Trends in influenza coverage rates in five consecutive immunisation seasons in the Local Health Unit of Ferrara (North Italy).

Seasonal influenza epidemics yearly affects 5-15% of the world’s population, resulting in 3-5 million serious cases and up to 650,000 deaths. Elderly, pregnant women and individuals with underlying conditions are at increased risk of complications. According to the Italian National Immunization Prevention Plan 2017-2019, these categories benefit from free vaccination. Influenza coverage rate in Italy are not optimal. The study investigated the coverage rate in five consecutive influenza seasons (2010/2011-2014/2015) in Local Health Unit (LHU) of Ferrara (Italy). The amount of delivered vaccinations was not constant, with a decreasing trend. An increase in coverage with increasing age was observed, but in no immunisation seasons the 75% target of over-65 years old individuals immunised was achieved. As number of delivered doses and coverage rates decreased, the percentage of immunisations delivered by the General Practitioners (GPs) increased. The District with the lowest vaccination coverage was the Western District. In elderly, coverage rates in South-Eastern and North-Central District were higher with a statistically significant difference compared to Western District. Higher levels of immunisation were observed in South-Eastern District in the pediatric age and in North-Central District in adult age group with a statistically significant difference. The trend in the LHU of Ferrara was similar to regional and national data, conditioned in the 2014/2015 season by the spreading of worrying news, although unfounded, on the safety of the vaccine. The GPs were essential in ensuring vaccine uptake, growing the percentage of delivered doses and achieving as much as possible effective elderly immunisatio

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

AN ITERATIVE HYBRID ALGORITHM FOR PROCESS OPTIMIZATION OF A MULTI-PRODUCT LIGNOCELLULOSIC BIOREFINERY

An iterative hybrid algorithm is proposed for the economic process optimization of a multiproduct biorefinery. The design approach is based on the construction of a process superstructure. The algorithm is based on the sequential and iterative use of Mixed Integer Linear Programming solvers and of process simulators. The MILP model takes into account the rigorous reactor modelling results obtained by separate MATLAB calculations. The optimal flowsheet separation and purification section resulting from the MILP solution is simulated by ASPEN Plus. Process yields and equipment size obtained by ASPEN Plus are updated in the MILP problem. Iterations provide the ultimate optimal flowsheet, biomass allocation and yield to products

Pediatric Testicular Cavernous Hemangioma With Acute Onset Mimicking Testicular Torsion: Case Report and Review of the Literature

Testicular cavernous hemangioma is a rare benign vascular tumor that typically occurs in childhood and adolescence. The clinical presentation may be variable and lead to diagnostic difficulties. We report an atypical presentation of intratesticular cavernous hemangioma with acute onset mimicking testicular torsion in a teenager. Inadvertent minor scrotal injury may have probably triggered the rupture of the hemangioma, leading to hemorrhage and infarction of the testicle. Although ultrasonography findings and serum tumor markers may be helpful in differential diagnosis, surgical exploration, and pathology examination are essential for definitive diagnosis

Superior PFS2 with VTD Vs TD for Newly Diagnosed, Transplant Eligible, Multiple Myeloma (MM) Patients: Updated Analysis of Gimema MMY-3006 Study

