Literatura académica sobre el tema "Fondazione Cassa di risparmio di Pesaro"

Abstract Abstract 1890 Poster Board I-913 Background. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) characterised by a proliferation of predominantly megakaryocytes and granulocytes in bone marrow that in fully developed disease is replaced by fibrous tissue. At molecular level, no specific defect has been identified yet. Cytogenetic abnormalities occur in up to 30% of patients, the commonest including del(13)(q12-22), der(6)t(1;6)(q21-23;p21.3), del (20q), and partial trisomy 1q. In addition, approximately 50% of patients with PMF exhibit a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2). However, such mutation is not specific, also occurring in other MPN. Recently a couple of reports dealt with single-nucleotide polymorphism (SNP) array karyotyping of MPD, including some PMF. Importantly, such studies could identify previously uncovered genetic lesions, highlighting the importance of novel high resolution technologies for the detection of formerly unknown, cryptic aberrations. In this study we performed high resolution karyotyping by SNP oligonucleotide microarray by using the most updated Affymetrix array (Genome-Wide Human SNP Array 6.0) in 20 cases of myelofibrosis (MF) in order to identify novel cryptic genomic aberrations. Methods. DNA (500 ng) was extracted from peripheral blood cells (PBMNC) of 14 primary and 6 secondary MF patients. PBMNC were depleted from lymphocytes by magnetic beads. Briefly, CD3+ cells were labeled with anti-CD3 MoAb directly coupled to magnetic microbeads (Miltenyi Biotech), washed and subsequently purified using Mini-MACS technology. After selection, cell present in the positive (CD3) and negative (PBMNC) fractions were counted and submitted to flow cytometry analysis. DNA was processed and hybridized to the Affymetrix SNP arrays 6.0 as for manufacturer instruction. A whole-genome copy number variation (CNV), genotyping, loss of heterozygosity (LOH) and uniparental disomy (UPD) analyses were performed using the Partek Suite 6.0. Ten lab-specific as well as 90 HapMap samples relative to Caucasian healthy donor were used as control reference. Genomic abnormalities were defined as recurrent when occurring in at least 25% of cases. JAK2 mutational status was assessed as reported, by alle-specific PCR. Clinical information and complete follow up were retrieved for all cases. Direct sequencing, FISH, qPCR and immunohistochemistry (IHC) has been chosen for validation. Results. In all patients we could detect several CNV. The median number of CNV was 60 (range, 34-72), including 46 amplifications (A) and 14 deletions (D). All commonest previously described abnormalities were detected. In addition, several formerly uncovered recurrent lesions were identified, mainly involving 1p, 1q, 2p, 4p, 4q, 5q, 6p, 6q, 7q, 8p, 9q 10q, 11p 11q, 12p, 14q, 15q, 16p, 16q, 17q, 18q, 19q, 20p, 22q. The median size of such CNV was 424,582 Kbp (1,379 Kbp-71,277 Mbp). We then compared JAK2+ vs. JAK2− cases. Of note, we found numerous definite aberrations (A or D) distinguishing the two groups and specifically affecting 16q23.1, 1p36.13, 3q26, 14q13.2, 5q33.2, 6q14.1, 7q33, 8p23.1, and 9p11.2. Grippingly, several genes of potential interest for PMF pathogenesis were identified within the involved loci, including RET, SCAPER, WWOX and SIRPB1. Among others, the product of such genes has been selected for validation by IHC. Similarly, many miRNA were recognized, which may deserve further investigation. Conclusions. By using a newly developed highly sensitive array we identified novel cryptic lesions in patients affected by MF. Future studies on larger series, as well as functional analyses will definitely assess their role in the pathogenesis of the disease. Of note, consistent differences were recorded in JAK2+ vs. JAK2−, supporting the hypothesis of different genetic mechanisms occurring in the two sub-groups. Acknowledgments: this work was supported by AIL Pesaro Onlus, Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi”, BolognAIL, AIRC, FIRB, RFO, Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006.*GV and MRS equally contributed to this work. Disclosures: No relevant conflicts of interest to declare.

