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Stefania Gallo,1,* Maria Vittoria Arcidiacono,2,* Veronica Tisato,1 Roberta Piva,3 Letizia Penolazzi,3 Cristina Bosi,1 Carlo V Feo,1 Roberta Gafà,1 Paola Secchiero1 1Department of Morphology, Surgery, Experimental Medicine and LTTA Center, University of Ferrara, Ferrara, Italy; 2Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,” Trieste, Italy; 3Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy *These authors contributed equally to this work Background: Tumor-specific isoforms generated by alternative splicing (AS) are demonstrated to contribute to tumor progression and can represent potential biomarkers. NOVA2 is an AS factor that in physiological conditions regulates endothelial cells’ (ECs) polarity and vessel lumen maturation, likely by mediating AS of apical–basal polarity regulators. However, NOVA2 expression in tumor ECs and its regulation have never been investigated. Methods: To elucidate this, 40 colorectal cancer patients were enrolled and NOVA2 expression was investigated by immunohistochemistry in samples bearing both the normal mucosa and the tumor tissue. Results: NOVA2 was found expressed in ECs of tumor vasculature and, importantly, it was upregulated in tumor ECs with respect to normal mucosa ECs in all cases (P

Azacitidine (AZA) has proven effective in Myelodysplastic Syndromes (MDS), and the currently approved AZA regimen is 75 mg/sqm/die subcutaneously for 7 days every 28 days. Subsequently, other alternative and more convenient AZA dosing regimens have shown to be effective, in terms of hematologic responses (Lyons, 2009). From September 2004, in our Institution, 57 MDS patients (pts) (43 males), with a median age of 70 (37-84) yrs, were treated with AZA, following 4 different treatment regimens. Group 1 (10 pts), received the currently approved regimen (AZA 7). Group 2 (6 pts), received the AZA 7 regimen with valproic acid and all-trans-retinoic acid. Group 3 (29 pts) received the AZA 5-2-5 regimen: 50 mg/sqm/die SC for 10 days/28 days. Group 4 (12 pts) received the AZA 5 regimen: 75 mg/sqm/die SC for 5 days/28 days. Moreover, we quantified the degree of phosphoinositide-phospholipase C (PI-PLC) beta1 methylation and gene expression before and during AZA administration. At AZA onset, IPSS risk was: low: 3 pts; intermediate-1: 12 pts; intermediate-2: 33 pts; high: 9 pts. R-IPSS risk was: very low: 1 pt; low: 3 pts; intermediate: 7 pts; high: 10 pts; very high: 36 pts. WPSS risk was low: 3 pts; intermediate: 5 pts; high: 9 pts; very high: 40 pts. 9 pts had therapy-related MDS. ECOG-PS was poor (≥2) in 15 pts. Transfusion need was high (≥4 RBC units/8 weeks) in 34 pts. 6 pts presented circulating blasts. Following Itzykson’s AZA prognostic scoring system, the risk was low in 7 pts (12.3 %), intermediate in 48 pts (84.1 %), and high in 2 pts (3.6 %). The pts received a median of 8 cycles of AZA (range: 1-59). 50 pts were considered evaluable for response (at least 6 cycles): 34/50 pts (68%) showed a favourable response following IWG criteria (Cheson, 2006): complete remission (CR) in 7 pts (14% %), hematologic improvement (HI): 27 pts (54%). The median duration of response was 12 (range: 1-88) months. Group 1: 5 responders (62.5%) (1 CR and 4 HI); Group 2: 3 responders (50%) (3 HI); Group 3: 19 responders (73.1%) (5 CR, 14 HI); Group 4: 7 responders (70%) (2 CR, 5 HI). A significant toxicity (grade >2) was observed in 23 (40.4 %) pts. 37 pts died, 13 for AML, 9 for infection, 17 for other causes. Median OS from the start of AZA was 18 (range: 5-108) months. The detection of an increase in PIPLCbeta1 gene expression within the first three cycles of AZA therapy was significantly associated with a better clinical outcome and a longer hematologic response.

