ALBERT

Description: It is widely accepted that the essential role of TRAF6 in vivo is to generate the Lys63-linked ubiquitin (K63-Ub) chains needed to activate the “master” protein kinase TAK1. Here, we report that TRAF6 E3 ligase activity contributes to but is not essential for the IL-1–dependent formation of K63-Ub chains, TAK1 activation, or IL-8 production in human cells, because Pellino1 and Pellino2 generate the K63-Ub chains required for signaling in cells expressing E3 ligase-inactive TRAF6 mutants. The IL-1–induced formation of K63-Ub chains and ubiquitylation of IRAK1, IRAK4, and MyD88 was abolished in TRAF6/Pellino1/Pellino2 triple-knockout (KO) cells, but not in TRAF6 KO or Pellino1/2 double-KO cells. The reexpression of E3 ligase-inactive TRAF6 mutants partially restored IL-1 signaling in TRAF6 KO cells, but not in TRAF6/Pellino1/Pellino2 triple-KO cells. Pellino1-generated K63-Ub chains activated the TAK1 complex in vitro with similar efficiently to TRAF6-generated K63-Ub chains. The early phase of TLR signaling and the TLR-dependent secretion of IL-10 (controlled by IRAKs 1 and 2) was only reduced modestly in primary macrophages from knockin mice expressing the E3 ligase-inactive TRAF6[L74H] mutant, but the late-phase production of IL-6, IL-12, and TNFα (controlled only by the pseudokinase IRAK2) was abolished. RANKL-induced signaling in macrophages and the differentiation of bone marrow to osteoclasts was similar in TRAF6[L74H] and wild-type cells, explaining why the bone structure and teeth of the TRAF6[L74H] mice was normal, unlike TRAF6 KO mice. We identify two essential roles of TRAF6 that are independent of its E3 ligase activity.

Description: The World Health Organization estimates that 100 thousand people in the world die every year from asbestos-related cancers and more than 300 thousand European citizens are expected to die from asbestos-related mesothelioma by 2030. Both the European and the Italian legislations have banned the manufacture, importation, processing and distribution in commerce of asbestos-containing products and have recommended action plans for the safe removal of asbestos from public and private buildings. This paper describes the quantitative mapping of asbestos-cement covers over a large mountainous region of Italian Western Alps using the Multispectral Infrared and Visible Imaging Spectrometer sensor. A very large data set made up of 61 airborne transect strips covering 3263 km2 were processed to support the identification of buildings with asbestos-cement roofing, promoted by the Valle d’Aosta Autonomous Region with the support of the Regional Environmental Protection Agency. Results showed an overall mapping accuracy of 80%, in terms of asbestos-cement surface detected. The influence of topography on the classification’s accuracy suggested that even in high relief landscapes, the spatial resolution of data is the major source of errors and the smaller asbestos-cement covers were not detected or misclassified.

Description: The role of mammalian skin in harbouring and transmitting arthropod-borne protozoan parasites has been overlooked for decades as these pathogens have been regarded primarily as blood-dwelling organisms. Intriguingly, infections with low or undetected blood parasites are common, particularly in the case of Human African Trypanosomiasis caused by Trypanosoma brucei gambiense. We hypothesise, therefore, the skin represents an anatomic reservoir of infection. Here we definitively show that substantial quantities of trypanosomes exist within the skin following experimental infection, which can be transmitted to the tsetse vector, even in the absence of detectable parasitaemia. Importantly, we demonstrate the presence of extravascular parasites in human skin biopsies from undiagnosed individuals. The identification of this novel reservoir requires a re-evaluation of current diagnostic methods and control policies. More broadly, our results indicate that transmission is a key evolutionary force driving parasite extravasation that could further result in tissue invasion-dependent pathology.