The work was developed in the ReScaLe FiAer project framework, funded by the Fondazione Cassa di Risparmio di Perugia. It is focused on the identification and collection of multiple high quality wood waste from a local window manufacturer. Three types of wood were available, from different tree species (pine, oak, and mahogany) and sizes (pieces of wood, mixed coarse chips, and mixed fine chips). Preliminary analyses were performed in order to evaluate the properties of the raw material. For each type of wood, eco-sustainable panels (300x300 mm2) were assembled by gluing. Multiple tests were carried out in order to identify the optimal mixtures and to ensure a good mechanical resistance with the minimum adhesive use. Panels were assembled by using vinyl glue, easily available and cheap, and flour glue, with a lower environmental impact and safe for people’s health. The thermal conductivity of the panels was measured by means of the Small Hot Box experimental apparatus: it varies in the 0.071-0.084 W/mK range, at an average temperature of 10°C, depending on the tree species and regardless of the type of adhesive used. Furthermore, 100-mm diameter cylindrical samples with two different thicknesses for each type of wood and glue were fabricated, in order to investigate their acoustic behaviour in an impedance tube. The use of flour glue improves the sound absorption and insulation performance of the samples.

e14569 Background: Trop-2 is a calcium signal transducer and a stem cell marker. Trop-2 is widely overexpressed by human cancers and stimulates their growth. A TROP2 mRNA was isolated as post-transcriptionally joined to CYCLIN D1 transcripts, suggesting this as one of the transforming mechanisms of TROP2. Methods: In vitro cell growth assays were utilized to assess the cell growth stimulatory capacity of the chimeric mRNA. Colony assays for growth in soft agarose and tumorigenicity assays in nude mice were utilized to assess for the transforming capacity of the fusion transcript. siRNA constructs were utilized for the stably shut-down of the expression of the CYCLIN D1-TROP2 mRNA. Results: The chimeric mRNA transforms primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. The CYCLIN D1-TROP2 mRNA is expressed by a large fraction of human ovarian, endometrial and gastro-intestinal tumors. The chimera is coexpressed with activated RAS in a subset of tumors, consistent with a cooperative transforming activity. The chimeric mRNA is a bicistronic transcript that independently translates wild type Cyclin D1 and Trop-2 proteins, i.e. it does not generate chimeric, oncogenic proteins. On the other hand, joining to the stable TROP2 mRNA leads to a higher CYCLIN D1 mRNA stability, with inappropriate persistence during the cell cycle and acquisition of transforming capacity. As essentially no normal tissues express the chimeric mRNA, we targeted it for destruction in cancer cells with stably expressed siRNA constructs. Specific targeting led to essential annnihilation of the CYCLIN D1-TROP2 mRNA, in the absence of off-target effects. Silencing of the chimeric mRNA blocked the growth of expressing breast cancer cells. Conclusions: Our findings demonstrate a novel, widespread oncogenic mechanism in human cancers, and open novel avenues for mRNA-targeted anti-cancer therapies. Acknowledgments This work was supported by the the Fondazione of the Cassa di Risparmio della Provincia di Chieti, the Association for the Application of Biotechnology in Oncology (ABO and ABO Project S.p.A., grant no. VE01D0019) and the Marie Curie Transfer of Knowledge Fellowship, contract number 014541. No significant financial relationships to disclose.

