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Fortunato Morabito,1,2 Giovanni Tripepi,3 Enrica Antonia Martino,4 Ernesto Vigna,4 Francesco Mendicino,4 Lucio Morabito,5 Katia Todoerti,6 Hamdi Al-Janazreh,2 Graziella D’Arrigo,3 Filippo Antonio Canale,7 Giovanna Cutrona,8 Antonino Neri,6,8 Massimo Martino,9 Massimo Gentile4 1Biotechnology Research Unit, AO of Cosenza, Cosenza, Italy; 2Hematology and Bone Marrow Transplant Unit, Hemato-Oncology Department, Augusta Victoria Hospital, East Jerusalem, Israel; 3HCNR-IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, Reggio, Calabria, Italy; 4Hematology Unit, AO of Cosenza, Cosenza, Italy; 5Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy; 6Hematology, Fondazione Cà Granda IRCCS Policlinico, Milan, Italy; 7Stem Cell Transplant Program, Clinical Section, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, Reggio, Calabria, Italy; 8IRCCS Ospedale Policlinico San Martino, Genoa, Italy; 9Department of Oncology and Hemato-oncology, University of Milan, Milan, ItalyCorrespondence: Fortunato MorabitoBiotechnology Research Unit, AO of Cosenza, Contrada San Nicola, Cosenza, Italy, Cosenza, 87100, ItalyTel +39-0984-015863Fax +39-0984-681329Email f.morabito53@gmail.comMassimo GentileHematology Unit, AO of Cosenza, Italy, viale della Repubblica snc, Cosenza, 87100, ItalyTel +39-0984-681329Fax +39-0984-681329Email massim.gentile@tiscali.itAbstract: Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptide-conjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased off-target cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third- or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.Keywords: multiple myeloma, relapsed resistant, melphalan flufenamide, melflufen, therapy, melphalan

Table S1. CAF levels in serum and bone marrow plasma of MM patients. Table S2. Cutoff for serum levels of cytokines and angiogenic factors (CAFs). Table S3. PFS and OS correlation with CAF levels (PDF 460 kb)

A rich strand of the economic literature has been studying the impact of different forms of early childcare on children cognitive and non-cognitive development in the short and medium run, and on a number of educational, labor market, and life outcomes in the long run. These studies agree in assessing the importance of the first years of life on future outcomes, and identify early childhood interventions as a powerful policy instrument to boost child development. Furthermore, most research agrees in identifying stronger beneficial effects among children from disadvantaged backgrounds, making a case for the role of childcare policies in reducing inequality. Instead, heterogeneity of results across gender is less clear-cut. Yet, it is important to understand how childcare arrangements differently affect boys and girls, to figure out how to boost cognitive and non-cognitive development of young children and how to reduce gender gaps later in life. Our paper offers a comprehensive review of the literature on early childcare impacts, shedding light on the heterogeneous effects across genders, considering the role of institutional background, type of the intervention, and age of the child. We also present some empirical results on the Italian case which indicates that gender differences in the outcomes is lower among children who attended an impact toddler center, while it is higher and more often statistically significant for those who received informal care. This result confirms the positive and equalizing role of early public childcare.

L’obiettivo di questo lavoro è stato quello di tracciare un excursus sull’origine e sullo sviluppo delle raccolte librarie al servizio degli studenti, dalla nascita dell’università fino ai nostri giorni, tenendo presenti i materiali e gli strumenti connessi alla didattica. Si è tentato di cogliere le trasformazioni e l’evoluzione di questi ultimi in relazione ai cambiamenti del metodo dell’insegnamento universitario avvenuti nel corso del tempo. Ai fini della ricerca è stato necessario indi...

Gender inequalities in the labor market are still significantly large in many developed countries. The unequal impact that childbirth has on men and women is one of the main reasons behind the gender gap. Family policies can encourage maternal employment and work-life reconciliation. Increasing childcare services and job protected parental leave have been proven to be effective instruments to increase female labor supply. Paternity leave can help redistributing housework load between spouses and promote a more equal sharing of parenthood. In Italy, the introduction of mandatory paternity leave failed to reach all eligible workers and to promote higher use of the optional parental leave by fathers. The Bonus Infanzia, which promotes shorter parental leaves for mothers, does not benefit marginal labor supply nor earnings in the medium run; nonetheless, it is correlated with lower risk of leaving the labor market.

DIDATTICA E RICERCA NELL’UNIVERSITA ITALIANA E CONFRONTI INTERNAZIONALI Il volume raccoglie la maggior parte dei contributi che sono stati presentati e discussi il 30 e 31 maggio 2013, nel corso del primo “Seminario nazionale di biblioteconomia” organizzato, nell’ambito delle attività scientifiche del Dipartimento di Scienze documentarie, linguistico-filologiche e geografiche dell’Università di Roma La Sapienza, da Alberto Petrucciani e Giovanni Solimine, con il patrocinio della Facoltà di Lettere, dell’Associazione italiana biblioteche (AIB) e della Società italiana di scienze bibliografiche e biblioteconomiche (SISBB).