Description: Background. Similar probabilities of survival have been reported for patients transplanted from Matched Unrelated Donor (MUD), Umbilical Cord Blood (UCB) or Haploidentical (Haplo) donors as alternative hematopoietic stem cell sources. However, few studies have compared these results with those obtained in patients transplanted from HLA Id-siblings (Id-sib). Moreover, all reported studies are retrospective and the criteria of donor selection were not predefined. We report the intention to treat (ITT) analysis results on 238 patients with high-risk acute myeloid leukemia (AML) prospectively transplanted according to the policy of the Rome Transplant Network (RTN), a metropolitan transplant program established in Rome in 2006. Patients and Methods. For AML patients eligible to an allogeneic transplant, the RTN policy consists of an algorithm of donor choice based on a hierarchy according to the following criteria: 1) HLA identical sibling; 2) MUD ≥8/10 HLA 3) UCB as single unit selected on the base of cell dose and number of HLA disparities (0-1/6 HLA: TNC ≥2.5x107/kg and CD34 ≥1x105/kg; 2/6 HLA: TNC ≥3.5x107/kg and CD34 ≥2x105/kg); 4) G-CSF primed, unmanipulated bone marrow Haplo donor. Myeloablative (MAC) or reduced intensity (RIC) TBF (Tiothepa, Busulfan, Fludarabine) conditioning regimen was identical for all patients, GVHD prophylaxis was uniform for each categories. of transplant Results. From January 2006 to December 2014, 238(89%) out of 303 adult patients candidates to an allogeneic transplant for high-risk AML were considered eligible. Overall, a donor was available for 205 (86%) of 238 eligible patients. At time of the analysis, 17 of these 205 patients (8%) had lost the transplant eligibility and 4 (2%) were still scheduled for transplant, therefore 184/205 (90%) patients with an available donor were finally transplanted from Id-sib (n=76), MUD (n=38), UCB (n=17) or Haplo (n=53) donors. The 8-yrs overall survival (OS) of the 238 eligible patients from time of HLA typing and of the 184 transplanted patients from time of the graft was 40±4%and 43±4%, respectively. By excluding the low number of UCB recipients (n=17), the OS was particularly dismal for the 34 patients transplanted in advanced disease phase (7±4% at 4 yrs), whereas for the 132 patients transplanted in early (CR1+ CR2) phase the 8-yr OS was 56±5%: 58±7% for 61 HLA Id-sib, 50±8% for 40 Haplo and 63±10% for 27 MUD recipients (P=NS). The OS of patients transplanted in early phase was 63±5% for 97 patients receiving MAC and 33±9% for RIC recipients. For these 97 patients, the survival by type of donor was 62±10% either for 47 Id-sib or 28 Haplo and 70±10% for 22 MUD recipients (P=NS). The results were analyzed by various donor/recipient (D/R) combinations such as age, sex and CMV status. The median donor age was 39 years (range, 18-70) and the median patient age was 43 years (range, 16-59): the 8-yr OS of patients (n=30) with younger D/R combination (D

Description: Background: This retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin® in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR. Methods: The median age was 63 years (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25mg/m2x 3 days), C (1gr/m2 day 1) and R (375mg/m2 day 4) for 4 cycles. Who achieved at least a partial remission, with

Description: Patients and Methods. At the Rome Transplant Network, a JACIE accredited metropolitan transplant program, a matched-pair analysis has been conducted on 116 of 255 patients transplanted between January 2008 and December 2012. The patients transplanted from Id Sib (n=58) or Haplo related donors (n=58) were completely matched for the following features: patient age, gender, diagnosis (7 subgroups), disease phase (early: CR1+CR2; advanced: 〉CR2+active disease), myeloablative or reduced intensity conditioning regimen consisting of Thiotepa, i.v. Busulphan and Fludarabine (TBF) association, donor age and donor/recipient sex, AB0 and CMV combinations. As GVHD prophylaxis, all patients received the standard CSA and MTX combination with the addition of ATG, MMF and Basiliximab in Haplo bone marrow recipients. The transfusion policy, supportive care and antinfectious prophylaxis were identical for all patients. Results. By comparingId Sib to Haplo recipients, the cumulative incidence (CI) of grade II-IV and III-IV acute-GVHD was 18±5% vs 42±7% (p=0.002) and 7±3% vs 14±5% (p=ns), respectively. The CI of extensive chronic GVHD was 23±6% for both patient series. The 5-year CI of TRM was 30±6% vs 36±6% (p=ns), respectively. The main causes of TRM were infections and the 6-month CI of Infection Related Mortality (IRM) was 26±6% in Haplo transplant and 10±4% in Id Sib (p=0.04). Although not statistically significant, the 5-year CI of relapse was higher in Id Sib (40±7%) than in Haplo recipients (28±6%). With a median follow-up of 3.5 years (range, 1 - 6), the 1- and 5-year disease free survival (DFS) was respectively 50±7% and 37±6% for Id Sibs and 45±7% and 36±6% for Haplo (Figure 1). Since 2 years after transplant, DFS curves of Id Sib and Haplo patients remained at plateau and were overlapping. Conclusions. This analysis considered a high number of factors for matching patients, who were grafted according to an identical transplant program. We can conclude that as consequence of a more intensive GVHD prophylaxis and therapy ensuing from higher incidence of 〉II grade acute GVHD, Haplo recipients are mainly exposed to a risk of early infection mortality. On the other hand, Id Sib patients seem to express less graft-versus-tumor activity with increasing risk of relapse after transplant. The identical long-term DFS justifies to consider the unmanipulated bone marrow transplant from haploidentical donor a valid alternative for patients lacking an HLA identical sib. Finally, it can appear at present provocative, but certainly realistic in perspective, the hypothesis that the donor choice in a familiar setting will mainly take into account other favourable donor/recipient combined characteristics rather than HLA compatibility. Figure 1 - Disease Free Survival Figure 1. - Disease Free Survival Disclosures No relevant conflicts of interest to declare.