Introduction. Azacitidine (AZA) has proven effective in myelodysplastic syndromes (MDS). The duration of haematological response is limited (median 13.6 months) (Fenaux, 2009), although some patients (pts) show a prolonged response. These data prompted us to retrospectively analyse our MDS pts treated with AZA, in order to enucleate longresponder pts (duration of response ≥20 months). METHODS. From September 2004, in our Institution, 52 MDS pts (40 males), median age: 70 (37-85) yrs, were treated with AZA, following 4 different treatment regimens: 9 pts received the AZA 7 regimen (AZA 7: 75 mg/sqm/die SC for 7 days/28 days); 6 pts received the combination of AZA 7 with valproic acid and all-trans-retinoic acid ; while 25 and 12 pts respectively received the alternative regimens AZA 5-2-5 and AZA 5 (Lyons, JCO 2009). 37 pts (71%) showed a IPSS high-risk MDS, while 15 pts (29%) with IPSS low-risk MDS received AZA because of refractoriness or ineligibility to erythropoietin, or secondary MDS. Moreover, as our group (Follo, 2009) demonstrated that phosphoinositide-phospholipase C (PIPLC) beta1 may represent a target for AZA, we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration. RESULTS. 9 pts (17.3%) showed a prolonged hematologic response (≥ 20 months). Pre-treatment clinical and haematologic features of long-responders: sex (M/F): 4/5; median age: 69 (52- 84); WHO: RCMD-RS: 1 pt; RAEB-1: 1 pt; RAEB-2: 7 pts; IPSS risk: low: 1 pt; int-1: 2 pts; int-2: 5 pts; high: 1 pt; IPSS cytogenetic risk: low: 7 pts; interm: 1 pt; high: 1 pt; ECOG: 0-1: 8 pts, ≥ 2: 1 pt; transfusion need (N° U)/8 weeks: < 4 : 4 pts; ≥ 4 : 5 pts; time from diagnosis (months): < 6 : 6 pts; ≥ 6 : 3 pts. Therapeutic regimen: AZA 7: 3 pts; AZA 5: 3 pts; AZA 5-2-5: 3 pts. Therapeutic response: median number of cycles: 19 (8-59); median time to 1st response: 3 (2-6) months; type of response: Complete Remission (CR): 3 pts; Hematologic Improvement (HI): 6 pts; cytogenetic remission: 1 pt; median duration of response: 30 (24-66) months; doubling of platelet count after 1st cycle: 4 pts; toxicity (grade > 2): 3 pts; 4 pts are still maintaining hematologic response, 3 pts are still alive but discontinued treatment because of disease progression, and 2 pts died (1 for AML and 1 for cachexy). Median survival (from the start of AZA): 38 (25-103) months. All the pts showed an increase in PI-PLCbeta1 expression, that was maintained along with the hematologic response. 15 pts (28.8%) showed a short-lived reponse (< 20 months), 5 pts (9.6%) show a shorter response but are still on treatment, 2 pts underwent allogeneic transplantation after 5 and 10 months. 7 pts (13.4%) are not evaluable for response (< 6 cycles), and 14 pts (26.9%) did not respond to AZA. Conclusions. Our data show that a limited but significant fraction of MDS pts show a long-lasting hematologic and molecular response to AZA.