e21096 Background: Systems biology together with translational oncology is a new approach to discover sensitive pathways in specific cancers. In this study, we propose a computational modeling technique to investigate the possible effects various alterations, such as protein overexpression, gene amplification or mutations, may have on signaling, through of the EGFR and IGF1R pathways, in non-small cell lung cancer (NSCLC). Methods: EGFR and IGF1R pathways and the downstream MAPK and PIK3 networks have been reproduced through a mathematical model. One hundred-twenty five tumors from surgical NSCLC patients were evaluated for EGFR and IGF1R protein expression, by immunohistochemistry (IHC) and gene amplification, by fluorescence in situ hybridization (FISH). KRAS mutations (exons 2 and 3) were evaluated by direct sequencing Results: To correlate EGFR and IGF1R expression levels, and KRAS mutations to tumor cell proliferation, we focused on the ERK signaling pathway, which plays a central role in several steps of cancer development including proliferation and cancer cell migration. The mathematical model predicts a relationship between a simultaneous high expression level of both receptors and a modification on ERK time behavior, implying a stronger attitude for cell proliferation. Furthermore KRAS activating mutations predict high level of active ERK and high probability to have cell proliferation. Cell growth can be closely related to disease progression and act, in survival analysis, as DFS estimator. Patients with concomitant IGF1R/EGFR FISH/IHC positivity had a worse DFS ( p=0.005). KRAS mutations have a statistically significant shorter DFS (p<0.001) as well Conclusions: We propose a Systems Biology approach, combined with Translational Oncology methodologies, to understand the interaction between EGFR, IGF1R and KRAS pathways in NSCLC. Computational model predictions confirm clinical evidences of survival analysis. Future work will validate our model with experiments on various NSCLC cell cultures and further investigate the response to drug administration. We thank AIRC and Fondazione Cassa di Risparmio for supporting the study.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease of controversial origin recently recognized as a neoplasm deriving from plasmacytoid dendritic cells (pDCs). Nevertheless, it remains an orphan tumor with obscure biology and dismal prognosis. In this study, we aimed to: 1) molecularly define the cellular counterpart of BPDCN and its relationship with other leukemias; 2) identify genes and cellular programs deregulated in the tumor; and 3) delineate novel potential therapeutic targets. To address these issues we collected and studied by gene expression profile (GEP) 27 BPDCN cases as well as 8 samples of non neoplastic pDCs. Further, a panel of samples including, myeloid precursors (MPs, N=4), lymphoid precursors (LPs, N=9), acute myeloid leukemias (AMLs, N=132), and acute lymphoblastic leukemias (ALLs, N=155) was analyzed. Validation was performed by immunohistochemistry (IHC) on tissue-microarrays, while functional experiments were carried out by using the CAL-1 cell line (derived from a BPDCN case). First, we recognized the cellular derivation of BPDCN, which proved to originate from the myeloid lineage and in particular from resting pDCs. Second, by comparing the GEP of BPDCN and resting pDCs, we identified genes and cellular programs deregulated in the tumor. Following, based on an integrated bio-informatic approach, including four different tools, we uncovered the aberrant activation of the NF-kB pathway that was confirmed in independent assays. Interestingly, among other molecules, we identified BCL2 and IRF4, two well known NFkB targets, as aberrantly upregulated in neoplastic samples and confirmed this observation by IHC. We then tested whether NFkB inhibition could represent a potential therapeutic strategy in this setting. We treated BPDCN cells ex vivowith either the proteasome inhibitor bortezomib or the selective IKKB inhibitor BMS-345541 and found them to be effective in inducing cell cycle arrest and apoptosis at relatively low dosage. By contrast, BPDCN cells turned out to be virtually insensitive to cytarabine, one of the most used drug in this condition. GEP and immunocytochemistry were then successfully used to prove that cell death was accompanied by NFkB shut-off. In conclusion, we identified a molecular signature representative of the transcriptional abnormalities of BPDCN and developed a cellular model proposing the first molecular targeted therapeutic approach in the setting of this currently incurable disease. Funding This work was supported by AIRC (IG10519 and 5xMille10007, Prof. Pileri), Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi”, BolognAIL, RFO (Prof. Pileri, Prof. Piccaluga), FIRB Futura 2011 RBFR12D1CB (Prof. Piccaluga), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006 (Prof. Pileri and Dr. Piccaluga) and by MIUR (PRIN 2011, Prof. Facchetti and Prof. Pileri). The authors have no conflicting financial interests to declare. Acknowledgments The Authors obtained the CAL-1 cell line from Takahiro Maeda (tmaeda@net.nagasaki-u.ac.jp), Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Disclosures: No relevant conflicts of interest to declare.

