Journal articles on the topic 'Sportelli'

In a paper concerning the relationship between coding theory and factorization theory Restivo, Salemi, and Sportelli made a conjecture that if subsets possess certain properties then they cannot form a factorization of a finite cyclic group. In this note it is shown that in fact such factorizations do exist.

Nell'ambito del "Progetto Dedalo", i sociologi del'Universitŕ di Pavia descrivono i risultati di una ricerca empirica sugli uffici di collocamento della Regione Sicilia (Sportelli Multifunzionali), nonché l'elaborazione dei dati cosě raccolti. In concreto, il primo contatto tra gli uffici di collocamento e i giovani immigrati rivela lacune culturali e carenze di capacitŕ linguistiche. Č quindi in questi settori che vanno prese misure concrete. Un database regionale distribuito in rete (insieme con un prototipo di terminale espressamente progettato a questo fine) č stato presentato alla Pubblica amministrazione siciliana e ai partecipanti al secondo congresso del "Progetto Dedalo", svoltosi a Monreale. Infine, l'analisi dei dati empirici consente di formulare una serie di proposte pratiche che l'Amministrazione regionale dovrŕ realizzare per migliorare la preparazione professionale e il collocamento dei giovani immigrati.

Il lavoro propone un'analisi del contributo offerto dal sistema bancario allo sviluppo economico nelle diverse regioni italiane; il presupposto č che la distribuzione e la qualitŕ del credito bancario riflettano le differenze in termini di sviluppo economico delle diverse regioni. L'analisi si concentra, in particolare, sulla qualitŕ del credito, in base alla considerazione per cui la disponibilitŕ delle banche nel concedere prestiti sia influenzata, secondo una relazione inversa, dalla dimensione dei crediti non-performing. Un ulteriore elemento incluso nell'analisi č la presenza delle banche sul territorio, valutata in base al numero degli sportelli per regione. Oltre a questi aspetti, sono oggetto di valutazione anche gli investimenti in ricerca e sviluppo, per i quali l'aspettativa č quella di un'influenza positiva sullo sviluppo economico della regione. La verifica empirica, condotta mediante un'analisi di regressione lineare multivariata, ha evidenziato come a livelli piů alti di qualitŕ del credito bancario corrispondano anche maggiori livelli del pil: un deterioramento del merito creditizio delle controparti bancarie si traduce, pertanto, in minore crescita economica e, quindi, in una stretta del credito, che a sua volta contrae i margini di aumento del prodotto interno lordo. La spesa per ricerca e sviluppo risulta premiare le regioni che credono sia necessario investire in tal senso.

Un interessante quesito ci viene posto dal sindaco del comune di Sernaglia della Battaglia, in provincia di Treviso, teatro di tragici eventi durante la prima guerra mondiale, e insignito dalla Presidenza della Repubblica nel 2009 di una Medaglia d’oro al merito civile per l’esemplare comportamento della popolazione. Il Comune ha istituito uno sportello al cittadino, della cui denominazione si chiede la correttezza linguistica.

Nel presente lavoro viene affrontata la tematica della localizzazione delle imprese e delle distanze geografiche che intercorrono con il loro sportello bancario di riferimento con lo scopo di verificarne gli effetti sulle condizioni contrattuali all'interno dei mercati locali del credito. In particolare, si cerca di individuare il soggetto che sostiene i costi generati dalle inefficienze dovute alla distanza (sportello od impresa) e la natura dei costi: trasporto o di informazione. I risultati evidenziano l'importanza del ruolo esercitato dalle distanze sui diversi elementi della decisione creditizia rilevando come un incremento della distanza bancaimpresa generi un aumento dei costi per quest'ultima, mentre la natura dei costi sembrerebbe ricadere su quelli d'informazione.

The study of the relationship between car accidents by young people and alcohol use is very interesting. The national statistics highlight that if numbers are small - about 3% of total - car accidents related to alcohol or other psychoactive substances abuse have the most serious consequences, especially for the youngest people (Higson e Winter, 2003; Sweedler, Biecheler e Laurel, 2004; ISTAT, 2008). From reading statistics two observations appear: the phenomenon is probably underestimated and there are not enough studies about psychological causes inducing young people to driving after drinking. It is to improve the knowledge about this phenomenon, both from the epidemiologic and psychological view, that the "Sportello per i Giovani" in the P.S. of Hospital S. Eugenio in Roma has been created. The Sportello in P.S. is a prevention model - Active Prevention (Carbone, 2003; 2009) - which, on the one hand, wants to know how many youngsters go to P.S. because of accident traumas and with which psychological characteristics, on the other hand, wants to offer a prevention space for each type.

Abstract Introduction: TGR-1202 is a once daily, oral PI3Kδ inhibitor that has demonstrated activity in patients (pts) with relapsed and refractory hematologic malignancies, with a favorable safety and tolerability profile compared to other PI3Kδ inhibitors (Burris, ASCO 2016). Brentuximab vedotin (BV) is a CD30 specific antibody-drug conjugate, which is FDA approved for the treatment of Hodgkin's Lymphoma (HL) and Systemic Anaplastic Large-cell Lymphoma (sALCL). BV has demonstrated impressive response rates in pts with rel/ref disease, however the duration of response is short in pts not achieving a complete response (median PFS of ~6 months for non-CR pts; Gopal et al, Blood 2015). Marked synergy has been demonstrated pre-clinically with TGR + BV, with the combination demonstrating a 3-fold increase in cell death in-vitro and a 55% increase in tumor growth inhibition over either TGR or BV alone in an in-vivo xenograft model of HL (Locatelli et al, ASH 2014). As the combination of TGR + BV displays strong synergy pre-clinically and incorporates non-overlapping mechanisms of activity, a Phase 1 trial evaluating the combination of TGR + BV in pts with rel/ref HL was undertaken. Methods: Eligible pts have relapsed or refractory HL, have received prior ASCT or at least 2 prior regimens, and have an ECOG PS < 3. Prior BV exposure is allowed. Two dose cohorts for TGR are evaluated (400 and 600 mg) dosed once daily with a fixed dose of BV 1.8 mg/kg on day 1 of each cycle (Cycle = 21 days) until off study. Safety is the primary endpoint evaluated by CTCAE v. 4.0. Efficacy (ORR and duration of response) is a secondary endpoint with responses determined according to response criteria of the International Working Group (Cheson, JCO 2007). Results: Fourteen pts have been enrolled. Median age is 34 (range 21 - 81); 9 Male/5 Female; Median ECOG PS = 1; with a median of 3 prior therapies (range 2 - 6). Seven pts had prior ASCT. Six pts had previously received BV, and all 6 were refractory to prior BV therapy. All pts are evaluable for safety. The most common AEs regardless of causality were nausea (71%; 0% Gr. 3/4), diarrhea (57%; 7% Gr. 3/4), neutropenia (50%; 43% Gr. 3/4), and rash (43%; 7% Gr. 3/4), followed by cough, dyspnea, and vomiting (36% each, all grades). Peripheral neuropathy was reported in 4 pts (29%), and were all Grade 1/2. Eleven pts were evaluable for efficacy, with 3 discontinuing prior to first efficacy assessment (1 withdrew consent, and 2 due to AEs). The ORR was 64% (7/11), with 45% (5/11) achieving a complete response with a median TTR of 8 weeks. Notably, 50% (3/6) of BV refractory patients responded to TGR-1202 + BV combination therapy (2 CRs, 1 PR). Three responding patients proceeded to stem cell transplant. Of the remaining 4 patients achieving a response, 2 patients remain in CR, and 2 have progressed (at 13 and 16.5 mos respectively). Conclusions: The combination of TGR-1202 + brentuximab vedotin exhibits an acceptable tolerability profile and is clinically active. Responses were observed in patients with advanced Hodgkin's Lymphoma, including responses in 50% of patients previously refractory to brentuximab vedotin. Further studies evaluating this combination are warranted. Disclosures Sportelli: TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau.

Abstract Abstract 3725 Background: Activation of PI3K has been shown to be required for the proliferation and survival of cancer cells. A selective PI3K-delta inhibitor, GS-1101/CAL-101, has produced promising results in the treatment of lymphoid malignancies. More recently, new chemical entities targeting PI3K have been developed, with pharmacologic and pharmacodynamic features distinct from CAL-101. We sought to determine the activities of two structurally related PI3K inhibitors, TGR-1202 and TGR-5237, in B- and T cell lymphoma models. Methods: The activity of TGR-1202 on individual PI3K isoforms was determined in a cell free system using the PI3K HTRF Assay Kit, and in a cell based assay using the Flow2CAST kit that measures the induction of CD63 surface expression on human whole blood basophils as a marker for PI3K-delta signaling. The cytotoxicity of TGR-1202 and TGR-5237 was studied in 4 mantle cell lymphoma (MCL) cell lines, 1 T-cell acute lymphoblastic leukemia (T-ALL) cell line (P12), and 1 cutaneous T cell lymphoma (CTCL) cell line (H9). Growth inhibition was determined using the ATP-based Cell Titer Glo assay, and apoptosis was determined by flow cytometry using the Alexa Fluo kit. The potency of ublituximab was determined in antigen recognition studies using the Human Whole Blood B-cell depletion assay. Cell cycle progression was evaluated using a Guava cell cycle assay kit in 4 lymphoma cell lines, including Daudi, Raji, U266B1, and DB. Results: In the enzyme based assay, TGR-1202 demonstrated marked potency against PI3K-delta, with a half maximal effective concentration (EC50) at 22 nM. TGR-1202 was 48- to 10,000-fold more selective for the PI3K-delta relative to the alpha, beta, and gamma isoforms. In the cell based assay, the EC50 of TGR-1202 for PI3K-delta was 67 nM, compared with 92 nM with CAL-101. In the cytotoxicity assay of TGR-5237, the concentration required to inhibit growth by 50% (IC50) ranged from 10 uM to 50 uM for the 4 MCL cells and the T-ALL cell P12. Surprisingly, the CTCL cell line H9, was exquisitely sensitive to TGR-5237, with IC50 below 0.1 uM (Figure 1). TGR-5237 induced concentration-dependent apoptosis in WSU-NHL, with its potency comparable to CAL-101 (Figure 2). TGR-1202 caused a concentration-dependent accumulation of cells in the G2-M phase in Raji, Daudi, U266B1, and DB. While TGR-1202 was not cytotoxic to CD20+ B-cells at the 1 uM concentration, combination of 1 uM TGR-1202 with ublituximab increased CD20+ cell depletion by 20% at the 0.1–10 ng/ml concentrations. Last, the combination of TGR-1202 and ublitiximab markedly increased the percentage of cells in sub-G0 phase in Daudi and Raji cells, indicative of their synergy in causing apoptosis (Figure 3). Conclusion: Two novel PI3K-delta inhibitors, TGR-1202 and TGR-5237, disrupted cell cycle progression, induced apoptosis, and inhibited cell growth and proliferation in B- and T cell lymphoma models. TGR-1202 enhanced the activity of a novel CD20 monoclonal antibody, ublituximab, in CD20 positive lymphoma cells. Disclosures: Sportelli: TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen Pharmaceuticals: Employment, Equity Ownership. Viswanadha:Incozen Therapeutics: Employment. O'Connor:Millenium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc: Consultancy; Seattle Genetics, Inc: Membership on an entity's Board of Directors or advisory committees; Allos Therapeutics, Inc: Consultancy.