Abstract Background: The phase 3 GIMEMA-MMY-3006 study comparing bortezomib-thalidomide-dexamethasone (VTD) vs. thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) provided demonstration of superior CR/nCR rates after induction (the primary study endpoint) and across all subsequent treatment phases, a gain which translated into significantly longer PFS for patients randomized to the VTD arm (Cavo, Lancet 2010; Blood 2012). We herein report an updated analysis of the study with a focus on PFS2, time to second anti-myeloma therapy, treatment-free interval, post-relapse OS and long term outcomes. Methods: Overall, 474 patients were included in the trial. After a median follow up of 65 months, 251 patients (53%) have progressed and of these 221 (88%) had available data on salvage therapy after relapse. Results: On an intention-to-treat basis, median PFS was 57 months for patients randomized to the VTD arm as compared to 42 months for those assigned in the TD arm (HR 0.67; p=0.001). No statistically significant difference in 5-years estimates of OS was observed between VTD and TD groups (80% vs 73%). PFS2, defined as the time from initial randomization to second disease progression or death from any cause, was significantly longer for patients randomised to VTD than for those in the TD group (76% vs. 63% at 5 years, respectively; HR 0.64, p=0.009). Globally, 73% and 83% of patients in the VTD and TD arms required the start of salvage therapy due to symptomatic relapse. Median time to subsequent anti-myeloma therapy (defined as the interval between start of induction treatment and the first dose of second-line therapy) was significantly longer for patients assigned to VTD than for those who experienced relapse in the TD cohort (40 vs 31 months, p=0.014). Similarly, median treatment-free interval (defined as the time between last administration of front-line therapy and start of salvage treatment) was 26 months in VTD group vs 16 months in TD arm (p=0.016). Most of the patients received a novel agent-containing salvage therapy, while 18% was treated with conventional chemotherapy. As expected, a greater percentage of patients in the TD arm were treated with second-line bortezomib-based combinations in comparison with those relapsing in the VTD arm (72% vs 46%, respectively, p=0.001). Within the VTD group, no statistically significant difference in PFS2 was seen regarding the use of bortezomib or an IMiD as (part of) second-line therapy (64 vs 57 months, respectively). Clinical benefit from primary randomization to VTD vs TD was also observed in terms of second PFS (defined as the interval between first and second progression) (HR 0.61, p=0.032). The median OS after relapse was 36 months for both TD and VTD groups. No differences in post relapse OS were observed for patients primarily assigned to VTD or TD who received a subsequent bortezomib-based salvage therapy. Conclusion: With an extended follow-up of approximately 5 years, VTD was superior to TD in terms of extended PFS2, time to subsequent anti-MM therapy and treatment-free interval. PFS2 was significantly longer for patients randomized to VTD, with no difference regardless of the use of bortezomib or an IMiD as part of second-line therapy. This finding, along with similar post-relapse OS values across the two groups, suggest that induction and consolidation therapy with VTD did not select the emergence of bortezomib- resistant clones at the time of relapse. Disclosures Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Sanofi Aventis: Honoraria. Cavo:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharm.: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Onyx: Honoraria. </jats:sec

Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Abstract Introduction. The administration of immuno-chemotherapy (ICT) followed by rituximab maintenance (RM) is the recommended approach for the front-line therapy of high tumor burden follicular lymphoma (HTB-FL) patients. Among available ICT regimens, RB (Rituximab-bendamustine) and R-CHOP regimen, are preferred options with high, similar efficacy. Regarding RM, its use is strongly supported after R-CHOP by the results of the PRIMA randomized trial; conversely, no prospective data are available to confirm the efficacy of RM in patients initially treated with RB. The FOLL12 trial was conducted to try to demonstrate that a response adapted post induction management of patients with HTB-FL could be as effective as standard RM in terms of Progression Free Survival (PFS). The trial actually showed the better efficacy of standard RM compared to the experimental approach thus providing indirect confirmation of the efficacy of RM after ICT, 10 years after the PRIMA trial. We here analyse the impact of initial ICT in the FOLL12 study that left treatment choice between RB and R-CHOP at physician discretion and on an individual patient basis. Methods. FOLL12 is a multicenter, randomized, phase III trial that compared standard RM vs. a response adapted post induction management in treatment naïve adult patients with grade 1-3a, stage II-IV and a HTB-FL. All patients received induction immunochemotherapy with 6 cycles of either R-CHOP or R-Bendamustine both followed by two additional doses of rituximab. Choice of ICT was at the physicians' discretion. After ICT, patients in the standard arm received bimonthly rituximab for up to two years. Patients in the experimental arm were managed according to centrally reviewed metabolic and molecular response. Patients achieving complete metabolic (CMR) and molecular response were managed with observation only, those in CMR with molecular persistence received 4 weekly rituximab doses. Patients not achieving CMR were treated with radioimmunotherapy with ibritumomab tiuxetan followed by standard RM. Primary study endpoint was 3 years progression free survival (PFS). Results. A total of 786 eligible patients were enrolled and 1:1 randomized either to standard or experimental arm. By backbone therapy, 341 patients received RB and 445 received RCHOP induction immunochemotherapy. RB was more frequently prescribed in older and female patients (OR 1.6, p=0.001) whereas RCHOP was preferred in patients with bulky disease (&amp;gt;6cm) and grade 3a histology (OR 0.65, p=0.013). The median follow-up of the analysis was 56 months (range 1-71). In the non-randomized comparison between RB and RCHOP, no difference in terms of PFS was observed between the two regimens (HR for RB 1.07, 95%CI 0.83-1.38, p=0.597, Figure 1). Standard maintenance arm was more effective than experimental arm both in patients initially treated with RCHOP and in those treated with RB (HR RCHOP 1.61, 95% CI 1.16-2.25; HR RB 1.89, 95% CI 1.27-2.82). An unequal interaction between RB and RCHOP and post-induction therapy was observed for sex and for bone marrow involvement. Considering grade 3 to 5 adverse events (AEs), neutropenia was less frequently observed in RB (35.7%) compared to RCHOP (46.2%). Among extra-hematological AEs, higher frequency of grade 3-4 infections and of cutaneous toxicity were observed in RB treated patients (3.8% vs. 1.2% and 2.4% vs. 0.2%). Overall, 54 second malignancies (SM) have been observed including 23 hematologic malignancies and 31 solid cancers. Cumulative incidence of secondary cancer (excluding non melanoma skin cancers) at 3 and 5 years was 3.7% (95%CI 2.4-5.3%) and 8.1% (95%CI 5.8-10.9%). Conclusion. The current update of the FOLL12 trial demonstrated superiority of standard RM compared to the response adapted post induction management irrespective of prescribed regimen thus proving a first prospective non-randomized evidence of RM efficacy in patients with high tumor burden follicular lymphoma patients treated with RB. Both R-CHOP and RB were associated with a similar efficacy profile. Figure 1. Progression free survival for the standard maintenance arm (A) versus response oriented experimental arm (B) of the FOLL12 trial in patients treated with R-CHOP or R-Bendamustine (RB). Figure 1 Figure 1. Disclosures Luminari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; GENELAB SRL: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ferrero: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau. Arcaini: Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda, Pfizer, Sandoz, Merk: Consultancy; Gilead, Bristol: Speakers Bureau. Musuraca: Janssen, Roche, Incyte: Honoraria; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Incyte, Roche: Consultancy. </jats:sec

Gene Expression Analysis Uncovers Similarity and Differences Among Burkitt Lymphoma Subtypes

