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Although follicular lymphoma (FL) patients relapsing within 24 months after first-line treatment (POD24) have a poor prognosis, some cases show notable survival after first relapse (SF1R). We aimed to characterize the POD24 FL population and to identify the main prognostic factors at progression. We selected 162 POD24 patients (80F; median age at first relapse 59 years) from a cohort of 1067 grades 1-3a FL-treated patients. The remaining 905 patients treated with first-line immunochemotherapy and diagnosed during the same period were used to compare outcomes in terms of survival. After a median follow-up of 11.0 years, 96 patients died (10y-SF1R of 40%). Age over 60 years (p 0.001), high lactate dehydrogenase (LDH) (p 0.001), haemoglobin (Hb) less than 120 g/L (p 0.001), advanced stage (p 0.001), high-risk Follicular Lymphoma International Prognostic Index (FLIPI) (p 0.001), histological transformation (HT) (p0.001) and reaching less than complete response (CR) after salvage therapy (p 0.001), predicted poor SF1R at relapse. In multivariate analysis only high-risk FLIPI and HT maintained prognostic significance for SF1R. POD24 patients not transformed and with low/intermediate FLIPI at relapse behaved better than the remaining cases. POD24 patients showed an excess mortality of 38% compared to the general population. Although outcome of POD24 FL patients is poor, a considerable group of them (low/intermediate FLIPI and not transformed at first relapse) behave better.

The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (-sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated β2 -microglobulin levels in the +sIFE group. With a median follow-up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression-free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2-5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B-cell biology and the tumour microenvironment.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico-biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next-generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety-seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or beta 2-microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R-IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R-IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15 center dot 33 (TERT), 12q13 (CDK2), 12q14 center dot 1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R-IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over-representation of gene sets related to extra-cellular matrix and tumour microenvironment.

AIMS The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied. METHODS AND RESULTS PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P

AIMS Mantle cell lymphoma (MCL) is a heterogeneous disease with an aggressive behaviour in most cases, which is associated with expression of sex determining region-Y-box11 (SOX11). Experimental studies have shown that SOX11 expression is associated with an angiogenic switch characterised by increased expression of angiogenic-related signatures and vascularisation of murine tumours. However, the relationship between angiogenesis and SOX11 expression in primary tumours is not well understood. Therefore, the aim of this study was to evaluate the development of microvascular angiogenesis in primary MCL in relation to SOX11 expression and its potential prognostic value. METHODS AND RESULTS Fifty-six patients diagnosed with MCL, 38 SOX11-positive and 18 SOX11-negative, were studied. The relative intratumoral microvascular area (MVA) and microvessel density (MVD) (number of intratumoral microvessels/μm2 ) were measured on CD34-stained slides using a computerised image analysis system. SOX11-positive MCL showed a significant higher microvascular development than negative tumours (median MVA = 14.5 × 10-3 versus 5.0 × 10-3 P

Follicular lymphoma (FL) is an indolent disease characterized by long survival but frequent relapses. Before the introduction of rituximab, the clinical course of these patients showed a shorter response duration (RD) after each relapse. In this study, we analysed if this pattern of shortened responses remains in patients treated in the rituximab era. We selected 348 patients newly diagnosed with FL in two institutions between 2001 and 2014 that received chemoimmunotherapy. After a median follow-up of 6 center dot 3 years, 10-year progression-free and overall survivals were 53% and 72%, respectively. All patients received first-line, 111 second-line and 41 third-line treatments, with a 5-year RD of 62%, 39% and 24%, respectively (P < 0 center dot 0001). Variables predicting longer RD after first-line treatment were normal beta 2microglobulin, complete remission achievement and maintenance with rituximab. Patients with longer RD after first-line showed significantly longer RD after second-line therapy. Autologous stem-cell transplantation after second-line therapy did not significantly impact RD. Median survival after first, second and third therapies was not reached, 7 center dot 6 and 4 center dot 8 years, respectively, whereas relative survival with respect to a sex- and age-matched Spanish population, the decrease in the life expectancy at 10 years was 17%, 45% and 79%, respectively. Thus, RD still shortens after each relapse in patients with FL treated in first line with rituximab combinations.

Objectives Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. Methods From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). Results Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. Conclusions (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.

Chronic lymphocytic leukemia (CLL) development and progression is known to be affected by a plethora of external signals. Among the receptors sensitive to such stimuli, toll-like receptor 9 (TLR9) is of interest because treatment with an agonist like CpG-oligodeoxynucleotide (CpG-ODN) impacts in tumor cell viability and immunogenicity through rendering them more sensitive to T cell-mediated cytotoxicity and chemotherapeutic agents in vitro. Long non-coding RNA (lncRNA) expression alterations have been implicated in various neoplasms including CLL, suggesting that they could also be therapeutic targets and/or clinically useful biomarkers. Transcribed Ultraconserved Regions (T-UCRs) are a class of lncRNA comprising a total of 481 different transcripts with an absolute degree of conservation among human, mouse and rat, that it is suggestive of an essential functional relevance in mammals. In the present study we have explored the possible role of T-UCR in the pathogenesis of CLL performing a global screening using microarrays and qRT-PCR in response to CpG-ODN stimulation. We have identified a AC092652.2-202 as the uc.70-related lncRNA which expression levels are related to the response to CpG-ODN and have prognostic significance in CLL. These findings warrant further studies on the functional characterization of this lncRNA in CLL as well of the particular role of uc.70 sequence in its expression regulation Fil: Bomben, Riccardo. University of Miami; Estados Unidos. Centro Di Riferimento Oncologico; Italia Fil: Roisman, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España. University of Miami; Estados Unidos Fil: D'Agaro, Tiziana. Centro Di Riferimento Oncologico; Italia Fil: Castellano, Giancarlo. Hospital Clínico de Barcelona; España Fil: Baumann, Tycho. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España. Hospital Clínico de Barcelona; España Fil: Delgado, Julio. Hospital Clínico de Barcelona; España. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España Fil: López Guillermo, Armando. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España. Hospital Clínico de Barcelona; España Fil: Zucchetto, Antonella. Centro Di Riferimento Oncologico; Italia Fil: Dal Bo, Michele. Centro Di Riferimento Oncologico; Italia Fil: Bravin, Vanessa. Centro Di Riferimento Oncologico; Italia Fil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Vlasova, Anna. Barcelona Institute Of Science And Technology.; España Fil: Guigó, Roderic. Barcelona Institute Of Science And Technology.; España Fil: Martin Subero, Jose I.. Centro de Investigación Biomédica en Red de Cáncer ; España. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España Fil: Chapaprieta, Vicente. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España Fil: Beekman, Renee. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España. Centro de Investigación Biomédica en Red de Cáncer ; España Fil: Martin García, David. Centro de Investigación Biomédica en Red de Cáncer ; España. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España Fil: Beà, Sílvia. Centro de Investigación Biomédica en Red de Cáncer ; España. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España Fil: Salaverria, Itziar. Centro de Investigación Biomédica en Red de Cáncer ; España. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España Fil: Aymerich, Marta. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España. Hospital Clínico de Barcelona; España Fil: Campo, Elias. Centro de Investigación Biomédica en Red de Cáncer ; España. Hospital Clínico de Barcelona; España. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España Fil: Gattei, Valter. Centro Di Riferimento Oncologico; Italia Fil: Hernández, Luis. Centro de Investigación Biomédica en Red de Cáncer ; España. Institut d'Investigacions Biomèdiques August Pi i Sunyer. Lymphoid Neoplasm Program; España