of 62.0% and specificity of 80.3%. GATA-3 gene expression level ≥ median was associated with poor 2-year OS for PTCL, NOS (46.7% versus 21.4%, p = 0.04) and ALK-negative ALCL (85.7% versus 54.5%, p = 0.04). In multivariate analysis, GATA-3 expression ≥ median was an independent factor associated with poor OS in nPTCL (HR: 2.34, 95% CI: 1.12-4.39, p = 0.041).GATA-3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL, NOS and ALK-negative ALCL. Moreover, it may also discriminate different subtypes of nPTCL. Further studies with larger series of patients should confirm our findings.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by a hyperinflammatory state and persistent macrophage activation, resulting in reactive phagocytosis of the hematopoietic elements. In children, it is usually a hereditary disorder, while in adults it is usually acquired secondary to viral infections, collagenoses, or tumors. Although accounting for 10% of hematologic malignancies, HLH is rarely associated with multiple myeloma (MM) and other plasmacytic dyscrasias. Patient concerns: A 64-year-old Brazilian man seeked medical care with a 3-month history of intermittent fever, weight loss, night sweats, and progressive anemic symptoms. Diagnosis: Total blood count showed severe bicytopenia (normocytic-normochromic anemia and thrombocytopenia), biochemical exams showed elevation of creatinine, as well as monoclonal peak in serum protein electrophoresis, high IgA dosage, and serum immunofixation with IgA kappa paraprotein. Bone marrow biopsy showed 30% of monoclonal and phenotypically anomalous plasmocytes, confirming the diagnosis of MM. Diagnosis of HLH was established by the presence of clinical and laboratory criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia, elevation of triglycerides, and several figures of erythrophagocytosis in bone marrow aspirate. Interventions: The patient experienced pulse therapy with methylprednisolone for hemophagocytic lymphohistiocytosis, followed by initial therapy for multiple myeloma with cyclophosphamide and dexamethasone. Outcomes: Once the diagnosis of MM and secondary hemophagocytic syndrome was established, the patient had a rapid clinical deterioration despite the established therapeutic measures, evolving with cardiovascular failure, acute liver failure, acute disseminated intravascular coagulation, worsening renal dysfunction requiring dialysis support, respiratory dysfunction, and lowering of consciousness, characterizing rapid multiple organ dysfunction, ultimately leading to the death of the patient. Innovation: Here, we aimed to describe the sixth reported case of HLH associated with MM, according to cases cataloged in the PubMed database, and the first case evaluated by 18-fluordeoxyglucose positron emission tomography (18-FDG-PETCT). Conclusion: Our case report seeks to provide support for a better clinical and laboratory characterization of this rare paraneoplastic entity associated with MM, and aims to call the attention of hematologists and intensivists to this condition that falls within the scope of the differential diagnosis of rapid onset multiple organ failure in patients with plasmacytic neoplasms.

Background: Nodal peripheral T-cell lymphomas (nPTCLs) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in the clinical practice. Accurate biomarkers to refine the different subtypes of nPTCLs and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA3 gene expression, and its capability to discriminate the different subtypes of nPTCLs. Patients and Methods: From 2000 to 2017, 80 patients with nPTCLs were eligible for GATA3 gene expression analysis that was assessed retrospectively by quantitative real time PCR (qRT-PCR) of neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE). Results: Median age was 49 years old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years. Of them, 36.3% were classified as PTCL/NOS, 31.2% ALK-negative ALCL, 21.2% ALK-positive ALCL and 11.3% AITL. The majority of cases had advanced stage (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA3 gene expression level was 0.49% (range 0 – 7.07) in all cohort, it was 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL/NOS and 0.67% for AITL. The difference of GATA3 gene expression among distinct variants of nPTCLs was statistically significant (p < 0.001). GATA3 gene expression levels ≥ 0.71% discriminate PTCL/NOS from ALK-negative ALCL and AITL with sensitivity of 62% and specificity of 80.3%. GATA3 gene expression levels ≥ median was associated with poor 2-year OS for PTCL/NOS (46.7% x 21.4%, p=0.04) and for ALK-negative ALCL (85.7% x 54.5%, p=0.04). Conclusion: Despite the relative small and heterogeneous group of patients with nPTCLs, GATA3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL/NOS and ALK-negative ALCL. Moreover it may also discriminate different subtypes of nPTCLs. Further studies with larger series of patients should confirm our findings.