Abstract Abstract 2494 Background. Burkitt lymphoma (BL) is currently listed in the WHO classification of lymphoid tumors as a single genetic and morphological entity with variation in clinical presentation. In particular, three clinical subsets of BL are recognized: endemic (eBL), sporadic (sBL) and immunodeficiency associated (ID-BL). Each affects different populations and can present with different features. So far, possible differences in their gene expression profiles (GEP) have not been investigated. In this study we aimed to 1) assess whether BL subtypes present with differences in their GEP; 2) investigate the relationship of the different BL subtypes with the non-neoplastic cellular counterparts; 3) Identify genes and programs specifically deregulated in BLs and possibly contributing to the malignant phenotype. Methods. We studied by GEP 128 cases of B-cell derived malignancies and 20 samples of normal B-cell subpopulations GEP analysis. In particular, we included 40 BLs (13 eBLs, 21 sBLs 6 HIV-BLs), 40 follicular lymphomas, 10 chronic lymphocytic leukemias, 10 GCB-type diffuse large B-cell lymphomas, 10 ABC-type DLBCL, 5 primary mediastinal B-cell lymphomas, 13 HIV-related DLBCL, as well as 10 germinal center (GC), 5 naïve and 5 memory cells samples. GEP results were confirmed by dividing BL cases into training and test subgroups. In addition, as further validation, we performed immunohistochemistry (IHC) on tissue microarrays containing 85 BL cases as well as functional assays in vitro and in vivo, by focusing on the role of RBL2, a tumor suppressor gene involved in cell cycle control and mutated in eBL. Specifically, we used cell transfection and shRNAs (for mimicking MYC over-expression and RBL2 silencing), soft agar and invasion capability assays, and xenografted mouse models. Results. First, we found that BLs constitute a unique molecular entity, with a relatively homogeneous GEP, distinct from other B-cell malignancies. Indeed, by unsupervised analysis all BLs clearly clustered apart of other lymphomas. However, by supervised analysis, we found that BL subtypes presented slight differences in their GEPs. Particularly, eBLs and ID-BLs appeared to be almost identical, diverging from sBLs. Specifically, they varied for genes involved in cell cycle control, BCR-signaling, and TNF/NFKB-pathways. Of note, eBLs and ID-BLs on one hand, and sBLs on the other (roughly corresponding to EBV+ vs. EBV− cases) also differed for genes target of mi-R127a, which is altered in EBV+ cases as a direct consequence of viral integration. To further investigate cell cycle regulation in BLs, we inferred a network of RBL2-depending genes by reverse engineering, by uncovering possible RBL2 transcriptional targets. Interestingly, we found that eBL and sBL diverged for genes belonging to such network. Notably, we provided evidences that RBL2 can cooperate with MYC in inducing a neoplastic phenotype in vitro and in vivo. In particular, lymphoblastoid cells engineered to carry both MYC over-expression and RBL2 silencing presented with increased colony formation and matrix invasion capabilities, and higher efficiency in inducing tumor formation in nude mice if compared to single transfectants (MYC+ or RBL2−). Moreover, as the present WHO classification does not definitely identify the counterpart of eBL, we compared BLs GEP to those of normal B-cells. We found that all BL subtypes were intimately related to GC cells (by showing an early stage GC differentiation arrest), differing from them for molecules specially involved in cell proliferation, immune response, and signal transduction. Finally, as further validation of GEP, we studied by IHC the expression of SPARC and CYR61, two molecules involved in human tumorigenesis. Indeed, they turned out to be consistently expressed by neoplastic elements in all instances, as indicated by GEP analysis. Conclusions. Our study provided substantial insights on the pathobiology of BLs, by offering novel evidences which may be relevant for its classification and possibly future treatment. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Gene expression analysis uncovers similarity and differences among Burkitt lymphoma subtypes

Burkitt lymphoma (BL) is classified into 3 clinical subsets: endemic, sporadic, and immunodeficiency-associated BL. So far, possible differences in their gene expression profiles (GEPs) have not been investigated. We studied GEPs of BL subtypes, other B-cell lymphomas, and B lymphocytes; first, we found that BL is a unique molecular entity, distinct from other B-cell malignancies. Indeed, by unsupervised analysis all BLs clearly clustered apart of other lymphomas. Second, we found that BL subtypes presented slight differences in GEPs. Particularly, they differed for genes involved in cell cycle control, B-cell receptor signaling, and tumor necrosis factor/nuclear factor \u3baB pathways. Notably, by reverse engineering, we found that endemic and sporadic BLs diverged for genes dependent on RBL2 activity. Furthermore, we found that all BLs were intimately related to germinal center cells, differing from them for molecules involved in cell proliferation, immune response, and signal transduction. Finally, to validate GEP, we applied immunohistochemistry to a large panel of cases and showed that RBL2 can cooperate with MYC in inducing a neoplastic phenotype in vitro and in vivo. In conclusion, our study provided substantial insights on the pathobiology of BLs, by offering novel evidences that may be relevant for its classification and possibly future treatment

The Addition of Bortezomib to R-DHAP Does Not Improve the Response Pre-Stem Cell Transplantation Compared to Standard R-DHAP in Young Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Preliminary Results of the Phase II Randomized Trial FIL-VERAL12 of the Fondazione Italiana Linfomi