Analyses of energy and redox status parameters are emerging technologies to improve oocyte quality assessment. Mitochondria (mt) play a vital role in the oocyte to support maturation, fertilization, and pre-implantation development. They are the major source of reactive oxygen species (ROS) produced during oxidative phosphorylation, which are not only by-products of cell metabolism but also important molecules for regulation of intracellular cell signaling. The aim of the present study was to test for mt/ROS colocalization in oocytes recovered from superovulated adult ewes and examined after in vivo or in vitro maturation (IVM). Cumulus–oocyte complexes of 8 superovulated (fluorogestone acetate + D-cloprostenol for oestrus synchronization, pFSH/pLH and eCG for superovulation) adult (2 to 8 years of age) ewes were recovered (ovariohysterectomy by midventral laparotomy performed 54 h after vaginal sponge removal) either from flushing oviducts (oviducal oocytes) or from ovarian growing follicles (1–5 mm in diameter; follicular oocytes). Follicular oocytes were analysed after IVM (Ambruosi et al. 2009 Theriogenology 71, 1093–1104). After cumulus cell removal, all oocytes underwent nuclear chromatin, mt, and ROS evaluation. Hoechst 33258 and Mitotracker Orange CMTM Ros were used to label nuclear chromatin and mt (Ambruosi et al. 2009) and 2′,7′-dichloro-dihydro-fluorescein diacetate was used for ROS labelling (Hashimoto et al. 2000 Mol. Reprod. Dev. 57, 353–360). Oocytes at the metaphase II (MII) stage showing regular ooplasmic size (>130 μm in diameter) and morphology were selected for confocal analysis of mt/ROS fluorescence distribution, intensity, and colocalization. Forty oviducal MII oocytes recovered from 8 ewes were analysed. Thirty-two oocytes recovered from the ovaries of 4 ewes underwent IVM, and 23 out of 32 (72%) reached nuclear maturation and were analysed. The rate of oocytes showing perinuclear mt distribution pattern did not differ between oviducal and IVM oocytes (33%, 13/40 v. 43%, 10/23; not significant). In these oocytes, fluorescent intensity of mt labelling and intracellular ROS levels did not differ between oviducal and IVM ooocytes (996.27 ± 363.57 v. 798.13 ± 275.91; not significant; and 1808.11 ± 442.78 v. 1473.29 ± 662.49, for mt and ROS, respectively; not significant), whereas mt/ROS colocalization was significantly higher in ovulated oocytes than in IVM oocytes (Pearson coefficient 0.67 ± 0.11 v. 0.39 ± 0.19, respectively; P < 0.001). In conclusion, in oocytes of adult ewes, mt aggregation, apparent energy status, and intracellular ROS levels do not differ between ovulated and IVM oocytes, but mt/ROS colocalization differs between the 2 groups. As it was reported for other cell systems that such a difference can be indicative of healthy status of ovulated oocytes, we suggest that mt/ROS colocalization could be considered as a suitable marker of oocyte quality. Financial support was provided by Fondazione Cassa di Risparmio di Puglia 2008. Project: Salvaguardia di razze ovine autoctone pugliesi (R.U. DPA Resp. Sci. Prof. M. E. DellAquila).