In this systematic review, we foresee what could be the approved scenario in the next few years for CAR-T cell therapies directed against hematological and solid tumor malignancies. China and the USA are the leading regions in numbers of clinical studies involving CAR-T. Hematological antigens CD19 and BCMA are the most targeted, followed by mesothelin, GPC3, CEA, MUC1, HER2, and EGFR for solid tumors. Most CAR constructs are second-generation, although third and fourth generations are being largely explored. Moreover, the benefit of combining CAR-T treatment with immune checkpoint inhibitors and other drugs is also being assessed. Data regarding product formulation and administration, such as cell phenotype, transfection technique, and cell dosage, are scarce and could not be retrieved. Better tracking of trials’ status and results on the ClinicalTrials.gov database should aid in a more concise and general view of the ongoing clinical trials involving CAR-T cell therapy.

Introduction: Splenic marginal zone lymphoma (SMZL) is a rare B-cell lymphoid malignancy with primary involvement of the white pulp of the spleen. It is a chronic disease, of indolent behavior and with prolonged survival. However, approximately 25% of cases have greater biological aggressiveness, a propensity for histological transformation to high-grade B-cell non-Hodgkin's lymphoma and shortened survival. The recognition of these cases of particular outcome is important for the selection of a risk-adapted therapeutic approach in resource-poor settings. Methods: In this single-center, retrospective and observational study, we describe the clinical and epidemiological characteristics, analysis of survival, determination of prognostic factors and propose a risk-adapted therapeutic approach, based on data from a cohort of 39 SMZL patients, treated in the largest cancer center in Latin America, from January 1992 to December 2016. Factors with prognostic implications were determined by Cox's univariate analysis, survival curves were estimated by the Kaplan-Meier method and the log-rank test was used to compare curves of survival and to verify the association between categorical variables and survival curves. Results: The clinical and epidemiological characteristics of the 39 SMZL patients are summarized inTable 1. There was predominance of female patients (71.8% - 28-29), with a median age of 63 years (28-76) and a higher incidence of B symptoms (56.4% - 22-39) and extra-splenic involvement (87.1% - 34-39) than the results described in series in Europe and North America. With a median follow-up of 8.7 years (0.6-20.2 years), the overall survival (OS) estimated at 5 years and progression-free survival (PFS) were 76.9% and 63.7%, respectively. Factors with an adverse prognostic impact on OS included: LDH ≥ 480 UL (HR: 4.55, 95% CI 1.05-19.70, p = 0.043), albumin < 3.5 g-dl (HR: 7.32, 95% CI 1.46-36.32, p = 0.015), hemoglobin < 100 gL (HR: 4.27, 95% CI 1.01-17.99, p = 0.048), platelets < 100 x 109 (HR: 7.32, 95% CI 2.26-60.54, p = 0.003), high-risk Arcaini score (HR: 14.26, 95% CI 1.65-123.20, p = 0.002) and high-risk SMZL-Working Group score (HR: 6.66, 95% CI 1.48-30.05, p = 0.004). Factors with adverse prognostic impact on PFS were: LDH ≥ 480 UL (HR: 4.47, 95% CI 1.42-13.73, p = 0.005), albumin < 3.5 g-dl (HR: 3.39, 95% CI 1.07-10.72, p = 0.007), hemoglobin < 100 gL (HR: 2.80, 95% CI 0.95-8.10, p = 0.048), platelets < 100 x 109 (HR: 2.78, 95% CI 0.95-8.02, p = 0.050), high-risk Arcaini score (HR: 7.32, 95% CI 1.96-27.34, p = 0.0007) and SMZL-Working Group high-risk score (HR: 7.29, 95% CI 2.25-23.56, p = 0.001). Despite the relatively low number of patients, no superiority was observed between the therapeutic regimens used, including rituximab monotherapy, splenectomy and low-intensity cytotoxic therapy, in relation to the outcomes 5 year-OS (p = 0.565) and PFS (p = 0.530) -Table 2. However, baseline characteristics differed between therapeutic groups in a statistically significant manner, and patients treated with rituximab or low-intensity cytotoxic therapy had a median LDH (p = 0.050) and B2 microglobulin (p = 0.048) higher than the group treated with splenectomy, as well as lower albumin value (p = 0.005), higher rate of comorbidities (p = 0.0002), worse performance status by ECOG (p = 0.050) and greater number of individuals with high-risk SMZL-Working Group score (p = 0.030) -Table 3, thus justifying the results described. Conclusion: Therefore, in resource-poor settings, where access to anti-CD20 immunotherapy is not universal for patients with SMZL, we suggest that the first-line treatment should consist of monotherapy with rituximab for elderly patients, with high surgical risk or with at least one risk factor identified in our study. Remainders can be safely managed with splenectomy. Disclosures No relevant conflicts of interest to declare.