Background: According to recent findings, the management of myeloproliferative neoplasms (MPNs) is highly dependent on presence or absence of thrombotic events. The JAK2 mutation has been identified as a marker of MPNs. It is also an occult marker in several patients with splanchnic venous thrombosis (SVT), but its contribution as an additional thrombotic risk factor in MPNs is still under discussion. Moreover, a pro-thrombotic risk factor, either inherited or acquired (Factor V Leiden mutation, deficiencies in protein C, protein S and Prothrombin mutation 20210) can be identified in these patients. Recently, another milestone in the molecular diagnosis of MPNs, somatic mutations in the CALR gene, has been reported. A total of 36 types of frame-shifting insertions and deletions were detected in the exon 9 of CALR gene, which encodes a Ca2+ binding protein in endoplasmic reticulum called calreticulin. Type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations These mutations were reported to have a incidence of over 60% to 80% in JAK2 and MPLmutation-negative Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) patients. Compared to those with JAK2 mutation, CALR-mutated ET patients are younger and have a lower leukocyte count and higher platelet count. CARL mutations have been also reported as a favorable prognostic factor on thrombosis-free survival (TFS) for ET patients. Aims: In this study, we evaluated the incidence of SVT, JAK2 and CALR mutations, and prothrombotic risk factors in patients with MPNs observed in our center from January 2000 to January 2014. Methods: We performed a retrospective review of clinical charts of 466 Ph1 negative MPN patients followed in our center, classified according to the WHO 2008 classification. Patient and disease characteristics, including JAK2V617F, MPL and CALR mutations and thrombotic risk factors were recorded. Results: The median age of patients with diagnosis of MPN was 43 years. Fourteen patients (13 females, 1 male; 3%) of median age 46 years presented a SVT. Three had a Budd Chiari syndrome and 11 a portal venous thrombosis. According to a histological review, these patients were classified as follows: ET, 2 cases, PMF, 3 cases, Polycythemia Vera (PV) 1 case, Myelofibrosis in a prefibrotic phase (MF0) 8 cases. Classification of 11 cases with Myelofibrosis according to the IPSS identified 7 as INT1, 1 as INT2 and 3 as low risk. Among all 14 patients diagnosed with SVT, 12 were JAK2V617F positive with a median allelic burden of 30%, 1 patient was MPL positive, and 1 patient was triple-negative. CALR mutation was not observed in any of the patients. Two cases were diagnosed with MPN 30 months after SVT, 3 patients experienced SVT after a median follow-up of 108 months from MPN diagnosis while in 9 patients the diagnosis of MPN was concomitant to SVT. In the latter patients, median Hb levels were 12.4 g/dL , WBC 8260 /µL, HCT 36.3%, PLT 337.000/ µL and a modest hepatomegaly and splenomegaly were documented. Prothrombotic risk factors were found in 9 of 13 patients. Two patients experienced a thrombotic episode prior to the diagnosis of SVT and two subsequently during the follow-up. Interestingly, 9 (70%) of MPN patients with SVT exhibited at least one prothromobtic risk factor, such as factor V Leiden, Protein C deficiency, hyperhomocystinemia and 50% had two or more associated defects. Thirteen of the 14 patients are currently being treated as follows hydroxyurea (9), interferon (1), and ruxolitinib (3). All patients received oral anticoagulant treatment except for three who are on antiplatelet therapy. MPN patients without SVT had a lower prevalence of prothrombotic risk factors and developed venous thrombosis in different anatomical sites: in these cases WBC count, platelet values and the presence of JAK2V617F mutation correlated with the development of the thrombotic event. Conclusions: Although SVT has a low incidence in MPN patients, a potential benefit of testing for mutations in CALR gene and for additional prothrombotic risk factors is suggested in the whole MPN population for the prevention and treatment of this complication. Disclosures No relevant conflicts of interest to declare.

The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with ISS stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups. This article is protected by copyright. All rights reserved.

In combination with lenalidomide and dexamethasone (KRd), Carfilzomib has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) on ASPIRE trial. Efficacy and safety of the triplet are still the object of investigation by many groups to confirm ASPIRE results in the setting of RRMM treated in real-life who don't meet trial restrictive inclusion criteria. Therefore, we report a retrospective multicenter analysis of 600 RRMM patients treated with KRd between December 2015 and December 2018. The median age was 64 years (range 33-85), and the median number of previous therapies was two (range 1-11). After a median of 11 KRd cycles, the overall response rate was 79.9%. The median progression-free survival (PFS) was 22 months, and the 2-year probability of PFS was 47.6%. Creatinine clearance30 ml/min,1 line of previous therapy, and high-risk FISH were all associated with a poor prognosis in multivariate analysis. The median overall survival (OS) was 34.8 months; the 2-year probability of OS was 63.5%. At multivariate analysis, creatinine clearance30 ml/min,1 line of previous therapy, and high-risk FISH were significantly associated with poor prognosis. After a median follow-up of 16 months (range 1-50), 259 withdrew from therapy. The main discontinuation reason was progressive disease (81.8%). Seventy-four patients (12.3%) discontinued therapy for toxicity. The most frequent side effects were hematological (anemia 49.3%, neutropenia 42.7%, thrombocytopenia 42.5%) and cardiovascular (hypertension 14.5%, heart failure 2.5%, arrhythmias 3.6%). Our study confirms the safety and efficacy of KRd in the real-life setting of RRMM patients and encourages its use in clinical practice.