Azacitidine (AZA) has proven effective (response rate: 60-80%) in myelodysplastic syndromes (MDS). The currently approved AZA regimen (AZA 7) is 75 mg/sqm/die subcutaneously (SC) for 7 days every 28 days. Recently a different AZA dosing schedule (AZA 5-2-5: 50 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m2/d for 5 days), which avoids week-end dosing, has shown to induce therapeutic responses consistent with the currently approved schedule, in a population of mainly low risk pts (Lyons, 2009). These data prompted us to investigate the therapeutic effect of the AZA 5-2-5 regimen in high risk MDS pts (IPSS risk: high or intermediate-2). From September 2004, in our Institution, 28 high risk MDS pts. were treated with 2 different AZA dosing schedules. Group 1 (9 pts, 8 males, median age: 68, range 60-84 yrs) received the AZA 7 regimen, while group 2 (19 pts, 13 males, median age: 69, range 37-81 yrs) received the 5-2-5 AZA regimen. Moreover, as our group (Follo, 2009) demonstrated that phosphoinositide-phospholipase C (PI-PLC) beta1 may represent a target for AZA, we quantified the degree of PI-PLCbeta1 methylation and gene expression before and during AZA administration in both groups. Pts of group 1 received a median number of 12 (1-59) AZA cycles. Among the 8 evaluable pts (i.e.: at least 6 cycles) 5 (62.5%) showed a favourable response, following IWG criteria (Cheson, 2006): 1 Complete Remission (CR), 1 Partial Remission (PR) and 3 Hematologic Improvement (HI). 3 pts died because of evolution into Acute Myeloid Leukemia (AML), and 4 pts for other causes. One pts, still alive and under imatinib therapy, developed Ph1+ Chronic Myeloid Leukemia (CML) after 59 courses of AZA. Mean follow-up of group 1 pts: 31 (13-79) months. Pts of group 2 received a median number of 8 (1-17) AZA cycles. Among the 15 evaluable pts, 13 (86.6%) showed a favourable response: 5 CR (33.3%) and 8 HI. 3 pts died because of evolution into AML, and 2 for other causes. 2 pts underwent allogeneic stem cell transplantation, both after achieving CR. 12 pts are alive, 9 of them still under AZA treatment. Mean follow-up of group 2 pts: 14 (1-35) months. PI-PLCbeta1 methylation and gene expression appeared to be related to the therapeutic response, but not to the dose schedule. Our results, although larger studies are required, seem to confirm the effectiveness of the more convenient AZA 5-2-5 regimen, even in high risk MDS.

New therapetic approaches for AML were described with special emphasis on targeted therapies.

La Leucemia Mieloide Cronica (LMC) è una patologia della cellila staminale emopoietica caratterizzata dalla presenza del gene di fusione BCR-ABL, che codifica per una proteina con attività tirosin-kinasica responsabile del fenotipo neoplastico. La terapia della LMC è stata rivoluzionata dall'avvento dei farmaci inibitori delle tirosin-kinasi, il cui capostipite è l'imatinib mesilato. Nel capitolo viene discussa in dettaglio la terapia di prima linea e la terapia di salvataggio dei pazienti affetti da LMC, ed il monitoraggio della risposta.

Le infezioni fungine viscerali sono una severa complicanza durante la chemioterapia nei pazienti con leucemia acuta mieloide (LAM) (1). In particolare, le Aspergillus spp. e le Candida species sono spesso responsabili di gravi infezioni in questo tipo di pazienti, durante le fasi di agranulocitosi. Il polmone ed i seni nasali sono le sedi più frequentemente interessate da questi patogeni. Entrambi questi tipi di infezione possono essere letali, essendo possibili eventi terminali drammatici l’interessamento dei vasi bronchiali principali (con conseguente emottisi massiva) e l’infiltrazione del sistema nervoso centrale attraverso la lamina cribrosa dell’osso etmoide. Anche l’interessamento epato-splenico è un evento non raro. Il recupero granulocitario ed un tempestivo trattamento specifico per via sistemica sono necessari per controllare l’infezione.Al momento, l’amfotericina-B deossicolato per e.v. è il farmaco più comunemente impiegato per il trattamento di queste forme; peraltro, la nefrotossicità e le reazioni infusionali sono effetti indesiderati molto comuni (2). La formulazione liposomiale dell’amfotericina- B (AmBisome) (GILEAD SCIENCE) si è rivelata particolarmente efficace e con un favorevole profilo di tossicità e viene pertanto comunemente utilizzata per i pazienti che risultino intolleranti alla formulazione convenzionale (3). Questi due farmaci possono essere impiegati anche in forma di aerosol, al fine di aumentare la concentrazione a livello polmonare riducendo la tossicità sistemica (4, 5). Inoltre, sono stati riportati successi con l’instillazione diretta di agenti antifungini in aspergillomi polmonari (6). In casi selezionati, per aspergillomi isolati,può essere proposta una terapia chirurgica.Infine, in caso di micosi invasiva, possono essere utilizzate anche trasfusioni di granulociti (7).Alcuni nuovi farmaci, sviluppati recentemente, hanno mostrato risultati promettenti, ma, allo stato attuale, non sono ancora comunemente adottati. Noi abbiamo utilizzato con successo AmBisome, e. v. e per la prima volta anche per diretta instillazione intranasale, in due pazienti con LAM e micosi dei seni nasali. In un caso, è stata anche associata la trasfusione di granulociti.