Influência dos sistemas de Quorum Sensing AI-1/AI-2/AI-3 nos fatores de virulência de EPEC atípica de origem animal. A secreção de moléculas sinalizadoras de baixo peso molecular que se acumulam no meio extracelular até atingir um limite crítico de concentração para sua detecção, acarretando em sinalizações intracelulares e respostas efetoras, define o sistema de comunicação bacteriano chamado Quorum Sensing. Este sistema, que regula comportamentos coletivos mostrou-se um mecanismo disseminado em diversas espécies bacterianas. Diversos estudos descreveram a existência de pelo menos 3 sistemas relacionados ao Quorum Sensing em bactérias Gram-negativas, LuxIR/AI-1, LuxS/AI-2 e QseBC/AI-3/Epinefrina/Norepinefrina. Fatores de virulência como formação de biofilme, motilidade e adesão ao epitélio do hospedeiro devem ser controlados de maneira adequada para tirar o melhor proveito da situação em que a bactéria se encontra. Este trabalho teve como objetivo analisar a influência e a correlação dos genes luxS, qseC e sdiA, relacionados ao sistema de comunicação bacteriana Quorum Sensing, nos principais fatores de virulência de uma amostra de EPEC atípica de origem animal. Foram construídos mutantes pela metodologia baseada na recombinação homóloga mediada pelo sistema Lambda Red, que foram submetidos a ensaios fenotípicos. A sinalização por AI-2 e luxS desempenham papéis na motilidade, formação de biofilme e adesão a células epiteliais. QseC influencia a produção de biofilme pela regulação de componentes da matriz extracelular, e participa de processos de motilidade e adesão. O hormônio epinefrina contribui na alteração de processos de motilidade, formação de biofilme e desenvolvimento da lesão A/E. O gene sdiA também tem um papel importante na regulação de fatores de virulência, mesmo na ausência de AHL. Uma interação antagônica parece existir entre os genes qseC e luxS. A ausência de sistemas de Quorum Sensing promove a produção de um biofilme robusto na amostra AP155. The secretion of low molecular weight signaling molecules that accumulate in the extracellular medium until reaching a critical concentration limit for its detection, leading to intracellular signaling and effector responses, defines the bacterial communication system called Quorum Sensing. This system regulates collective behaviors and has been proven to be a widespread mechanism in several bacterial species. Several studies have described the existence of at least 3 Quorum Sensing-related systems in Gram-negative bacteria, LuxIR/AI-1, LuxS/AI-2 and QseBC/AI-3/Epinephrine/Norepinephrine. Virulence factors such as biofilm formation, motility and adhesion to the host epithelium should be adequately regulated to make the most of the situation in which the bacterium is found. The aim of this work was to analyze the influence and correlation of luxS, qseC and sdiA genes, related to the bacterial communication system Quorum Sensing, on the main virulence factors of an atypical EPEC strain isolated from an animal. Mutants were obtained through homologous recombination mediated by the Lambda Red system, and then were submitted to phenotypic assays. AI-2 signaling and luxS play roles in motility, biofilm formation, and adhesion to epithelial cells. QseC influences the production of biofilm by the regulation of components of the extracellular matrix, and participates in the processes of motility and adhesion as well. The epinephrine hormone alters the processes of motility, biofilm formation and development of the A/E lesion. The sdiA gene also plays an important role in the regulation of virulence factors, even in the absence of AHL. An antagonistic interaction seems to exist between the qseC and luxS genes. The absence of Quorum Sensing systems promotes the production of a robust biofilm in the AP155 strain.