Abstract Background: Constitutively activated PI3K/AKT/mTOR pathway plays a critical role in the proliferation and survival of cancer cells, through the expression of numerous pro-survival and proliferative genes. Specific inhibitors of the various isoforms of PI3K have shown promising activity in the treatment of indolent B-cell lymphoma. However, they have not shown similar activity in aggressive lymphoma, potentially because the expression of many PI3K/AKT/mTOR dependent pro-survival genes may be activated by alternative signals, for example, NF-kappaB (NF-kB). While specific inhibitors of NF-kB are currently not available in the clinic, proteasome inhibitors are well known to inhibit NF-kB, among its pleiotropic mechanisms of action. We hypothesize that if cancer cell survival is dependent on a complex protein network involving PI3K and NF-kB, then complimentary inhibition of PI3K and the proteasome will become highly synergistic. Our results provide strong support for the hypothesis, by demonstrating that TGR-1202, a PI3Kdelta inhibitor, and carfilzomib, a proteasome inhibitor, are unique among the combinations of PI3K and proteasome inhibitors in potently suppressing the mTORC1 complex and NF-kB, and are highly effective in models of B- and T-cell lymphoma. Methods: Cytotoxicity of PI3K and proteasome inhibitors was studied in a panel of B and T-cell lymphoma cell lines. Growth inhibition was determined using Cell Titer Glo that measures ATP produced by live and proliferating cells. Cell death was determined by flow cytometry, using the probes Annexin V and propidium iodide. Drug: drug synergy was determined by calculating the combination index (CI) and relative risk ratio (RRR). Values below 1 indicate synergy, with smaller RRR and CI values indicating higher levels of synergy. The mechanistic basis of the synergy is determined through in-depth interrogation of the PI3K/AKT/mTOR pathway and its downstream targets and interacting pathways. Results: We used a high-throughput platform to screen the cytotoxicity of TGR-1202, idelalisib/CAL-101, bortezomib, and carfilzomib, in a panoply of B- and T-cell lymphoma cell lines. We found that TGR-1202 and idelalisib as single agent caused only minimal to mild cytotoxicity in lymphoma cells. Bortezomib and carfilzomib as single agent caused dose dependent inhibition of cell growth. Surprisingly, when TGR-1202 or Cal-101 were combined with bortezomib or carfilzomib in a 2x2 design, the combination of TGR-1202 and carfilzomib was consistently the most synergistic, while the other 3 combinations were either much less or not at all synergistic. For example, Table 1 clearly demonstrated that TGR-1202 and carfilzomib demonstrated much higher inhibitory effect and stronger synergy than Cal-101 and bortezomib in two T-ALL cell lines. We have systematically interrogated the effects of these drug combinations on the PI3K/AKT/mTOR pathway, and found that the combination of TGR-1202 and carfilzomib was able to uniquely and potently inhibit components of the mTORC1 complex, causing inhibition of mTORC1 dependent signals such as phosphorylated 4E-BP1, leading to markedly reduced expression of critical genes such as c-myc (Figure 1). Furthermore, the combination of TGR-1202 and carfilzomib uniquely and potently inhibited activation of NF-kB, resulting in markedly suppressed expression of Bcl-xL. The complementary inhibition of the PI3K/AKT/mTOR and NF-kB pathways resulted in robust growth inhibition and apoptosis (Figure 1), and warrants further clinical evaluation for aggressive B- and T-cell lymphoma. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Sportelli: TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Viswanadha:Incozen: Employment.

Background The constitutively activated PI3K/AKT/mTOR pathway plays a key role in the proliferation and survival of cancer cells. Specific inhibitors of the delta isoform of PI3K, such GS-1101 (idelalisib), have shown promising activity in the treatment of B-cell lymphoma. In contrast, some data from models of T-cell lymphoma (TCL) have suggested that these diseases may require inhibition of both PI3Kdelta and PI3Kgamma for optimal cytotoxicity. Proteasome inhibitors, such as carfilzomib, potently inhibit the activation of NF-kappaB (NF-kB) by preventing degradation of the NF-kB inhibitor IkB. We hypothesize that inhibition of this pathway at both the proximal (PI3K) and distal (NF-kB) aspects, using both inhibitors of PI3K and proteasome, could lead to a synergistic cyototoxic effect in models of lymphoma. Methods Cytotoxicity of TGR-1202 and carfilzomib was studied in a panel of B and T-cell lymphoma cell lines. Growth inhibition was determined using Cell TiterGlo that measures ATP produced by live and proliferating cells. Cell death was determined by flow cytometry, using the probes Annexin V and propidium iodide. Drug: drug synergy was determined by calculating relative risk ratio (RRR). Values below 1 indicate synergy, with smaller RRR values corresponding to higher levels of synergy. Results TGR-1202 as a single agent active against a panel of diverse B- and T-lymphomas. By the Cell TiterGlo assay, the concentration required to inhibit growth by 50% (IC50) following 48-hour exposure ranged from 10 uM to 15 uM in most of the cell lines. Maver and H9, representing mantle cell lymphoma (MCL) and TCL respectively, were more resistant to TGR-1202. Carfilzomib, on the other hand, is a potent inhibitor of B- and T cell lymphomas, with an IC50 in the range of 2-8 nM most lymphomas (Table 1). Remarkably, when TGR-1202 is combined with carfilzomib at minimally, or mildly inhibitory concentrations, there was a highly synergistic inhibition in both B and T-cell lymphomas. Following a 24 hour exposure, carfilzomib alone achieved only 20% growth inhibition of the MCL cell line Jeko-1, while TGR-1202 at concentrations ranging from 2.5 to 15 uM did not produce any growth inhibition (Figure 1). However, the combination of carfilzomib and TGR-1202 markedly inhibited growth of Jeko-1, with a synergy index, RRR, as low as 0.10. In contrast, the synergy of carfilzomib and TGR-1202 in the TCL cell line H9 following a 48-hour exposure, as shown in Figure 2, demonstrated remarkable synergy with a RRR as low as 0.02. To further confirm the synergy of these two drugs in lymphoma, apoptosis was determined in H9 cells treated either with each drug as a single agent or together in combination. Figure 4 illustrates that the combination of these two drugs at marginally active concentrations caused apoptosis in as many as 90% of the H9 cells. The synergy of TGR-1202 and carfilzomib stood out among the combinations tested, as being among one of the most synergistic combinations explored. Table 2 contains a summary of the synergy seen with TGR-1202 and carfilzomib, in contrast to the effects seen with other drug: drug combinations. In conclusion, the combination of the PI3K delta inhibitor TGR-1202 and the proteasome inhibitor carfilzomib remarkably and distinctively synergize to kill both B and T-cell lymphoma cells, and represents a promising therapeutic strategy in the treatment of these diseases. C-: Negative control CFZ: carfilzomib TG: TGR-1202 RRR: Relative risk ratio. Values below 1 indicate synergy. C-: Negative control CFZ: carfilzomib TG: TGR-1202 RRR: Relative risk ratio. Values below 1 indicate synergy. NR: IC50 was not reached at the highest tested concentrations of 32 nM. DLBCL: Diffuse large B cell lymphoma MCL: Mantle cell lymphoma CTCL: Cutaneous T cell lymphoma Disclosures: Sportelli: TG Therapeutics, Inc. : Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:3Rhizen Pharmaceuticals: Employment, Equity Ownership. Viswanadha:Incozen Therapeutics Pvt. Ltd.: Employment, Equity Ownership.

Abstract Abstract 1842 Perifosine (Keryx Biopharmaceuticals) is an oral alkylphospholipid that has been shown to have clinical activity in multiple myeloma and Waldenstrom's macroglobulinemia. Pre-clinical data suggest that its activity is due to inhibition of the Akt signal transduction pathway. The Akt pathway is known to be important for viability in CLL, another B-cell malignancy. Therefore, we investigated the in vitro activity of perifosine in freshly isolated primary CLL cells. CLL patients at the Duke University and Durham VA Medical Centers were enrolled in an IRB-approved research protocol for blood sample collection. CLL cells were negatively selected using the RosetteSep B-cell enrichment cocktail (StemCell Technologies) and a ficoll-Hypaque gradient. This method yields greater than 95% purity of malignant lymphocytes, determined by flow cytometry. Prognostic markers such as IgVH mutation status, CD38 and ZAP70 expression, and interphase cytogenetics were determined. We found the 50% effective dose (ED50) of perifosine for inducing cytotoxicity in CLL cells after a three-day incubation using the MTS colorimetric assay to be 510 nM (n = 29, range 120 – 1540 nM). CLL cells were obtained from patients with generally poor prognostic markers: 52% CD38+, 93% ZAP70+, 78% IgVH unmutated, 42% 17p deletion, 8% 11q deletion, 27% trisomy 12, 12% normal, and 12% 13q deletion as a sole abnormality. There were no statistical differences in ED50 between cells obtained from patients in high or low risk prognostic groups. Perifosine induced apoptosis in a dose- and time-dependent manner, measured by Annexin V and PI staining (n = 4). Based upon these pre-clinical results, we initiated a phase II study of perifosine (50 mg orally, twice daily) in relapsed or refractory CLL/small lymphocytic lymphoma (SLL) (NCT00873457). The primary objective of this study is to assess the response rate at 3 and 6 months of perifosine treatment in patients with relapsed or refractory CLL/SLL. Secondary objectives are to monitor toxicity, evaluate overall survival, progression-free survival and response duration, and perform laboratory correlates. Early interim results of this study are presented. Since trial initiation in September 2009, 13 patients have been enrolled. Nine patients had Rai stage III/IV disease at the time of therapy, and 4 patients were fludarabine-refractory. Patients had extensive prior treatment (median 4, range 1 – 11). Many patients had high-risk prognostic features: 9/11 IgVH unmutated, 10/13 CD38+, and 11/13 ZAP70+. Evaluation of interphase and metaphase cytogenetics demonstrated 4 patients with 17p deletion, two with 11q deletion, 2 with trisomy 12, 4 normal, and 4 with other complex cytogenetic anomalies. Of 12 patients who began therapy, 5 patients withdrew from the study prior to 3 months, 6 patients received at least 3 months of therapy, and 1 patient completed 6 months of therapy. Of the patients who received at least 3 months of therapy, there were 5 patients with stable disease, and one patient with partial response, using iwCLL response criteria. Grade 3/4 toxicities included anemia (n=2), fatigue (n=2), dehydration (n=1), febrile neutropenia (n=1), hyperbilirubinemia (n=1), hyponatremia (n=1), cough (n=1), and dyspnea (n=1). One patient required a dose reduction to 50 mg daily and two patients required dose delays due to toxicities. In conclusion, perifosine has potent in vitro activity against primary CLL cells. Preliminary results of this ongoing phase II study of oral perifosine in relapsed or refractory CLL/SLL demonstrate mostly disease stabilization in a group of very high-risk patients and an acceptable toxicity profile. Completion of this clinical study is necessary to determine if perifosine monotherapy has a potential role in the treatment of CLL/SLL. Disclosures: Sportelli: Keryx Biopharmaceutical: Employment, Equity Ownership. Weinberg:Keryx Biopharmaceuticals: Research Funding.

- After an overall framing of the main features of the "welfare access", the article analyses the experimentations by the Emilia Romagna Region and the experience of the Province of Bologna in the field of "social counters". Within the year 2003, the Emilia Romagna region has promoted and sustained a regional experimentation in order to start up a number of "social counters", as required by the Regional Law L.R. 2/03, art. 7. The regional welfare reform provided for the development of a network of counters on the regional territory, in order to answer for the citizens' access to the local system of social and sociomedical services. Following up such an experimentation, the communes belonging to the Province of Bologna opted for the sharing of the same informational system, which had already been positively tested, was working in one of the sociomedical territorial districts and was strongly orientated towards integration. The choice greatly marked the development of the social counters project in the Province of Bologna: the peculiar sharing of the same software by the whole of the provincial territory has been a fundamental element, which allowed to carry out not only the territorial social counters project, but also an effective provincial network of such social desks.Keywords: welfare; access; social counters network; integration; social system.