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Thanks to the potential weight saving, aluminium castings are good candidates for automotive, electronic, aeronautic, sport equipments and other high performance products. At present, one of the main limits to a wide use of aluminium alloys for these applications is a lack of complete understanding of their fatigue behaviour and of the relationships to microstructural features, particularly as far as casting alloys are concerned.In this paper, the rotating bending fatigue behaviour of a cast Al-10Si-0.6Cu alloy has been investigated. The specimens for both the fatigue tests and the microstructural analyses have been drawn directly from the rims of car wheels. The wheel design influences the microstructure of the alloy, conditioning the cooling rate during solidification and, of consequence, may have important effects on the wheel fatigue performances.Measurements of the sizes of the microstructural constituents, such as secondary dendrite arm spacing and of porosity, have been also carried out by means of optical microscopy, supported by an image analysis software.Rotating bending fatigue tests have been performed on specimens with different types of notches. In this way, after the fatigue tests, it was possible to study the effect of the wheel design and so, of stress concentrations, on the fatigue life.

Background: Although azacitidine (AZA) has proven effective in myelodysplastic syndromes (MDS), the duration of haematologic response is limited. Introduction: The French Group (Itzykson 2011) identified some clinical and haematologic parameters (poor ECOG performance status, IPSS intermediate and poor risk cytogenetics, circulating blasts, high transfusion need) independently associated with a a poorer outcome, and these 4 criteria were integrated in a 3-group prognostic score. Purpose: These data prompted us to retrospectively analyse our MDS pts treated with AZA who showed a favourable long-lasting response to AZA (i.e: duration of response ≥ 20 months). Materials and Methods: The type of response was defined according to IWG criteria (Cheson 2006): Complete Remission (CR), Marrow CR, Partial Remission (PR), and Hematologic Improvement (HI). Results: Thirty-six pts (M/F: 21/15), from nine Institutions, with a median age of 72 (range 52-84) yrs, showed a response duration ≥ 20 months. At AZA onset, IPSS risk was: low: 3 pts; intermediate- 1: 7 pts; intermediate-2: 21 pts; high: 5 pts. IPSS cytogenetic risk was: low: 23 pts; intermediate: 7 pts; high: 6 pts.Transfusion need was high (≥ 4 RBC units/8 weeks) in 17 pts. Following Itzykson’s AZA prognostic scoring system, the risk was low in 14 pts (38.9%), intermediate in 21 pts (58.3%), and high in 1 pt (2.8%), respectively. The pts received a median of 23.5 cycles of AZA (range: 8-59). The best response achieved was: CR in 21 pts (58.3%); marrow CR: 4 pts (11.1%); PR in 2 pts (5.5%); and HI in 9 pts (25%). Cytogenetic remission was achieved in 7 pts (19.4%). The median duration of response was 24.5 (range: 20-88) months. Twenty-two pts (61.1%) are still maintaining hematologic response, 9 pts (25%) are still alive but discontinued treatment because of disease progression, and 5 pts died (2 for AML). Median OS from the start of AZA was 35.5 (range: 22-120) months. Conclusions: Our data show that a long-lasting hematologic response can be achieved even in a significant fraction of pts presenting one or more poor risk features.