Description: Introduction. The outcome of invasive fungal infections (IFI), particularly aspergillosis in acute leukemia (AL) patients (pts), has improved over the last years, but IFI still remain a major clinical issue in hematological pts, both for its severity and for the toxicity and potential drug interactions of antifungal treatments. Isavuconazole (ISV) is a new antifungal agent, with a modest drug-drug interaction profile, reduced drug-related adverse events and efficacy similar to voriconazole as demonstrated in a non-inferiority trial of IFI treatment (Maertens, Lancet 2016). To confirm the efficacy and safety of ISV in a clinical care setting, we planned a multicenter retrospective epidemiological study on behalf of SEIFEM (Sorveglianza Epidemiologica delle Infezioni nelle Emopatie) Group, collecting all cases of IFI treated with ISV in hematological pts. Patients and Methods. Since July 2016, we collected all cases of IFI occurring in adult and pediatric hematological pts who were treated with ISV in 13 Centers. IFI was diagnosed according to EORTC/MSG criteria and categorized as possible (poss) or probable/proven (p/p). The effects on outcome of age, gender, type and status of hematological disease at IFI (diagnosis [Dx], complete and partial remission [CR/PR], relapse/refractory [Rel/Refr]), type of IFI, allogeneic stem cell transplantation (alloSCT), neutropenia and timing of ISV treatment were evaluated. Results. IFI was diagnosed in 69 pts (M/F ratio: 47/22, median age 54.5y, range 5-80), affected by AL in 49 (71%) (myeloid 35, 51%; lymphoblastic 14, 28%), lymphoma in 15 (22%), myeloma in 2 (3%), severe aplastic anemia in 2 (3%) and myelodysplastic syndromes in 1 (1%) pts, respectively. AlloSCT pts were 20 (29%). IFI were categorized as p/p in 36 (52%) and as poss in 33 (48%) cases. Aspergillus spp was responsible for 31/36 (86%) p/p IFI; in the remaining 5 cases, 1 Rhizomucor pusillus was isolated and in 4, despite histology proven for IFI, no specific agent could be identified. Lung was the more frequent site of IFI (58/69, 84%), followed by paranasal sinuses (5, 7%), liver (3, 5%), brain (2, 3%), and bone (1, 1%). ISV was employed as first-line therapy in 19 (28%) and as subsequent line of treatment in 50 pts (72%; 41 as second and 9 as subsequent, respectively), following voriconazole in 15 cases, L-AmB in 22, caspofungin in 1 and combination therapy in 12. The median duration of previous treatments was 17.5 days (range 5-1110). Reasons for ISV use were failure of previous treatments in 16 (32%) and intolerance in 17 (34%) of 50 cases, respectively. In 16 cases (32%) ISV was chosen because of the need to switch antifungal treatment to an oral agent for outpatients and in 3 (4%) for a favorable drug-drug interaction profile. Median duration of ISV treatment was 60 days (3-210). After a median follow-up of 4.2 mo, 24/69 (35%) pts died; IFI-attributable mortality was 10/69 (15%). The estimated 1-year overall survival (OS) from IFI event of the entire cohort was 56% (CI 0.22-0.45); it was similar when considering poss vs p/p IFI (62% vs 51%, p=0.39), AL vs no AL (51% vs 69%, p=0.395) and first vs subsequent line use of ISV (66% vs 59%, p=0.6). OS was significantly lower for pts with failure to previous treatments (1y OS: refractory IFI 26% vs not refractory IFI 66%, p=0.001) (Fig. 1a) and for pts with rec/ref hematological disease (1y OS: rec/ref 29% vs CR/PR 86%, p=0.0027, or vs Dx 53%, p=0.06; no differences between Dx and CR/PR, p=0.27) (Fig. 1b). Clinical and radiological overall response rate (ORR) was 44 of 64 evaluable pts (69%). In multivariate analysis, only underlying disease status was a predictive factor for response to ISV (rec/ref HR 0.202, CI 0.062-0.658). Adverse events (AE) were reported in 10/69 pts (15%) (hepatic in 5, cutaneous in 3, gastroenteric in 3 and hypokaliemia in 1); grade 3-4 AE were reported in 5 cases and led to permanent ISV discontinuation. Conclusions. ISV is widely used in hematological pts with IFI also in diseases other than acute myeloid leukemia and it is overall well tolerated. ORR to ISV is at least comparable with other antifungal agents. A rec/ref underlying hematological disease impacts both on OS and response to ISV, while having an IFI refractory to other antifungal agents including azoles does not seem to compromise the response to ISV, although this promising result should be confirmed in prospective studies and larger groups of patients. Disclosures Busca: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merk: Honoraria, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Novartis: Speakers Bureau. Fanci:Gilead: Honoraria; Pfizer Pharmaceuticals: Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Candoni:Pfizer: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau. Fracchiolla:Amgen: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tumbarello:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Angelini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nordic Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Pfizer: Speakers Bureau. Aversa:Merck: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rossi:Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Novartis: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sandoz: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Pagano:Basilea: Speakers Bureau; Merck: Speakers Bureau; Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Gilead: Speakers Bureau.