Viene presentato un progetto realizzato in una scuola media inferiore al fine di ascoltare i ragazzi e i loro problemi ed effettuare un'opera di prevenzione delle dipendenze e promozione della salute. Pur nella limitatezza delle risorse messe a disposizione, il progetto ha incontrato il gradimento degli adolescenti coinvolti.

Abstract Introduction The phosphatidylinositol 3-kinase (PI3K) pathway is consistently activated in relapsed/refractory Hodgkin lymphoma (HL), suggesting that TGR-1202, a novel inhibitor of the delta isoform of PI3K (PI3K-δ), in clinical development for patients with hematologic malignancies, might represent an attractive therapeutic option. The anti-CD30 monoclonal antibody Brentuximab Vedotin (BV) conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) has recently been reported to induce an overall response rate of 75% in relapsed/refractory HL, but is associated with limited response duration. Combination therapies aimed at enhancing the anti-tumor activity of BV and reducing its side effects may have significant clinical impact in the treatment of relapsed/refractory HL. The present study was aimed at investigating the activity and mechanism(s) of action of the PI3K-δ inhibitor TGR-1202, in combination with BV in non-clinical models of HL. Methods Three HL cell lines, including L-540, KM-H2 and L-428, were used to test the effects of TGR-1202 alone, BV alone, or the combination of TGR-1202 with BV. Cell cycle effects and cell survival were determined by flow cytometry and Western blotting (WB). Additionally, WB was used to assess modulating effects of TGR-1202 on the PI3K/AKT pathway as well as microtubule interacting proteins. Cyclin B1, p21, and α-tubulin were detected by indirect immunofluorescence microscopy. The activity of TGR-1202 and/or BV on microtubule distribution and polymerization were quantified using a three-dimensional volume rendering technique. Results TGR-1202 and BV used as single agents were able to induce a time- and dose-dependent inhibition of cell proliferation and induction of cell death in all cell lines. Compared to the single agent effects, the combination of TGR-1202 (10 µM) and BV (10 ng/ml) synergistically inhibited the mean (±SEM) growth of L-540, KM-H2, and L-428 cell lines (TGR-1202: 40 ± 4%; BV: 30 ± 2%; TGR-1202/BV: 85 ± 1%). Inhibition of cell proliferation induced by the 2-drug combination was associated with a dramatic G2/M cell cycle arrest. Upon TGR-1202/BV treatment, the mean (±SEM) percentages of cells in G2/M phases were increased by 4-fold (72 ± 3%) as compared to TGR-1202 (18 ± 1%) or BV (18 ± 1%) alone. This finding was paralleled by a 3-fold reduction of cells in S phase (TGR-1202: 25 ± 1%; BV: 23 ± 1%; TGR-1202/BV: 9 ± 1%, mean ± SEM) and a marked Cyclin B1 and p21 overexpression. In comparison to each drug as a single agent, the TGR-1202/BV combination led to a synergistic cell death induction. In fact, upon TGR-1202/BV treatment, mean (±SEM) cell death values detected in L-540, KM-H2, and L-428 cell lines were increased by 3-fold over TGR-1202 or BV alone (TGR-1202: 27 ± 2%; BV: 27 ± 2%; TGR-1202/BV: 75 ± 2%). Analysis of caspase-3 and PARP cleavage and blocking experiments with the pan-caspase inhibitor Z-VAD-FMK revealed a caspase-dependent cell death mechanism. In addition, the antiproliferative and cytotoxic effects of TGR-1202 were associated with a marked time-dependent inhibition of PI3K/Akt pathway and dephosphorylation of GSK-3β, Aurora kinases, and stathmin, suggesting that modulation of molecules associated with microtubule polymerization are critically involved in TGR-1202/BV-triggered cell death. To asses potential effects on microtubule dynamics, HL cells were treated with TGR-1202, BV, or the combination for 24 hours, and the effect on microtubules was determined by α-tubulin staining. Compared with controls, TGR-1202 and BV treatment alone led to a modest loss of microtubules (TGR-1202: 11%; BV: 9%), while the combined TGR-1202/BV treatment resulted in a potent synergistic microtubule disruption (mean values of α-tubulin inhibition of 40%, P ≤.0001), supported by a diffuse stain and irregular microtubule fragments throughout the cytosol. Additionally, TGR-1202/BV was found to interfere with the mitotic spindle integrity which may suggest that the G2/M arrest and cytotoxicity of the combined TGR-1202/BV treatment primarily arises from the inhibition of tubulin polymerization. Conclusions Novel PI3K-δ inhibitor TGR-1202 enhances the anti-tumor activity of BV by increasing drug-induced apoptosis and tubulin disruption in all HL cell lines analyzed in the present study. Our data provides a strong rationale for evaluating TGR-1202 in combination with BV in patients with relapsed/refractory HL. Disclosures: Sportelli: TG Therapeutics, Inc.: Employment, Equity Ownership.

Il Comitato Etico per la Pratica Clinica (CEPC) dell’Aulss N. 8 Berica di Vicenza si fatto promotore nei due anni che hanno seguito la pubblicazione della Legge 219/2017, di una intensa attivit di formazione e informazione sulle importanti novit da essa introdotte. In particolare stato redatto un testo, pubblicato sul sito aziendale, avente l’obiettivo da un lato di spiegare ai non addetti ai lavori il senso e lo scopo della legge, dall’altro di fornire una indicazione semplice e concreta del percorso da fare per redigere una Disposizione Anticipata di Trattamento (DAT) e cos registrarla in via ufficiale. Molte altre attivit formative, rivolte in alcuni casi ai professionisti sanitari, in altri alla cittadinanza in generale, sono seguite alla pubblicazione del documento. Una iniziativa particolarmente innovativa stata la creazione di uno spazio di Consulenza Etica per le DAT, uno sportello di ascolto dove un componente del CEPC, un professionista sanitario in possesso di una laurea in filosofia e di un master in consulenza etica, per una mattina al mese si rende disponibile a fornire informazioni sulle DAT, ad aiutare nella redazione di una nuova DAT oppure a leggere e analizzare una DAT gi predisposta. Un piccolo gruppo di lavoro del CEPC, allo scopo di rispondere alla richiesta di un gran numero di utenti di uno strumento che potesse aiutarli a redigere una DAT, ha elaborato e sottoposto all’approvazione del Comitato un documento intitolato “Guida per preparare e personalizzare una Disposizione Anticipata di Trattamento”, pubblicato anch’esso sul sito aziendale.

Abstract Background: While time-limited novel agent combinations have demonstrated high overall response rates and durable responses for patients with chronic lymphocytic leukemia (CLL), they also have high rates of adverse events and possibly overtreat many favorable risk patients. Meanwhile, patients receiving indefinite ibrutinib monotherapy are at risk for cumulative toxicity and acquired resistance with continuous exposure. To address these challenges, we utilized an "add-on" approach to combination therapy after a period of ibrutinib monotherapy exposure. We examined the addition of umbralisib (a selective PI3Kδ and casein kinase-1epsilon [CK1ε] inhibitor) and ublituximab (a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity; U2) to ibrutinib in CLL patients with detectable minimal residual disease (MRD) after an initial period of treatment with ibrutinib monotherapy. With this strategy, we aimed to induce undetectable MRD (uMRD), minimize the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and achieve a durable treatment-free observation (TFO) period in CLL patients who would most benefit from combination therapy. Methods: This is a phase II, multicenter, open label clinical trial (NCT04016805). Eligible patients were receiving ongoing ibrutinib, in any line of therapy, for a minimum duration of 6 months and had detectable residual CLL in the peripheral blood via MRD assay (flow cytometry with a cutoff of 10^-4 for uMRD). Umbralisib (administered daily at 800mg) and ublituximab (administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and on Day 1 every 3 cycles after Cycle 6) were added to ibrutinib, and patients were monitored serially for MRD starting on Cycle 3 Day 1. Once uMRD was achieved and confirmed 4 weeks later, patients entered a period of TFO. Patients who did not attain uMRD continued treatment for up to 24 cycles followed by TFO. The primary objective of the study was rate of uMRD, with a prespecified MRD conversion rate of 25% defined as promising. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. Results: In this fully accrued study, U2 was added to ibrutinib in 26 patients. Median age was 63 years (range, 48-81) and 77% were male. Disease characteristics included del(17p) in 8%, del(11q) in 12%, and unmutated IGHV in 31%. Median duration of ibrutinib treatment prior to addition of U2 was 22 months (range 7-66 months). The swimmer plot in Figure 1 depicts time on ibrutinib prior to enrolling in this study, the duration of treatment with triplet therapy, achievement of uMRD, and TFO. MRD has been assessed in 24 patients; 71% (17/24) had uMRD in at least 1 assessment. Median time to first uMRD result was 5 months (range 2 - 12). A total of 16 patients (67%) entered TFO; 15 had 2 consecutive uMRD assessments and 1 completed 24 cycles with detectable MRD. TFO appears durable, with a median of 242 days off therapy (range 5-538 days) as of the data cutoff. 73% remain uMRD at last follow up. No patient has progressed or required re-treatment per iwCLL criteria. U2 plus ibrutinib was well tolerated. All-causality grade 3/4 adverse events of special interest included ALT/AST increase (4%), diarrhea (4%), and hypertension (8%). Two patients discontinued all therapy due to rash; both were uMRD at the time of treatment discontinuation and remain uMRD. One patient died due to complications of COVID-19. Conclusions: This is the first MRD-driven approach utilizing the combination of BTKi, PI3Ki, and anti-CD20 monoclonal antibody. This novel agent combination therapy was well tolerated and effective, with achievement of uMRD in 71% of evaluable patients. This "add-on" approach for patients on continuous ibrutinib resulted in deep remissions that allowed for a tailored, time-limited therapy and sustained treatment-free observation. Figure 1 Figure 1. Disclosures Roeker: Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; Loxo Oncology: Consultancy. Leslie: Karyopharm Therapeutics: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Merck: Consultancy; Janssen: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Soumerai: Abbvie: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; BostonGene: Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Zelenetz: MorphoSys: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; NCCN: Other; Gilead: Honoraria; LFR: Other; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; SecuraBio: Honoraria; Amgen: Honoraria; Pharmacyclics: Honoraria; MethylGene: Research Funding; Genentech/Roche: Honoraria, Research Funding; Novartis: Honoraria. Falchi: Abbvie: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding; Genmab: Consultancy, Research Funding. Park: Curocel: Consultancy; PrecisionBio: Consultancy; BMS: Consultancy; Minerva: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy; Kite Pharma: Consultancy; Autolus: Consultancy; Kura Oncology: Consultancy; Servier: Consultancy; Amgen: Consultancy; Artiva: Consultancy; Intellia: Consultancy. Battiato: Janssen Pharmaceutical: Other: Advisory Board July 2020; Abbvie Pharmaceuticals: Other: CLL Steering Committee November 2020-present. Thompson: VJHemOnc: Honoraria; Curio Science: Honoraria; MJH Life Sciences: Honoraria. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; AstraZeneca: Consultancy; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genmab: Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Abstract Background: Umbralisib, a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, is pharmacologically distinct from other PI3K inhibitors and is administered orally once daily. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody dependent cellular cytotoxicity (ADCC) that targets a unique epitope on CD20. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, registration-directed Phase 2 study designed to evaluate the safety and efficacy of the umbralisib + ublituximab (umbra+ubli, U2) combination in patients with previously treated NHL . Umbra has been recently approved for the treatment (tx) of previously treated marginal zone lymphoma (MZL) based on reported data (Fowler JCO 2021), and the U2 combination has been shown to be active with a manageable safety profile in patients with relapsed/refractory (R/R) NHL (Lunning Blood 2019). In contrast with other PI3Kis, there has been a low incidence of immune-mediated toxicities with umbra, possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1ε. Herein, we present results from the MZL cohort treated with U2. Methods: Eligible patients had histologically confirmed MZL (splenic, nodal, extranodal) and were R/R to ≥1 prior lines of tx which must have included an anti-CD20. Patients were treated with U2: umbra was given orally at 800 mg once daily until progression or unacceptable tolerability and ubli was administered intravenously on Days 1, 8, and 15 of Cycle 1, on Day 1 of Cycles 2-6, and on Day 1 every 3 cycles until Cycle 24 in 28-day tx cycles. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee according to the revised IWG criteria (Cheson 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to response (TTR), and safety. Results: 72 MZL patients were enrolled and received U2. The median age was 70 years (range 40-89), 53% were female, 74% had stage III or IV disease, and 25% were refractory to their immediate prior therapy. Patients had received a median of 2 prior regimens (range 1-9). As of the cutoff date, 41 patients remain on tx. The ORR was 68%, with 19% achieving complete response (CR). At a median follow-up of 16 months, median DoR was not reached (12 - not estimable). 90% of patients had a reduction in disease burden from baseline while on U2. Figure 1a depicts efficacy data for U2, and Figure 1b shows the best % change in target lesions from baseline for MZL patients treated with at least 1 dose of U2. The most common adverse events (AEs) were diarrhea (all grades: 49%, grade ≥3: 13%), nausea (all grades: 30%, grade ≥3: 0%), and fatigue (all grades: 36%, grade ≥3: 6%). Other AEs of interest included non-infectious colitis (all grades: 2.8 %, grade ≥3: 2.8%) and rash (all grades: 11%, grade ≥3: 0%). Four patients (5.6%) discontinued due to an AE. Conclusions: U2 was highly active in patients with R/R MZL, with improved efficacy when compared to a prior cohort of MZL patients treated in this study with umbra mono (Fowler JCO 2021). The safety profile of the U2 combination was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. Figure 1 Figure 1. Disclosures Chavez: Bristol Myers Squibb: Speakers Bureau; AstraZeneca: Research Funding; BeiGene: Speakers Bureau; Epizyme: Speakers Bureau; MorphoSys: Speakers Bureau; Karyopharm Therapeutics: Consultancy; Merck: Research Funding; Adaptive: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Kite/Gilead: Consultancy. Goldschmidt: AbbVie: Consultancy, Research Funding. Samaniego: Imbrium: Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding. Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Servier: Speakers Bureau. Fonseca: Sanofi: Honoraria; Karyopharm: Honoraria; Epizyme: Honoraria; Dava Oncology: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Abbvie: Honoraria. Drgona: Abbvie: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sandoz: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Teva: Honoraria; Viatris: Honoraria. Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Specialised Therapeutics: Consultancy; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Regeneron: Speakers Bureau; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Levi: AbbVie: Consultancy, Research Funding. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Mundipharma: Consultancy; Nomocan: Consultancy; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Zinzani: ROCHE: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; SANDOZ: Other: Advisory board; BMS: Other: Advisory board, Speakers Bureau; Incyte: Other, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; ADC Therap.: Other.