The present study aimed to develop two survival risk scores (RS) for overall survival (OS, SRSKRd/EloRd) and progression-free survival (PFS, PRSKRd/EloRd) in 919 relapsed/refractory multiple myeloma (RRMM) patients who received carfilzomib, lenalidomide, and dexamethasone (KRd)/elotuzumab, lenalidomide, and dexamethasone (EloRd). The median OS was 35.4 months, with no significant difference between the KRd arm versus the EloRd arm. In the multivariate analysis, advanced ISS (HR = 1.31; P = 0.025), interval diagnosis–therapy (HR = 1.46; P = 0.001), number of previous lines of therapies (HR = 1.96; P < 0.0001), older age (HR = 1.72; P < 0.0001), and prior lenalidomide exposure (HR = 1.30; P = 0.026) remained independently associated with death. The median PFS was 20.3 months, with no difference between the two strategies. The multivariate model identified a significant progression/death risk increase for ISS III (HR = 1.37; P = 0.002), >3 previous lines of therapies (HR = 1.67; P < 0.0001), older age (HR = 1.64; P < 0.0001), and prior lenalidomide exposure (HR = 1.35; P = 0.003). Three risk SRSKRd/EloRd categories were generated: low-risk (134 cases, 16.5%), intermediate-risk (467 cases, 57.3%), and high-risk categories (213 cases, 26.2%). The 1- and 2-year OS probability rates were 92.3% and 83.8% for the low-risk (HR = 1, reference category), 81.1% and 60.6% (HR = 2.73; P < 0.0001) for the intermediate-risk, and 65.5% and 42.5% (HR = 4.91; P < 0.0001) for the high-risk groups, respectively. Notably, unlike the low-risk group, which did not cross the median timeline, the OS median values were 36.6 and 18.6 months for the intermediate- and high-risk cases, respectively. Similarly, three PRSKRd/EloRd risk categories were engendered. Based on such grouping, 338 (41.5%) cases were allocated in the low-, 248 (30.5%) in the intermediate-, and 228 (28.0%) in the high-risk groups. The 1- and 2-year PFS probability rates were 71.4% and 54.5% for the low-risk (HR = 1, reference category), 68.9% and 43.7% (HR = 1.95; P < 0.0001) for the intermediate-risk, and 48.0% and 27.1% (HR = 3.73; P < 0.0001) for the high-risk groups, respectively. The PFS median values were 29.0, 21.0, and 11.7 months for the low-, intermediate-, and high-risk cases. This analysis showed 2.7- and 4.9-fold increased risk of death for the intermediate- and high-risk cases treated with KRd/EloRd as salvage therapy. The combined progression/death risks of the two categories were increased 1.3- and 2.2-fold compared to the low-risk group. In conclusion, SRSKRd/EloRd and PRSKRd/EloRd may represent accessible and globally applicable models in daily clinical practice and ultimately represent a prognostic tool for RRMM patients who received KRd or EloRd.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia (platelet count

We document an episode with considerable tax avoidance that occurred in Italy after 2008 when the Italian government reformed the property taxation by abolishing taxation on principal residences an ...

The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.

Il lavoro analizza l’evoluzione dell’occupazione e dei salari dei migranti in Italia dalla metà degli anni novanta ad oggi. Sfruttando la qualità dei dati amministrativi INPS è possibile sviluppare una serie di analisi empiriche accurate e senza errori di misurazione legate all’informazione sulla cittadinanza sul lavoro dei migranti. La prima parte dell’articolo descrive il lavoro migrante in Italia e la sua evoluzione. Dal confronto con i lavoratori nativi emergono differenze interessanti: i migranti mostrano avere una elevata mobilità aziendale e geografica relativamente ai lavoratori nativi, determinata probabilmente da family ties meno stringenti e da una minore incidenza di proprietà immobiliari. Ciò contribuisce a spiegare perché i migranti, in un contesto di eccesso di domanda locale, possono allocarsi nel mercato italiano senza sostituirsi al lavoro nativo. L’articolo si conclude con un’analisi empirica dei salari individuali dei lavoratori italiani. I risultati delle nostre analisi mostrano come l’ingresso dei migranti nei mercati locali del lavoro non riduce, ma anzi aumenta, seppure in maniera molto lieve, i salari dei nativi: una variazione dell’offerta di lavoro migrante del 10% aumenta i salari dei nativi di 0.1%.