Background. The outcome of relapsed/refractory diffuse large-B cell lymphoma (DLBCL) patients after first line chemoimmunotherapy is poor, and the choice of the best salvage treatment is challenging. Acisplatin-containing regimen (DHAP, cisplatin, high-dose citarabine, dexamethasone) is worldwide accepted as induction pre-stem cell transplantation (SCT). Bortezomib had proven activity in aggressive lymphomas. On these bases, the Fondazione Italiana Linfomi designed the FIL-VERAL12 trial, aimed at evaluating whether the addition of bortezomib to rituximab-DHAP (BR-DHAP) increases complete response rate (CR, according to Lugano 2007 criteria) prior SCT compared to standard R-DHAP. Methods. FIL-VERAL12 was a prospective, multicenter, two-arm randomized phase II trial (NCT01805557).The primary study endpoint wasCR after 4 courses of R-DHAP or BR-DHAP, assuming a 30% CR for the standard arm and a 50% CR in experimental arm. Inclusion criteria were: patients aged 18-65 years with relapsed/refractory DLBCL after first line chemoimmunotherapy, eligible to high-dose therapy. A centrally histological review and classification according to cell of origin profile was planned. Patients were stratified by relapsed or refractory and randomized 1:1 to receive: a) the standard salvage therapy R-DHAP every 28 days for 4 cycles and b) subcutaneous 1.5 mg/sqm bortezomib on days 1 and 4 of each 4-week cycle in addition to the same regimen. Restaging, mobilization and harvesting of peripheral stem cell were performed after the second course. Results. From January 2013 to November 2018, 114 patients were screened; 108 eligible patients were enrolled into the trial and randomized to receive R-DHAP or BR-DHAP (54 patients in each arm). Principal clinical characteristics were: median age 57 years (IQR: 48;62); stage III/IV 81 patients (75%); IPI risk &gt;3 32 (30%). All patients received rituximab and anthracycline-based regimens as first line treatment. Considering the time at relapse, 52 patients (48%) were registered as relapsed (median time at relapse 10.8 months, IQR: 6.9;20.9) and 46 (43%) as refractory (0.9 months, IQR 0.52;1.3); in the remaining 10 patients the data is missing at the time of this analysis. 51 (47%) patients completed the planned 4 cycles of therapy; 57 did not, due to progressive disease in 20, adverse events in 2, unknown causes in 35 cases. Intermediate response after 2 courses was: CR 16 (15%), partial response (PR) 37 (34%), stable disease (SD) 16 (15%); 24 (22%) were in progression (PD) and 15 (14%) were not available for response. At the end of treatment, the pre-ASCT response was: : CR 30 (28%), PR 10 (9%), SD 13 (12%), PD 38 (35%), NA 17 (16%). According to arm of randomization, the primary end point was not met, with CR 30% for R-DHAP and 26% for BR-DHAP (Pr 0.667). 38 patients performed a consolidation SCT, autologous SCT in 38, allogeneic SCT in 4. The addition of bortezomib to standard R-DHAP did not impact the mobilization: only one patient was poor mobilizer and the median number of CD34+ collected was 6.9 x 10^6 cells CD34/kg (IQR: 4.8; 9.7), with no differences between the two arms. No toxic deaths were recorded into the trial. On 294 cycles with data available, haematological and extra-haematological toxicities were: grade 3-4 neutropenia in 152 of 294 courses (52%), g 3-4 thrombocytopenia in 209 (71%); g 3-4 febrile neutropenia in 4 (1%), g3-4 infection in 5 (2%), g3-4 neurotoxicity in 5 (2%); the incidence of adverse events were similar in the two arms. At a median follow-up of 9.8 months, 12-months PFS was: overall 48.8% (38.4-58.4), 44.6% (30.4-57.8) and 53.1% (37.9-66.1) for R-DHAP and BR-DHAP, respectively (log rank, p 0.464). At a median follow-up of 15.9 months, 12-months OS was: overall 69% (58.2-77.7), 62.7% (46.4-75.3) and 75.1% (59.6-85.4) for R-DHAP and BR-DHAP, respectively (log rank, p 0.628). Conclusions. In the FIL-VERAL12 phase II randomized trial, the addition of bortezomib to R-DHAP did not improve the outcome of relapsed/refractory DLBCL patients eligible to high-dose therapy plus SCT. This series of patients is mainly represented by true refractory patients after first line chemoimmunotherapy and the results underline the poor outcome of such patients. The treatment for these patients is still an unmet clinical need. The role of immunotherapies such as the integration of CAR-T therapy in this setting of patients should be investigated. Disclosures Chiappella: Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau. Corradini:Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Servier: Honoraria; KiowaKirin: Honoraria; Sanofi: Honoraria; Gilead: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Takeda: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Nassi:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: the use of subcutaneous bortezomib is not registered in diffuse large B-cell lymphoma. Bortezomib was provided free by Janssen </jats:sec