Abstract Background: Patients with relapsed or refractory (R/R) DLBCL generally have a poor prognosis, particularly if they are not candidates for autologous stem cell transplantation (ASCT) or experience relapse following approved CAR-T therapies. The UNITY-NHL study systematically explored the efficacy and tolerability of the PI3K-d/CK1-e inhibitor, umbralisib, alone (umbra), and in combination with the glycoengineered anti-CD20 monoclonal antibody ublituximab (U2), followed by a cohort treated with U2 plus bendamustine (U2+benda). Herein we report on the experience in a large cohort of patients with R/R DLBCL. Methods: This study explored a sequential combination design as described above. Eligible patients had histologically confirmed R/R DLBCL and were ineligible for ASCT, with no limit on number or type of prior treatment. Umbra was given orally at 800 mg once daily in 28-day cycles (C) until disease progression or unacceptable tolerability. Ublituximab was administered intravenously (IV) on Days 1, 8, and 15 of C1, on Day 1 of C2-6, and on Day 1 every 3C through C24. Benda was administered IV (90 mg/m 2) on Days 1/2 of C1-6. Cell of origin, NGS, and c-myc (FISH) were analyzed centrally. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee. Secondary endpoints included duration of response, progression-free survival, time to response, and safety. Results: 226 patients with DLBCL were enrolled as follows: umbra monotherapy (n=30), U2 (n=66), and U2+benda (n=130). The population demographics included the following features: median age was 72 years (range 32-95); 59% were male; 64% of patients had stage III or IV disease; 58% were refractory to their immediate prior therapy; and the median number of prior therapies was 2 (range 1-8). There were no substantive differences in these characteristics across cohorts. Median follow-up for the umbra, U2, and U2+benda arms was 51 months (range 47-61), 46 months (range 41-57), and 40 months (range 35-47), respectively. Overall and complete response rates for the umbra mono, U2, and U2+benda arms were 13.3% (CR 3.3%), 31.8% (CR 10.6%), and 43.1% (CR 16.9%), respectively. Results pertaining to secondary endpoints are listed in Table 1. Correlation of response to cell of origin and mutation/c-myc status is ongoing and will be available at the time of presentation. Adverse events (AEs) were similar across the cohorts, with the exception of hematologic AEs which were increased in patients receiving benda. The most common all-grade AEs by treatment arm (umbra, U2, and U2+benda, respectively) were diarrhea (47%; 41%; and 48%), nausea (40%; 45%; and 45%), fatigue (33%; 30%; and 41%) and neutropenia (3.3%; 18%; and 32%). All-grade AEs of special interest included non-infectious colitis (3.3%, 1.5%, and 2.3%) and pneumonitis (3%, 1.5%, and 1.5%) in umbra, U2 and U2+benda treated patients respectively. Grade 3/4 AEs were uncommon, with the only events &gt;10% being limited to neutropenia (11% for U2; 27% for U2+benda), and anemia (17% for U2+benda). Conclusions: In the DLBCL cohort of UNITY-NHL, the U2+benda triplet regimen was active and well tolerated in patients with R/R DLBCL who were unsuitable for transplant or who had relapsed following ASCT. Umbra monotherapy and U2 were also well tolerated but resulted in lower ORR than in the U2+benda cohort. Figure 1 Figure 1. Disclosures Burke: X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Kura: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Kymera: Consultancy; AbbVie: Consultancy; Verastem: Consultancy. Fonseca: Amgen: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; Dava Oncology: Honoraria; Epizyme: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Islas-Ohlmayer: Seagen Inc.: Research Funding. Reeves: Apollomics, Inc.: Research Funding; Tarveda Therapeutics: Research Funding; Ascentage Pharmaceuticals: Research Funding; Clovis Oncology: Research Funding; Arvinas: Research Funding; Pfizer: Research Funding; Ellipses: Research Funding; ImmunoGen: Research Funding; Karyopharm Therapeutics: Honoraria, Research Funding; Moderna: Research Funding; Thrive: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Astellas Pharma: Research Funding; IDEAYA Biosciences: Research Funding; Pharmacyclics: Research Funding; Loxo Oncology: Research Funding; AbbVie Inc.: Research Funding; Celgene: Research Funding; GSK: Research Funding; Jiangsu Hengrui Medicine Co.: Research Funding; Arcus Biosciences: Research Funding; Calithera: Research Funding; Amgen: Research Funding; Mirati Therapeutics, Inc.: Research Funding; Array BioPharma Inc.: Research Funding; Taiho Pharmaceutical: Research Funding; Boehringer Ingelheim: Research Funding; GI Therapeutics Inc.: Research Funding; Hutchison: Research Funding; MacroGenics: Research Funding; Ipsen: Research Funding; MedImmune, LLC.: Research Funding; BeiGene: Research Funding; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; Verastem: Research Funding; Janssen Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Co.: Research Funding, Speakers Bureau; Roche Pharma: Research Funding; Novartis Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Arvinas: Research Funding; CytomX: Research Funding; Sermonix Pharmaceutical: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Evelo Biosciences: Research Funding. Wróbel: Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria; Janssen: Honoraria, Speakers Bureau. Pagel: Incyte/MorphoSys: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Nomocan: Consultancy; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Kymera: Consultancy, Current equity holder in publicly-traded company; Mundipharma: Consultancy. Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Genentech: Research Funding; Karyopharma: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau.

Abstract Background: The median age at diagnosis of patients with Chronic Lymphocytic Leukemia (CLL) is 70 years, which presents unique challenges for disease management, as these patients have more comorbidities and often require multiple concomitant medications. While some baseline characteristics (e.g., history of cardiovascular or bleeding issues) may create potential risk for significant medical events, others (e.g., hypertension, joint pain) threaten the ability of patients to stay on long-term continuous BTKi, compromising optimal therapeutic benefit. The tolerability of Bruton's tyrosine kinase inhibitors (BTKi) can be suboptimal in these patients, emphasizing the need for novel non-chemotherapy regimens with a differentiated risk profile. The combination of umbralisib and ublituximab (U2) demonstrated superior progression-free survival (PFS) and overall response rates (ORR) compared to chemoimmunotherapy in the primary analysis of the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311) (Gribben et al. 2020). Herein, an analysis was conducted of patients treated with U2 on UNITY-CLL who had a pre-existing comorbidity or concomitant medication that could potentially preclude the use of BTKi. Methods: Patients ≥18 years of age with CLL who were treatment-naïve (TN) or previously treated (PT) requiring treatment per iwCLL criteria with adequate organ function and ECOG PS ≤2 were eligible. Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy. Stratification factors included treatment status (TN vs. PT) and deletion 17p (del17p) status. Umbralisib was given orally at 800 mg once daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and on Day 1 every 3 cycles after Cycle 6. The primary endpoint was independent review committee (IRC)-assessed PFS of U2 compared to O+Chl. Key secondary endpoints included IRC-assessed ORR, complete response, undetectable minimal residual disease (uMRD), duration of response, and safety, assessed from the first dose until 30 days after the last dose of study medication. BTKi risk factors were defined by the comorbidities and concomitant medication categories listed in Table 1 and include pre-existing arrythmias, cardiovascular dysfunction, history of major bleeding, hypertension, and joint pain. Results: In the UNITY-CLL study, 206 subjects with CLL received treatment with U2. Among these patients, the median age was 67 years, 9% had del17p, 54% had unmutated IGHV, and 57% were TN. Among these patients, 131 (63.6%) met at least 1 BTKi risk factor criteria (Table 1). Among patients with BTKi risk factors, the median age was slightly higher at 69 years, 11% had del17p, 56% were unmutated IGHV, and 57% were TN. At a median follow-up of 36.7 months, 40% remain on U2 as compared to 37% for the entire U2 population. The median PFS for patients with a BTKi risk factor was equivalent to the entire U2 population at 31.9 months, and a similar ORR (88% vs 83%, difference not statistically significant) was observed in this population as compared to the overall U2 population. In terms of safety, there were no differences in the incidences of SAEs, grade ≥3 AEs, fatal AEs, or discontinuations due to AEs. Conclusions: Patients with BTKi risk factors attained durable clinical benefit from U2. In this population with BTKi risk factors, the baseline disease characteristics aligned with the overall population treated with U2, and efficacy and safety outcomes did not appear to be negatively impacted by the presence of comorbidities or the use of concomitant medications. These data suggest that U2 can be a valuable treatment option for patients with these conditions. Figure 1 Figure 1. Disclosures Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; MEI, Sunesis: Research Funding. Jurczak: Abbvie: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Mei Pharma: Research Funding; Morphosys: Research Funding; Novo Nordisk: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Lech Maranda: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board, lectures; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board, lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board, lectures; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board, lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board, lectures; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board, lectures. Wróbel: BeiGene: Honoraria; Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Sharman: AstraZeneca: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; Lilly: Consultancy; BMS: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy. Hoffmann: TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmcyclics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Huntington: Flatiron Health Inc.: Consultancy; DTRM Biopharm: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Novartis: Consultancy; AbbVie: Consultancy; SeaGen: Consultancy; Genentech: Consultancy; Servier: Consultancy; Bayer: Honoraria; Thyme Inc: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Jacobs: Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy; SecuraBio: Consultancy, Speakers Bureau; Genentech: Consultancy; Jannsen: Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Verastem: Consultancy; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; TeneoBio: Research Funding; MEI Pharma: Research Funding. Rowland: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Weiss: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Nomocan: Consultancy; Mundipharma: Consultancy. Flinn: Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding.