Abstract Abstract 4631 Background Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of tumors representing approximately 12% of lymphoid neoplasms, basically subdivided into specified and not specified (NOS) forms. PTCL/NOS, corresponding to about 60%–70% of PTCLs, cannot be further classified on the basis of morphology, phenotype, or conventional molecular studies. Clinically, PTCLs/NOS are highly aggressive lymphomas, with a poor response to therapy, and dismal overall survival (20-30%). Their pathobiology is poorly known, though recent gene expression profiling (GEP) studies have provided some hints for better understanding their pathogenesis. In particular, GEP and immunohistochemical studies on tissue-microarrays (TMAs) demonstrated PDGFRA to be systematically activated in almost all PTCLs/NOS, by nominating it as potential therapeutic target. Aims In this study, we aimed to identify the determinants of PDGFRA activation in PTCL/NOS. Specifically, we studied PDGFRA locus in order to identify possible mutations, translocations, or copy number variations and we explored the possible existence of an autocrine/paracrine loop sustaining an otherwise integer kinase. Methods The PDGFRA locus (4q1.1-4q1.3) was studied by FISH and wide-genome SNPs analysis (Affymetrix 500K Array). Direct sequencing of all PDGFRA exons and introns as well as of the promoter region was also performed in 90 cases. IHC and ELISA were adopted in order to study the expression of PDGF-A, PDGF-B and PDGF-C on tissue sections and in supernatants from PTCL/NOS cell cultures, respectively. Finally, the expression of PDGFRA and its activated (phosphorilated) form, p-PDGFRA, was assessed by IHC on TMAs, and by flow-citometry in PTCL/NOS cultured cells as well as in a FIP1L1-PDGFRApos chronic eosinophilic leukemia cell line (EOL-1) before and after the exposure to an anti-PDGF ligand neutralizing antibody (R&D System), given at various concentrations (20-40-60-80 ug/mL). Vitality assessments, proliferation/cell cycle assay (by In Situ Cell Proliferation kit, FLUOS – Roche) and evaluation of PDGFRA and p-PDGFRA were performed at 24, 48, 96 hours. A human PDGF peptide (R&D Sytems) was added to cultured cells for 6 hours to evaluate whether PDGFRA de-phosphorilation was really due to PDGF ligand remotion. Results First, FISH, SNPs analysis and direct sequencing showed preserved integrity of PDGRA locus. Thus we tested the hypothesis of an autocrine/paracrine stimulation. PDGF-A, PDGF-B and PDGF-C were found to be expressed by neoplastic cells at IHC in 93-95% of cases. In addition, PDGF-AA was found to be secreted by cultured neoplastic cells by ELISA. Notheworthy, PTCL cells secreted much more ligand than any other cell taken as control. We then tested whether PDGFRA phosphorylation was actually due to the presence of a PDGF ligand. Indeed, PTCL cells treated with anti-PDGF ligand neutralizing antibody at various concentrations showed PDGFRA dephosphorilation ranging from 30% up to 90% in a time dependent manner. Notably, the effect was specific as in EOL-1 PDGFRA phosphorylation was not modified at all. In addition, PTCL cells treated with a minimum of 20ug/mL of anti-PDGF ligand neutralizing antibody for 48h showed a 70% blockade of proliferation in comparison to untreated cells (BrdU assay). A further addition of 20 ug/ml of inhibitory antibody at 48 hours, increased the proliferation arrest up to 80% at 96 hours. Finally, the addition of a natural human PDGF peptide to cells previously treated with the anti-PDGF antibody, could restore PDGFRA phosphorylation confirming that PDGFRA de-phosphorilation was due to ligand remotion. Conclusions Taken together, our data demonstrate that PDGFRA activity is sustained by an autocrine loop in PTCL/NOS. In fact, though, in vivo, a possible additive paracrine effects mediated by reactive components cannot be excluded, we provide evidence that the phenomenon is largely due to neoplastic cells. Importantly, as PDGFRA signaling abrogation was associated to proliferation arrest, PDGFRA was confirmed as potential therapeutic target. Acknowledgments: this work was supported by Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi”, BolognAIL, AIRC, FIRB, RFO, Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006, and Vanini-Cavagnino grant. Disclosures: No relevant conflicts of interest to declare.