Introduction: Nodal peripheral T-cell lymphomas (nPTCLs) comprise a heterogeneous group of mature and aggressive T-cell lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphomas (ALCL) ALK1-positive and ALK1-negative. The differential diagnosis of nPTCL can be very challenging in clinical practice and it has a markedly heterogeneous prognosis. Accurate biomarkers to distinguish the different histological subtypes of nPTCL and to stratify its prognosis are essential to improve the therapeutic approach. The aim of this study was to assess the prognostic impact of GATA3 gene expression, as well as its ability to discriminate between different histopathological subtypes of nPTCLs. Methods: In this observational, retrospective and single-center study, we analyzed clinical-epidemiological data, outcomes and molecular characteristics of 80 nPTCL patients treated at the largest Brazilian cancer center from January 2000 to December 2017. Analysis of GATA3 gene expression was assessed by quantitative real-time polimerase chain reaction (qRT-PCR) of tumor tissue biopsies fixed in formalin and embedded in paraffin (FFPE) at the time of diagnosis. The association of relative expression of the GATA3 gene with pathological variants of nPTCL was determined by the Kruskal-Wallis test and the Dunn's post-hoc test. The cutoff value of GATA3 expression capable of differentiating nPTCLs variants was determined by constructing receiver-operator-characteristic (ROC) curves. Overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method. Results: The clinical and epidemiological characteristics of the 80 nPTCL patients are summarized in Table 1. Median age was 49 years (IqR 34-59), 43-80 (53.7%) of patients were male. Of these, 36.3% were classified as PTCL-NOS, 31.2% as ALK-negative ALCL, 21.2% as ALK-positive ALCL and 11.3% as AITL. Most of the cases had an advanced stage (III and IV Ann Arbor). With a median follow-up of 1.72 years, the estimated OS at 2 years and PFS were 52.2% and 39.5%, respectively. The median level of GATA3 gene expression was 0.49% (range 0 - 7.07%) in the global cohort, being 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL, NOS and 0.67% for AITL. The difference in expression of the GATA3 gene between different nPTCL variants was statistically significant (p Conclusion: Despite the relatively small number of patients in our cohort, preliminary results suggest that overexpression of the GATA3 gene may be an important biomarker associated with poor prognosis in PTCL, NOS and ALK-negative ALCL. Our results corroborate the findings of Iqbal et al, 2014, reinforcing the adverse prognostic impact of GATA3 gene expression in PTCL/NOS, and we show that its overexpression may be a potential novel biomarker related to poor prognosis for ALK-negative ALCL. In addition, it has been demonstrated here that GATA3 can play an auxiliary role in discriminating different subtypes of nPTCLs, aiding the differential diagnosis of these neoplasms, which often have overlapping clinical and pathological aspects. Other studies with larger series of patients should confirm our findings. Disclosures No relevant conflicts of interest to declare.

Atypical enteropathogenic Escherichia coli are capable to form biofilm on biotic and abiotic surfaces, regardless of the adherence pattern displayed. Several E. coli mechanisms are regulated by Quorum sensing (QS), including virulence factors and biofilm formation. Quorum sensing is a signaling system that confers bacteria with the ability to respond to chemical molecules known as autoinducers. Suppressor of division inhibitor (SdiA) is a QS receptor present in atypical enteropathogenic E. coli (aEPEC) that detects acyl homoserine lactone (AHL) type autoinducers. However, these bacteria do not encode an AHL synthase, but they are capable of sensing AHL molecules produced by other species, establishing an inter-species bacterial communication. In this study, we performed experiments to evaluate pellicle, ring-like structure and biofilm formation on wild type, sdiA mutants and complemented strains. We also evaluated the transcription of genes involved in different stages of biofilm formation, such as bcsA, csgA, csgD, fliC and fimA. The sdiA mutants were capable of forming thicker biofilm structures and showed increased motility when compared to wild type and complemented strains. Moreover, they also showed denser pellicles and ring-like structures. Quantitative real-time PCR (qRT-PCR) analysis demonstrated increased csgA, csgD and fliC transcription on mutant strains. Biofilm formation, as well as csgD, csgA and fimA transcription decreased on wild type strains by the addition of AHL. These results indicate that SdiA participates on the regulation of these phenotypes in aEPEC and that AHL addition enhances the repressor effect of this receptor on the transcription of biofilm and motility related genes.