Abstract Background: Umbralisib, a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, is pharmacologically distinct from other PI3K inhibitors and is administered orally once daily. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20. The primary analysis of the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311) demonstrated that the umbralisib+ublituximab (U2) combination prolonged progression-free survival (PFS) compared to chemoimmunotherapy in both treatment-naïve (TN) and previously treated (PT) populations (Gribben et al. 2020). Herein, results are presented for patients treated with U2 by treatment status. Methods: Patients ≥18 years of age with TN or PT CLL requiring treatment, per iwCLL criteria with adequate organ function and ECOG PS ≤2, were eligible. Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy. Stratification factors included treatment status (treatment-naïve vs. previously treated) and deletion 17p status. Umbralisib was administered orally at 800 mg once daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2 - 6, and on Day 1 every 3 cycles after Cycle 6. The primary endpoint was independent review committee (IRC)-assessed PFS of U2 compared to O+Chl. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response, undetectable minimal residual disease (uMRD), duration of response, and safety, assessed from the first dose until 30 days after the last dose of study medication. While the primary analysis reported results for the pooled intent-to-treat population, the current analysis focuses on outcomes in patients treated with U2 by treatment status. Results: At data cut-off date of May 1, 2020, U2-treated patients had a median follow-up of 35.27 months. Of the 210 patients treated with U2, 119 were TN and 91 were PT. TN patients had a median age of 68 years (39 - 88 years) and 63% were male. Median PFS for U2 in TN patients was 38.5 mos (95% CI, 33.2, NE) with an estimated 24-mo PFS rate of 76.6%. IRC-assessed ORR was 84.0% (95% CI, 77.5%-90.6%). The median duration of exposure to umbralisib and ublituximab was 26.5 and 29.5 mos, respectively. In TN patients, AEs of special interest (AESI) of grade ≥3 included: neutropenia (24.1%), diarrhea (13.8%), ALT increased (12.1%), AST increased (7.8%), non-infectious colitis (2.6%), infusion-related reaction (IRR, 0.9%), and pneumonitis (0.9%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 5.2% (neutropenia), 2.6% (diarrhea), 3.4% (ALT increase), 1.7% (AST increase), 1.7% (colitis), 0.9% (IRR), and 0.9% (pneumonitis) of patients. PT patients had a median of 2 prior (1 - 9) lines of therapy, the median age was 65 years (43 - 87 years) and 65.9% were male. Median PFS was 19.5 mos (95% CI, 14.6-27.7) with an estimated 24-mo PFS rate of 41.3%. The IRC-assessed ORR was 82.4% (95% CI, 74.6%-90.2%). Among 14 patients previously treated with ibrutinib, the ORR was 57%. The median duration of exposure to umbralisib and ublituximab were 15.6 mos and 14.6 mos, respectively. In PT patients, AESI of grade ≥3 included: neutropenia (40.0%), diarrhea (10.0%), IRR (3.3%), ALT increase (3.3%), AST increase (2.2%), and non-infectious colitis (2.2%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 1.1% (ALT increase), 1.1% (AST increase), and 1.1% (colitis) of patients. Conclusions: U2 demonstrated a tolerable safety profile in both the TN and PT populations. These results mark the first randomized Phase 3 trial of a PI3K in TN CLL, establishing a new mechanism of action in this setting. Disclosures Jacobs: Genentech: Consultancy; Jannsen: Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Verastem: Consultancy; AbbVie: Consultancy, Speakers Bureau; SecuraBio: Consultancy, Speakers Bureau; TeneoBio: Research Funding; MEI Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Flinn: ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Giannopoulos: Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Wróbel: Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria. Cultrera: Beigene: Research Funding. Danilov: Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Rigel Pharm: Honoraria; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Burke: Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Beigene: Consultancy, Speakers Bureau; Epizyme: Consultancy; AbbVie: Consultancy; MorphoSys: Consultancy; Verastem: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Roche/Genentech: Consultancy; AstraZeneca: Consultancy; SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Beach: TG Therapeutics: Speakers Bureau. Huntington: TG Therapeutics: Research Funding; DTRM Biopharm: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy, Honoraria; Flatiron Health Inc.: Consultancy; Bayer: Honoraria; Servier: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Thyme Inc: Consultancy; SeaGen: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sharman: TG Therapeutics: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Lilly: Consultancy; AbbVie: Consultancy. Siddiqi: AstraZeneca: 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; BMS: 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; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Brander: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; DTRM: Research Funding; Ascentage: Research Funding; Genentech: Consultancy, Research Funding; Novartis: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Verastem: Consultancy; MEI Pharma: Research Funding; LOXO: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; BeiGene: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Pagel: AstraZeneca: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Dlugosz-Danecka: Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Acerta Pharma: Research Funding; AbbVie: Research Funding; Macrogenics: Research Funding; Beigene: Research Funding; MEI Pharma: Research Funding; Incyte Corp.: Research Funding; Takeda: Research Funding. Ghosh: Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Mundipharma: Consultancy; Nomocan: Consultancy; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Weiss: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Gribben: Takeda: Honoraria; Novartis: Honoraria; Morphosys: Honoraria; Gilead/Kite: Honoraria; BMS: Honoraria; Abbvie: Honoraria; AZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria.

In this paper, we consider the complex dynamics of a fiscal dynamical model, which was improved from Wolfstetter classical growth cycle model by Sportelli et al. The main work of the present paper is to study the impact of fiscal policy delays on the national income adjustment processes using a dynamical method, such as double Hopf bifurcation analysis. We first use DDE-BIFTOOL to find the double Hopf bifurcation points of the system, and draw the bifurcation diagrams with two bifurcation parameters, i.e. the tax collection delay [Formula: see text] and the public expenditure decision-making delay [Formula: see text]. Then we employ the method of multiple scales to obtain two amplitude equations. By analyzing these amplitude equations, we derive the classification and unfolding of these double Hopf bifurcation points. And three types of double Hopf bifurcations are found. Finally, we verify the results by numerical simulations. We find complex dynamic behaviors of the system via the analytical method, such as stable equilibrium, stable periodic, quasi-periodic and phase-locked solutions in respective regions. The dynamical phenomena can help policy makers to choose a proper range of the delays so that they could effectively formulate fiscal policies to stabilize the economy.

Leggi, regolamenti e decreti statali1. Decreto del Presidente della Repubblica 30.7.2009 n. 189Regolamento concernente il riconoscimento dei titoli di studio accademici, a norma dell'art. 5 della legge 11.7.2002 n. 1482. Decreto del Presidente del Consiglio dei Ministri 19.11.2009Proroga dello stato di emergenza per proseguire le attivitŕ di contrasto e di gestione dell'afflusso di extracomunitari (09A14317)3. Decreto Ministro dell'interno 28.11.2009Regole tecniche e di sicurezza relative al permesso ed alla carta di soggiorno4. Decreto Ministro del lavoro, della salute e delle politiche sociali 2.11.2009Modalitŕ di corresponsione delle somme e degli interessi dovuti per colf e badanti a titolo di contributi previdenziali ed assistenziali relativi a periodi lavorativi antecedenti il trimestre sanato con il pagamento del contributo forfetarioCircolariCittadini comunitariLavoro1. Ministero interno 20.1.2010 n. 2Regime transitorio in materia di accesso al mercato del lavoro dei cittadini della Romania e della BulgariaSoggiorno2. Ministero interno 21.7.2009 n. 18Direttiva n. 2004/38 CE, sul diritto dei cittadini dell'Unione europea e dei loro familiari di circolare e di soggiornare liberamente nel territorio degli Stati membri. Pubblicazione delle Linee guida della Commissione europea. Chiarimenti sulla copertura sanitaria richiesta ai fini del soggiorno del cittadino dell'Unione e sulla nozione di "risorse economiche sufficienti al soggiorno"3. Ministero interno 28.8.2009 n. 400-aD.lgs. 6.2.2007, n. 30, come modificato dal d.lgs. 28.2.2008, n. 32, recante "Attuazione della Direttiva 2004/38/CE relativa al diritto dei cittadini dell'Unione e dei loro familiari di circolare e di soggiornare liberamente nel territorio degli Stati membri"Comunicazione della Commissione delle Comunitŕ europee al Parlamento europeo e al Consiglio in data 2.7.20094. Agenzia entrate 17.9.2009 n. 250/EIstanza di interpello -imposta di bollorilascio della carta di soggiorno a favore dei familiari dei cittadini dell'Unione non aventi la cittadinanza in uno Stato membrorichiesta parereCittadini extracomunitariAsilo5. Ministero interno 6.8.2009 n. 4902 - Circolare prot. n. 16560 del 3.3.2009 del Ministero dell'economia e delle finanzeDipartimento del TesoroDirezione VI. Aggiornamento dei prezzi di cessione dei "Documenti di viaggio per rifugiati" (copertina grigia) e Titoli di viaggio per stranieri" (copertina verde)6. Ministero interno 24.8.2009 n. 5234 - Permesso di soggiorno CE per soggiornanti di lungo periodo allo straniero cui č riconosciuto lo status di rifugiato7. Istituto nazionale previdenza sociale (INPS) 22.1.2010 n. 9 - Titolari dello status di rifugiati politici e di protezione sussidiaria. Assegno per il nucleo familiare con almeno tre figli minori concesso dai ComuniAssistenza sanitaria8. Agenzia entrate 26.8.2009 n. 238/E - Consulenza giuridica (IVA. art. 10, n. 27 ter) del d.p.r. 26.10.1972, n. 633prestazioni socio-sanitarie e assistenziali rese a persone migranti, senza fissa dimora, richiedenti asilo9. Ministero interno 27.11.2009 n. 780/A7 - Assistenza sanitaria per gli stranieri non iscritti al Servizio sanitario nazionale, divieto di segnalazione degli stranieri non in regola con le norme sul soggiorno. SussistenzaCittadinanza10. Ministero interno 7.10.2009 - Legge 15.7.2009 n. 94 recante "Disposizioni in materia di sicurezza pubblica"Modifiche in materia di cittadinanzaChiarimenti11. Ministero interno 2.11.2009 -Legge 15.7.2009 n. 94 recante "Disposizioni in materia di sicurezza pubblica"Modifiche in materia di cittadinanza.Ulteriori chiarimentiDetenuti stranieri12. Ministero giustizia 9.11.2009 - Legge 15.7.2009 n. 94 "Disposizioni in materia di sicurezza pubblica" Ingresso13. Ministero interno 20.7.2009 - Istanze di nulla osta per ricerca scientifica ai sensi dell'art. 27 ter d.lgs. n. 286/98 Famiglia14. Ministero interno 24.9.2009 n. 5987 - Art. 29, co. 6, del d.lgs. 286/98 e successive modificazioni. Conversione del permesso di soggiorno per assistenza minori in motivi familiari. Risposta quesito15. Ministero interno 18.11.2009 n. 7170 - Legge 15.7.2009, n. 94 recante "Disposizioni in materia di sicurezza pubblica" Lavoro16. Ministero interno 12.10.2009 n. 5920 - Istanza di conversione del permesso di soggiorno per studio in permesso di soggiorno per lavoro. Art. 14 co. 5 del d.p.r. n. 394/99 (regolamento al testo unico per l'immigrazione)Minori17. Ministero istruzione, universitŕ e ricerca 8.10.2010 n. 2 -Indicazioni e raccomandazioni per l'integrazione di alunni con cittadinanza non italianaRegolarizzazione dei lavoratori addetti ai servizi domestici e di assistenza alle famiglie18. Ministero interno 2.10.2009 n. 6241 - Legge 3.8.2009 n. 102. Conversione in legge, con modificazioni del D.L. 1.7.2009, n. 78 art. 1 ter - Emersione del lavoro irregolare e di sostegno alle famiglie. Ricevuta attestante l'avvenuta presentazione della domanda di emersione19. Ministero interno 7.12.2009 n. 7950 - Procedura di emersione dal lavoro irregolare nell'attivitŕ di assistenza e di sostegno alle famiglie ex l. 102/09. Interruzione del rapporto di lavoro20. Istituto nazionale previdenza sociale (INPS) 9.12.2009 n. 28660 - Lavoratori domestici. Denunce a seguito di emersione ai sensi dell'art. 1 ter della legge 3.8.2009, n. 102.Chiarimenti21. Ministero interno 23.12.2009 n. 8456 - Procedura di emersione dal lavoro irregolare nell'attivitŕ di assistenza e di sostegno alle famiglie ex l. 102/09. Circolare INPS del 9.12.200922. Ministero interno 28.12.2009 n. 8392 - Legge 3.8.2009 n.102. Procedure di emersione dal lavoro irregolare prestato da cittadini stranieri nell'attivitŕ di assistenza e di sostegno alle famiglie. Interruzione del rapporto di lavoro 23. Istituto nazionale della previdenza sociale (INPS) 29.12.2009 n. 30264 - Lavoratori domestici - Contributi dovuti nelle more della definizione del procedimento di emersione ai sensi dell'art. 1 ter della legge 3.8.2009, n. 102. Iscrizione rapporti di lavoro dopo la sottoscrizione del contratto di soggiorno presso gli Sportelli unici per l'immigrazione - istruzioni operative.Chiarimenti24. Ministero interno 18.2.2010 - Procedura di emersione dal lavoro irregolare nell'attivitŕ di assistenza e sostegno alle famiglie ex l. 102/09. Presentazione della documentazione relativa all'alloggio - mancata presentazione delle parti - dati relativi alla domanda25. Ministero interno 19.2.2010 - Procedura di emersione dal lavoro irregolare nell'attivitŕ di assistenza e di sostegno alle famiglie ex l. 102/09. Presentazione della documentazione relativa all'alloggio - mancata presentazione delle parti - dati relativi alla domandaSoggiorno26. Ministero interno 27.5.2009 n. 3111 - Permesso di soggiorno CE per soggiornanti di lungo periodo - revoca - risposta quesito