Introduction: Our objective was to develop a prognostic model that predicts progression-free survival (PFS) and overall survival (OS) to enable risk-adapted strategies in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). We retrospectively investigated the value of quantitative image texture features (i.e. 'radiomics' evaluating tumor heterogeneity) using FDG PET/CT data sets in a large, prospective Phase III trial, GOYA (NCT01287741). Methods: In the GOYA trial, which compared obinutuzumab versus rituximab both in combination with CHOP chemotherapy, there was no significant treatment effect between the two arms, thus the two arms were combined for this study. Baseline PET/CT images with regions of interests (ROIs) defined by qualified physicians were analyzed for radiomics features. Image texture features (ITF) were computed using the open-source and validated PET Oncology Radiomics Test Suite (PORTS). The clinical risk factors (International Prognostic Index [IPI], Ann Arbor stage, extranodal disease, bulky disease), cell of origin (COO), standard PET-derived metrics (standard uptake value [SUV]-mean, SUV-max, total metabolic tumor volume [TMTV], total lesion glycolysis [TLG]), SUV histogram metrics (variance, skewness, and kurtosis), and ITF were evaluated for prediction of PFS and OS. TMTV was estimated using adaptive thresholding. Prognostic models were generated by means of multivariate Cox regression analysis, modeling PFS, and OS. In the absence of an independent patient cohort for external model validation, an internal validation, based on c-index and Brier score, was carried out using bootstrap resampling methods. Stratification of patients into risk groups was achieved through maximally selected rank statistics. Multivariate analysis was also carried out on a subgroup of patients with available COO information. Results: The median follow-ups for PFS and OS were 46 and 50 months, respectively. Baseline PET scans were available for 1334 patients with detectable lesions, and 1077 baseline scans were evaluable for calculating ITFs. In the univariate analysis, high TMTV, histogram mean, histogram variance, and the ITFs gray-tone spatial dependence matrices (GTSDM) difference entropy and low gray-level zone length matrix (GLSZM) small zone high gray emphasis were risk factors for PFS, while high TMTV, histogram mean, and the ITF GTSDM inverse difference moment were risk factors for OS (Table 1, showing 95% CI, HR, and p-values for both univariate and multivariate analyses). In multivariate analysis, the risk factors included IPI, Ann Arbor stage, high TMTV, histogram mean, and GTSDM inverse difference moment; results were generally consistent in the multivariate subgroup analysis on patients with COO data available (Table 1). Based on the multivariate model, the probabilities for PFS and OS at 2 and 4 years for individual patients were established (Table 2). By combining TMTV (four categorical groups) with ITF, COO, and predictive clinical factors, three prognostic subgroups of treatment failure risk were identified: low (55% of patients), intermediate (34%), and high (11%). Hazard ratios for high and intermediate risk compared with low risk were 2.16 (p&lt;0.001) and 1.17 (p=0.004) for PFS, and 3.82 (p&lt;0.001) and 1.85 (p&lt;0.001) for OS. The corresponding probability of survival at 2-years for high, intermediate and low risk groups were 87%, 82%, and 75% for PFS, and 94%, 90%, and 82% for OS. The 4-year survival probabilities were 83%, 77%, and 68% for PFS, and 91%, 86%, and 75% for OS (Table 2). For PFS, the accuracy of the Cox model was 0.63 with clinical variables only, 0.65 with the addition of TMTV, and 0.69 with the addition of ITFs; for OS, the corresponding values were 0.63, 0.65, and 0.70. Conclusion: A model including PET-derived quantitative ITF, in addition to significant clinical features, was able to predict survival probability for untreated DLBCL patients with good precision. The proposed PET-based prognostic model may help identify patients who could benefit from risk-adapted treatment modifications or novel approaches. Acknowledgments: GOYA was sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial assistance, under the direction of Lale Kostakoglu, was provided by Katie Smith of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Dalmasso:I-See s.r.l.: Employment. Pierce:Precision Sensing LLC: Equity Ownership. Vitolo:Janssen: 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; 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; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria. Sehn:Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria. Trněný:Takeda: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bolen:Genentech, Inc.: Employment; F. Hoffmann-La Roche: Equity Ownership. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lee:Genentech: Employment; F. Hoffman-La Roche: Equity Ownership. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Kinahan:Co-founded PET/X LLC: Equity Ownership; Philips Medical: Research Funding; GE Healthcare: Research Funding; F. Hoffmann-La Roche: Consultancy. Chauvie:International Agency on Atomic Energy (IAEA): Consultancy; Co-owner of Dixit srl (spin-off University of Torino): Equity Ownership; F. Hoffmann-La Roche: Research Funding; Fondazione Cassa di Risparmio di Cuneo (CRC): Research Funding; Italian Foundation on Lymphoma (FIL): Research Funding; Italian Association for Cancer Research (AIRC): Research Funding; SIRTEX: Speakers Bureau.