“We have made Italy, now we must make Italians,” in the (probably apocryphal) words of the Prime Minister, sometime after the unification of the nation in 1860. Perhaps in French, if it was said at all. (The quotation is typically attributed to Massimo D’Azeglio, the prime minister of Piedmont and predecessor of the first Italian prime minister Camillo Cavour. Many have suggested that the phrase was misquoted and misunderstood (see Doyle.) D’Azeglio spoke in Italian when he addressed the newly-formed Italian parliament, but my reference to French is meant to indicate the fragility of the national language in early Italy where much of the ruling class spoke French while the majority of the people in the peninsula still spoke regional dialects.) It was television – more than print media or even radio – that would have the biggest impact in terms of ‘making Italians.’ Writing about Italy in the 1950s, a well-known media critic suggested that television, a game show actually, “was able to succeed where The Divine Comedy failed … it gave Italy a national language” (qtd. in Foot). But these are yesterday’s problems. We have Italy and Italians. Moreover, the emergence of global ways of being and belonging are evidence of the ways in which the present transcends forms of belonging rooted in the old practices and older institutions of the nation-state. But, then again, maybe not. “A country that allows you to vote in its elections must be able to provide you with information about those elections” (Magliaro). This was 2002. The country is still Italy, but this time the Italians are anywhere but Italy. The speaker is referring to the extension of the vote to Italian citizens abroad, represented directly by 18 members of parliament, and the right to information guaranteed the newly enfranchised electorate. What, then, is the relationship between citizenship, the state and global television today? What are the modalities of involvement and participation involved in these transformations of the nation-state into a globally-articulated network of institutions? I want to think through these questions in relation to two ways that RAI International, the ‘global’ network of the Italian public broadcaster, has viewed Italians around the world at different moments in its history: mega-events and return information. Mega-Events Eighteen months after its creation in 1995, RAI International was re-launched. This decision was partially due to a change in government (which also meant a change in the executive and staff), but it was also a response to the perceived failure of RAI International to garner an adequate international audience (Morrione, Testimony [1997]). This re-launch involved a re-conceptualisation of the network’s mandate to include both information services for Italians abroad (the traditional ‘public service’ mandate for Italy’s international broadcasting) as well as programming that would increase the profile of Italian media in the global market. The mandate outlined for Roberto Morrione – appointed president as part of the re-launch – read: The necessity of strategic and operative certainties in the international positioning of the company, both with regard to programming for our co-nationals abroad and for other markets…are at the centre of the new role of RAI International. This involves bringing together in the best way the informative function of the public service, which is oriented to our community in the world in order to enrich its cultural patrimony and national identity, with an active presence in evolving markets. (Morrione, Testimony [1998]) The most significant change in the executive of the network was the appointment of Renzo Arbore, a well-known singer and bandleader, to the position of artistic director. At the time of Arbore’s appointment, the responsibilities of the artistic director at the network were ill defined, but he very quickly transformed the position into the ‘face’ of RAI International. In an interview from 1998, Arbore explained his role at the network as follows: “I’m the artistic director, which means I’m in charge of the programs that have any kind of artistic content. Also, I’m the so called “testimonial”, which is to say I do propaganda for the network, I’m the soul of RAI International” (Affatato). The most often discussed aspect of the programming on RAI International during Arbore’s tenure as artistic director was the energy and resources dedicated to events that put the spotlight on the global reach of the service itself and the possibilities that satellite distribution gave for simultaneous exchange between locations around the world. It was these ‘mega-events’ (Garofalo), in spite of constituting only a small portion of the programming schedule, that were often seen as defining RAI’s “new way” of creating international programming (Milana). La Giostra [The Merry Go Round], broadcast live on New Year’s Eve 1996, is often cited as the launch of the network’s new approach to its mission. Lasting 20 hours in total, the program was hosted by Arbore. As Morrione described it recently, The ‘mother of live shows’ was the Giostra of New Year’s ’97 where Arbore was live in the studio for 20 consecutive hours, with many guests and segments from the Pole, Peking, Moscow, Berlin, Jerusalem, San Paolo, Buenos Aires, New York and Los Angeles. It was a memorable enterprise without precedent and never to be duplicated. (Morrione, RAI International) The presentation of television as a global medium in La Giostra draws upon the relationship between live broadcasting, satellite television and conceptions of globality that has developed since the 1960s as part of what Lisa Parks describes as ‘global presence’ (Parks). However, in keeping with the dual mandate of RAI International, the audience that La Giostra is intended to constitute was not entirely homogenous in nature. The lines between the ‘national’ audience, which is to say Italians abroad, and the international audience involving a broader spectrum of viewers are often blurred, but still apparent. This can be seen in the locations to which La Giostra travelled, locations that might be seen as a mirror of the places to which the broadcast might be received. On the one hand, there are segments from a series of location that speak to a global audience, many of which are framed by the symbols of the cold war and the ensuing triumph of global capitalism. The South Pole, Moscow, Beijing and a reunified Berlin can be seen as representing this understanding of the globe. These cities highlighted the scope of the network, reaching cities previously cut off from Italy behind the iron curtain (or, in the case of the Pole, the extreme of geographic isolation.) The presence of Jerusalem contributed to this mapping of the planet with an ecclesiastical, but ecumenical accent to this theme. On the other hand, Sao Paolo, Buenos Aires, and Melbourne (not mentioned by Morrione, but the first international segment in the program) also mapped the world of Italian communities around the world. The map of the globe offered by La Giostra is similar to the description of the prospective audience for RAI International that Morrione gave in November 1996 upon his appointment as director. After having outlined the network’s reception in the Americas and Australia, where there are large communities of Italians who need to be served, he goes on to note the importance of Asia: “China, India, Japan, and Korea, where there aren’t large communities of Italians, but where “made in Italy,” the image of Italy, the culture and art that separate us from others, are highly respected resources” (Morrione, “Gli Italiani”). La Giostra served as a container that held together a vision of the globe that is centered around Italy (particularly Rome, caput mundi) through the presentation on screen of the various geopolitical alliances as well as the economic and migratory connections which link Italy to the world. These two mappings of the globe brought together within the frame of the 20-hour broadcast and statements about the network’s prospective audiences suggest that two different ways of watching RAI International were often overlaid over each other. On the one hand, the segments spanning the planet stood as a sign of RAI International’s ability to produce programs at a global scale. On the other hand, there was an attempt to speak directly to communities of Italians abroad. The first vision of the planet offered by the program suggests a mode of watching more common among disinterested, cosmopolitan viewers belonging to a relatively homogenous global media market. While the second vision of the planet was explicitly rooted in the international family of Italians constituted through the broadcast. La Giostra, like the ‘dual mandate’ of the network, can be seen as an attempt to bring together the national mission of network with its attempts to improve its position in global media markets. It was an attempt to unify what seemed two very different kinds of audiences: Italians abroad and non-Italians, those who spoke some Italian and those who speak no Italian at all. It was also an attempt to unify two very different ways of understanding global broadcasting: public service on the one hand and the profit-oriented goals of building a global brand. Given this orientation in the network’s programming philosophy, it is not surprising that Arbore, speaking of his activities as Artistic director, stated that his goals were to produce shows that would be accessible both to those that spoke very little Italian as well as those that were highly cultured (Arbore). In its attempt to bring these divergent practices and imagined audiences together, La Giostra can be seen as part of vision of globalisation rooted in the euphoria of the early nineties in which distance and cultural differences were reconciled through communications technology and “virtuous” transformation of ethnicity into niche markets. However, this approach to programming started to fracture and fail after a short period. The particular balance between the ethnic and the economically ecumenical mappings of the globe present in La Giostra proved to be as short lived as the ‘dual mandate’ at RAI International that underwrote its conception. Return Information The mega-events that Arbore organised came under increasing criticism from the parliamentary committees overseeing RAI’s activities as well as the RAI executive who saw them both extremely expensive to produce and of questionable value in the fulfillment of RAI’s mission as a public broadcaster (GRTV). They were sometimes described as misfatti televisivi [broadcasting misdeeds] (Arbore). The model of the televisual mega-event was increasingly targeted towards speaking to Italians abroad, dropping broader notions of the audience. This was not an overnight change, but part of a process through which the goals of the network were refocused towards ‘public service.’ Morrione, speaking before the parliamentary committee overseeing RAI’s activities, describes an evening dedicated to a celebration of the Italian flag which exemplifies this trend: The minister of Foreign Affairs asked us to prepare a Tricolore (the Italian flag) evening – that would go on air in the month of January – that we would call White, Red and Green (not the most imaginative name, but effective enough.) It would include international connections with Argentina, where there exists one of the oldest case d’italiani [Italian community centers], built shortly after the events of our Risorgimento and where they have an ancient Tricolore. We would also connect with Reggio Emilia, where the Tricolore was born and where they are celebrating the anniversary this year. Segments would also take us to the Vittoriano Museum in Rome for a series of testimonies. (Morrione, Testimony [1997]) Similar to La Giostra, the global reach of RAI International was used to create a sense of simultaneity among the dispersed communities of Italians around the world (including the population of Italy itself). The festival of the Italian flag was similarly deeply implicated in the rituals and patterns that bring together an audience and, at another level, a people. However, in the celebration of the Italian flag, the notion that such a spectacle might be of interest to those outside of a global “Italian” community has disappeared. Like La Giostra, programs of this kind are intended to be constitutive of an audience, a collectivity that would not exist were it not for the common space provided through television spectatorship. The celebration of the Italian flag is part of an attempt to produce a sense of global community organised by a shared sense of ethnic identity as expressed through the common temporality of a live broadcast. Italians around the world were part of the same Italian community not because of their shared history (even when this was the stated subject of the program as was the case with Red, White and Green), but because they co-existed by means of their experience of the mediated event. Through these events, the shared national history is produced out of the simultaneity of the common present and not, as the discourse around Italian identity presented in these programs would have it (for example, the narratives around the origin around the flag), the other way around. However, this connection between the global television event that was broadcast live and national belonging raised questions about the kind of participation they facilitated. This became a particularly salient issue with the election of the second Berlusconi government and the successful campaign to grant Italians citizens living abroad the vote, a campaign that was lead by formerly fascist (but centre-moving) Alleanza Nazionale. With the appoint of Massimo Magliaro, a longtime member of Alleanza Nazionale, to the head of the network in 2000, the concept of informazione di ritorno [return information] became increasingly prominent in descriptions of the service. The phrase was frequently used, along with tv di ritorno (Tremaglia), by the Minister for Italiani nel Mondo during the second Berlusconi administration, Mirko Tremaglia, and became a central theme in the projects envisioned for the service. (The concept had circulated previously, but it was not given the same emphasis that it would gain after Magliaro’s appointment. In an interview from 1996, Morrione is asked about his commitment to the policy of “so-called” return information. He answers the question by commenting in support of producing a ‘return image’ (immagine di ritorno), but never uses the phrase (Morrione, “Gli Italiani”). Similarly, Arbore, in an interview from 1998, is also asked about ‘so-called’ return information, but also never uses the term himself (Affatato). This suggests that its circulation was limited up until the late 1990s.) The concept of ‘return information’ – not quite a neologism in Italian, but certainly an uncommon expression – was a two-pronged, and never fully implemented, initiative. Primarily it was a policy that sought to further integrate RAI International into the system of RAI’s national television networks. This involved both improving the ability of RAI International to distribute information about Italy to communities of Italians abroad as well as developing strategies for the eventual use of programming produced by RAI International on the main national networks as a way of raising the awareness of Italians in Italy about the lives and beliefs of Italians abroad. (The programming produced by RAI International was never successfully integrated into the schedules of the other national networks. This issue remained an issue that had yet to be resolved as recently as the negotiations between the Prime Minister’s office and RAI to establish a new agreement governing RAI’s international service in 2007.) This is not to say that there was a dramatic shift in the kind of programming on the network. There had always been elements of these new goals in the programming produced exclusively for RAI International. The longest running program on the network, Sportello Italia [Information Desk Italy], provided information to Italians abroad about changes in Italian law that effected Italians abroad as well as changes in bureaucratic practice generally. It often focused on issues such as the voting rights of Italians abroad, questions about receiving pensions and similar issues. It was joined by a series of in-house productions that primarily consisted of news and information programming whose roots were in the new division in charge of radio and television broadcasts since the sixties. The primary change was the elimination of large-scale programs, aside from those relating to the Italian national soccer team and the Pope, due to budget restrictions. This was part of a larger shift in the way that the service was envisioned and its repositioning as the primary conduit between Italy and Italians abroad. Speaking in 2000, Magliaro explained this as a change in the network’s priorities from ‘entertainment’ to ‘information’: There will be a larger dose of information and less space for entertainment. Informational programming will be the privileged product in which we will invest the majority of our financial and human resources, both on radio and on television. Providing information means both telling Italians abroad about Italy and allowing public opinion in our country to find out about Italians around the world. (Morgia) Magliaro’s statement suggests that there is a direct connection between the changing way of conceiving of ‘global’ Italian television and the mandate of RAI International. The spectacles of the mid-nineties, implicitly characterised by Magliaro as ‘entertainment,’ were as much about gaining the attention of those who did not speak Italian or watch Italian television as speaking to Italians abroad. The kind of participation in the nation that these events solicited were limited in that they did not move beyond a relatively passive experience of that nation as community brought together through the diffuse and distracted experience of ‘entertainment’. The rise of informazione di ritorno was a discourse that offered a particular conception of Italians abroad who were more directly involved in the affairs of the nation. However, this was more than an increased interest in the participation of audiences. Return information as developed under Magliaro’s watch posited a different kind of viewer, a viewer whose actions were explicitly and intimately linked to their rights as citizens. It is not surprising that Magliaro prefaced his comments about the transformation of RAI’s mandate and programming priorities by acknowledging that the extension of the vote to Italians abroad demands a different kind of broadcaster. The new editorial policy of RAI International is motivated from the incontrovertible fact that Italians abroad will have the right to vote in a few months … . In terms of the product that we are developing, aimed at adequately responding to the new demands created by the vote… (Morgia) The granting of the vote to Italians abroad meant that the forms of symbolic communion that produced through the mega-events needed to be supplanted by a policy that allowed for a more direct link between the ritual aspects of global media to the institutions of the Italian state. The evolution of RAI International cannot be separated from the articulation of an increasingly ethno-centric conception of citizenship and the transformation of the Italian state over the course of the 1990s and early 2000s towards. The transition between these two approaches to global television in Italy is important for understanding the events that unfolded around RAI International’s role in the development of a global Italian citizenry. A development that should not be separated from the development of increasingly stern immigration policies whose effect is to identify and export undesirable outsiders. The electoral defeat of Berlusconi in 2006 and the ongoing political instability surrounding the centre-left government in power since then has meant that the future development of RAI International and the long-term effects of the right-wing government on the cultural and political fabric of Italy remain unclear at present. The current need for a reformed electoral system and talk about the need for greater efficiency from the new executive at RAI make the evolution of the global Italian citizenry an important context for understanding the role of media in the globalised nation-state in the years to come. References Affatato, M. “I ‘Segreti’ di RAI International.” GRTV.it, 17 Feb. 1998. Arbore, R. “‘Il mio sogno? Un Programma con gli italiani all’estero.’” GRTV.it, 18 June 1999. Foot, J. Milan since the Miracle: City, Culture, and Identity. Oxford: Berg, 2001. Garofalo, R. “Understanding Mega-Events: If We Are the World, Then How Do We Change It? In C. Penley and A. Ross, eds., Technoculture. Minneapolis, University of Minnesota Press, 1991. 247-270. Magliaro, M. “Speech to Second Annual Conference.” Comites Canada, 2002. Milana, A. RAI International: 40 anni, una storia. Rome: RAI, 2003. Morgia, G. La Rai del Duemila per gli italiani nel mondo: Intervista con Massimo Magliaro. 2001. Morrione, R. “Gli Italiani all’estero ‘azionisti di riferimento.’” Interview with Roberto Morrione. GRTV.it, 15 Nov. 1996. Morrione, R. Testimony of Roberto Morrione to Commitato Bicamerale per la Vigilanza RAI, 12 December 1997. Rome, 1997. 824-841. Morrione, R. Testimony of Roberto Morrione to Commitato Bicamerale per la Vigilanza RAI, 17 November 1998. Rome, 1998. 1307-1316. Morrione, R. “Tre anni memorabili.” RAI International: 40 anni, una storia. Rome: RAI, 2003. 129-137. Parks, L. Cultures in Orbit: Satellites and the Televisual. Durham, NC: Duke UP, 2005.

“We have made Italy, now we must make Italians,” in the (probably apocryphal) words of the Prime Minister, sometime after the unification of the nation in 1860. Perhaps in French, if it was said at all. (The quotation is typically attributed to Massimo D’Azeglio, the prime minister of Piedmont and predecessor of the first Italian prime minister Camillo Cavour. Many have suggested that the phrase was misquoted and misunderstood (see Doyle.) D’Azeglio spoke in Italian when he addressed the newly-formed Italian parliament, but my reference to French is meant to indicate the fragility of the national language in early Italy where much of the ruling class spoke French while the majority of the people in the peninsula still spoke regional dialects.) It was television – more than print media or even radio – that would have the biggest impact in terms of ‘making Italians.’ Writing about Italy in the 1950s, a well-known media critic suggested that television, a game show actually, “was able to succeed where The Divine Comedy failed … it gave Italy a national language” (qtd. in Foot). But these are yesterday’s problems. We have Italy and Italians. Moreover, the emergence of global ways of being and belonging are evidence of the ways in which the present transcends forms of belonging rooted in the old practices and older institutions of the nation-state. But, then again, maybe not. “A country that allows you to vote in its elections must be able to provide you with information about those elections” (Magliaro). This was 2002. The country is still Italy, but this time the Italians are anywhere but Italy. The speaker is referring to the extension of the vote to Italian citizens abroad, represented directly by 18 members of parliament, and the right to information guaranteed the newly enfranchised electorate. What, then, is the relationship between citizenship, the state and global television today? What are the modalities of involvement and participation involved in these transformations of the nation-state into a globally-articulated network of institutions? I want to think through these questions in relation to two ways that RAI International, the ‘global’ network of the Italian public broadcaster, has viewed Italians around the world at different moments in its history: mega-events and return information. Mega-Events Eighteen months after its creation in 1995, RAI International was re-launched. This decision was partially due to a change in government (which also meant a change in the executive and staff), but it was also a response to the perceived failure of RAI International to garner an adequate international audience (Morrione, Testimony [1997]). This re-launch involved a re-conceptualisation of the network’s mandate to include both information services for Italians abroad (the traditional ‘public service’ mandate for Italy’s international broadcasting) as well as programming that would increase the profile of Italian media in the global market. The mandate outlined for Roberto Morrione – appointed president as part of the re-launch – read: The necessity of strategic and operative certainties in the international positioning of the company, both with regard to programming for our co-nationals abroad and for other markets…are at the centre of the new role of RAI International. This involves bringing together in the best way the informative function of the public service, which is oriented to our community in the world in order to enrich its cultural patrimony and national identity, with an active presence in evolving markets. (Morrione, Testimony [1998]) The most significant change in the executive of the network was the appointment of Renzo Arbore, a well-known singer and bandleader, to the position of artistic director. At the time of Arbore’s appointment, the responsibilities of the artistic director at the network were ill defined, but he very quickly transformed the position into the ‘face’ of RAI International. In an interview from 1998, Arbore explained his role at the network as follows: “I’m the artistic director, which means I’m in charge of the programs that have any kind of artistic content. Also, I’m the so called “testimonial”, which is to say I do propaganda for the network, I’m the soul of RAI International” (Affatato). The most often discussed aspect of the programming on RAI International during Arbore’s tenure as artistic director was the energy and resources dedicated to events that put the spotlight on the global reach of the service itself and the possibilities that satellite distribution gave for simultaneous exchange between locations around the world. It was these ‘mega-events’ (Garofalo), in spite of constituting only a small portion of the programming schedule, that were often seen as defining RAI’s “new way” of creating international programming (Milana). La Giostra [The Merry Go Round], broadcast live on New Year’s Eve 1996, is often cited as the launch of the network’s new approach to its mission. Lasting 20 hours in total, the program was hosted by Arbore. As Morrione described it recently, The ‘mother of live shows’ was the Giostra of New Year’s ’97 where Arbore was live in the studio for 20 consecutive hours, with many guests and segments from the Pole, Peking, Moscow, Berlin, Jerusalem, San Paolo, Buenos Aires, New York and Los Angeles. It was a memorable enterprise without precedent and never to be duplicated. (Morrione, RAI International) The presentation of television as a global medium in La Giostra draws upon the relationship between live broadcasting, satellite television and conceptions of globality that has developed since the 1960s as part of what Lisa Parks describes as ‘global presence’ (Parks). However, in keeping with the dual mandate of RAI International, the audience that La Giostra is intended to constitute was not entirely homogenous in nature. The lines between the ‘national’ audience, which is to say Italians abroad, and the international audience involving a broader spectrum of viewers are often blurred, but still apparent. This can be seen in the locations to which La Giostra travelled, locations that might be seen as a mirror of the places to which the broadcast might be received. On the one hand, there are segments from a series of location that speak to a global audience, many of which are framed by the symbols of the cold war and the ensuing triumph of global capitalism. The South Pole, Moscow, Beijing and a reunified Berlin can be seen as representing this understanding of the globe. These cities highlighted the scope of the network, reaching cities previously cut off from Italy behind the iron curtain (or, in the case of the Pole, the extreme of geographic isolation.) The presence of Jerusalem contributed to this mapping of the planet with an ecclesiastical, but ecumenical accent to this theme. On the other hand, Sao Paolo, Buenos Aires, and Melbourne (not mentioned by Morrione, but the first international segment in the program) also mapped the world of Italian communities around the world. The map of the globe offered by La Giostra is similar to the description of the prospective audience for RAI International that Morrione gave in November 1996 upon his appointment as director. After having outlined the network’s reception in the Americas and Australia, where there are large communities of Italians who need to be served, he goes on to note the importance of Asia: “China, India, Japan, and Korea, where there aren’t large communities of Italians, but where “made in Italy,” the image of Italy, the culture and art that separate us from others, are highly respected resources” (Morrione, “Gli Italiani”). La Giostra served as a container that held together a vision of the globe that is centered around Italy (particularly Rome, caput mundi) through the presentation on screen of the various geopolitical alliances as well as the economic and migratory connections which link Italy to the world. These two mappings of the globe brought together within the frame of the 20-hour broadcast and statements about the network’s prospective audiences suggest that two different ways of watching RAI International were often overlaid over each other. On the one hand, the segments spanning the planet stood as a sign of RAI International’s ability to produce programs at a global scale. On the other hand, there was an attempt to speak directly to communities of Italians abroad. The first vision of the planet offered by the program suggests a mode of watching more common among disinterested, cosmopolitan viewers belonging to a relatively homogenous global media market. While the second vision of the planet was explicitly rooted in the international family of Italians constituted through the broadcast. La Giostra, like the ‘dual mandate’ of the network, can be seen as an attempt to bring together the national mission of network with its attempts to improve its position in global media markets. It was an attempt to unify what seemed two very different kinds of audiences: Italians abroad and non-Italians, those who spoke some Italian and those who speak no Italian at all. It was also an attempt to unify two very different ways of understanding global broadcasting: public service on the one hand and the profit-oriented goals of building a global brand. Given this orientation in the network’s programming philosophy, it is not surprising that Arbore, speaking of his activities as Artistic director, stated that his goals were to produce shows that would be accessible both to those that spoke very little Italian as well as those that were highly cultured (Arbore). In its attempt to bring these divergent practices and imagined audiences together, La Giostra can be seen as part of vision of globalisation rooted in the euphoria of the early nineties in which distance and cultural differences were reconciled through communications technology and “virtuous” transformation of ethnicity into niche markets. However, this approach to programming started to fracture and fail after a short period. The particular balance between the ethnic and the economically ecumenical mappings of the globe present in La Giostra proved to be as short lived as the ‘dual mandate’ at RAI International that underwrote its conception. Return Information The mega-events that Arbore organised came under increasing criticism from the parliamentary committees overseeing RAI’s activities as well as the RAI executive who saw them both extremely expensive to produce and of questionable value in the fulfillment of RAI’s mission as a public broadcaster (GRTV). They were sometimes described as misfatti televisivi [broadcasting misdeeds] (Arbore). The model of the televisual mega-event was increasingly targeted towards speaking to Italians abroad, dropping broader notions of the audience. This was not an overnight change, but part of a process through which the goals of the network were refocused towards ‘public service.’ Morrione, speaking before the parliamentary committee overseeing RAI’s activities, describes an evening dedicated to a celebration of the Italian flag which exemplifies this trend: The minister of Foreign Affairs asked us to prepare a Tricolore (the Italian flag) evening – that would go on air in the month of January – that we would call White, Red and Green (not the most imaginative name, but effective enough.) It would include international connections with Argentina, where there exists one of the oldest case d’italiani [Italian community centers], built shortly after the events of our Risorgimento and where they have an ancient Tricolore. We would also connect with Reggio Emilia, where the Tricolore was born and where they are celebrating the anniversary this year. Segments would also take us to the Vittoriano Museum in Rome for a series of testimonies. (Morrione, Testimony [1997]) Similar to La Giostra, the global reach of RAI International was used to create a sense of simultaneity among the dispersed communities of Italians around the world (including the population of Italy itself). The festival of the Italian flag was similarly deeply implicated in the rituals and patterns that bring together an audience and, at another level, a people. However, in the celebration of the Italian flag, the notion that such a spectacle might be of interest to those outside of a global “Italian” community has disappeared. Like La Giostra, programs of this kind are intended to be constitutive of an audience, a collectivity that would not exist were it not for the common space provided through television spectatorship. The celebration of the Italian flag is part of an attempt to produce a sense of global community organised by a shared sense of ethnic identity as expressed through the common temporality of a live broadcast. Italians around the world were part of the same Italian community not because of their shared history (even when this was the stated subject of the program as was the case with Red, White and Green), but because they co-existed by means of their experience of the mediated event. Through these events, the shared national history is produced out of the simultaneity of the common present and not, as the discourse around Italian identity presented in these programs would have it (for example, the narratives around the origin around the flag), the other way around. However, this connection between the global television event that was broadcast live and national belonging raised questions about the kind of participation they facilitated. This became a particularly salient issue with the election of the second Berlusconi government and the successful campaign to grant Italians citizens living abroad the vote, a campaign that was lead by formerly fascist (but centre-moving) Alleanza Nazionale. With the appoint of Massimo Magliaro, a longtime member of Alleanza Nazionale, to the head of the network in 2000, the concept of informazione di ritorno [return information] became increasingly prominent in descriptions of the service. The phrase was frequently used, along with tv di ritorno (Tremaglia), by the Minister for Italiani nel Mondo during the second Berlusconi administration, Mirko Tremaglia, and became a central theme in the projects envisioned for the service. (The concept had circulated previously, but it was not given the same emphasis that it would gain after Magliaro’s appointment. In an interview from 1996, Morrione is asked about his commitment to the policy of “so-called” return information. He answers the question by commenting in support of producing a ‘return image’ (immagine di ritorno), but never uses the phrase (Morrione, “Gli Italiani”). Similarly, Arbore, in an interview from 1998, is also asked about ‘so-called’ return information, but also never uses the term himself (Affatato). This suggests that its circulation was limited up until the late 1990s.) The concept of ‘return information’ – not quite a neologism in Italian, but certainly an uncommon expression – was a two-pronged, and never fully implemented, initiative. Primarily it was a policy that sought to further integrate RAI International into the system of RAI’s national television networks. This involved both improving the ability of RAI International to distribute information about Italy to communities of Italians abroad as well as developing strategies for the eventual use of programming produced by RAI International on the main national networks as a way of raising the awareness of Italians in Italy about the lives and beliefs of Italians abroad. (The programming produced by RAI International was never successfully integrated into the schedules of the other national networks. This issue remained an issue that had yet to be resolved as recently as the negotiations between the Prime Minister’s office and RAI to establish a new agreement governing RAI’s international service in 2007.) This is not to say that there was a dramatic shift in the kind of programming on the network. There had always been elements of these new goals in the programming produced exclusively for RAI International. The longest running program on the network, Sportello Italia [Information Desk Italy], provided information to Italians abroad about changes in Italian law that effected Italians abroad as well as changes in bureaucratic practice generally. It often focused on issues such as the voting rights of Italians abroad, questions about receiving pensions and similar issues. It was joined by a series of in-house productions that primarily consisted of news and information programming whose roots were in the new division in charge of radio and television broadcasts since the sixties. The primary change was the elimination of large-scale programs, aside from those relating to the Italian national soccer team and the Pope, due to budget restrictions. This was part of a larger shift in the way that the service was envisioned and its repositioning as the primary conduit between Italy and Italians abroad. Speaking in 2000, Magliaro explained this as a change in the network’s priorities from ‘entertainment’ to ‘information’: There will be a larger dose of information and less space for entertainment. Informational programming will be the privileged product in which we will invest the majority of our financial and human resources, both on radio and on television. Providing information means both telling Italians abroad about Italy and allowing public opinion in our country to find out about Italians around the world. (Morgia) Magliaro’s statement suggests that there is a direct connection between the changing way of conceiving of ‘global’ Italian television and the mandate of RAI International. The spectacles of the mid-nineties, implicitly characterised by Magliaro as ‘entertainment,’ were as much about gaining the attention of those who did not speak Italian or watch Italian television as speaking to Italians abroad. The kind of participation in the nation that these events solicited were limited in that they did not move beyond a relatively passive experience of that nation as community brought together through the diffuse and distracted experience of ‘entertainment’. The rise of informazione di ritorno was a discourse that offered a particular conception of Italians abroad who were more directly involved in the affairs of the nation. However, this was more than an increased interest in the participation of audiences. Return information as developed under Magliaro’s watch posited a different kind of viewer, a viewer whose actions were explicitly and intimately linked to their rights as citizens. It is not surprising that Magliaro prefaced his comments about the transformation of RAI’s mandate and programming priorities by acknowledging that the extension of the vote to Italians abroad demands a different kind of broadcaster. The new editorial policy of RAI International is motivated from the incontrovertible fact that Italians abroad will have the right to vote in a few months … . In terms of the product that we are developing, aimed at adequately responding to the new demands created by the vote… (Morgia) The granting of the vote to Italians abroad meant that the forms of symbolic communion that produced through the mega-events needed to be supplanted by a policy that allowed for a more direct link between the ritual aspects of global media to the institutions of the Italian state. The evolution of RAI International cannot be separated from the articulation of an increasingly ethno-centric conception of citizenship and the transformation of the Italian state over the course of the 1990s and early 2000s towards. The transition between these two approaches to global television in Italy is important for understanding the events that unfolded around RAI International’s role in the development of a global Italian citizenry. A development that should not be separated from the development of increasingly stern immigration policies whose effect is to identify and export undesirable outsiders. The electoral defeat of Berlusconi in 2006 and the ongoing political instability surrounding the centre-left government in power since then has meant that the future development of RAI International and the long-term effects of the right-wing government on the cultural and political fabric of Italy remain unclear at present. The current need for a reformed electoral system and talk about the need for greater efficiency from the new executive at RAI make the evolution of the global Italian citizenry an important context for understanding the role of media in the globalised nation-state in the years to come. 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Testimony of Roberto Morrione to Commitato Bicamerale per la Vigilanza RAI, 17 November 1998. Rome, 1998. 1307-1316. Morrione, R. “Tre anni memorabili.” RAI International: 40 anni, una storia. Rome: RAI, 2003. 129-137. Parks, L. Cultures in Orbit: Satellites and the Televisual. Durham, NC: Duke UP, 2005. Citation reference for this article MLA Style Hayward, Mark. "Two Ways of Being Italian on Global Television." M/C Journal 10.6/11.1 (2008). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0804/05-hayward.php>. APA Style Hayward, M. (Apr. 2008) "Two Ways of Being Italian on Global Television," M/C Journal, 10(6)/11(1). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0804/05-hayward.php>.