Effetti clinici e biologici della terapia epigenetica nelle sindromi mielodisplastiche a basso rischio

Background: Nucleoside 5-Azacitidine (5-Aza) in high risk MDS patients (pts) at a dose of 75mg/mq/day subcutaneously for 7 days, every 28 days, induces high hematologic response rates (hematologic improvement (HI) 50-60%, complete remission (CR) 10-30%) and prolongation of survival (at 2 years 50,8%). Aim: The role of 5-Aza in low-risk MDS patients is not well defined but its use in the earlier phases of disease could be more effective and useful to control the expansion of MDS clone and disease progression. In our phase II, prospective, multicentric trial a low-dose schedule of 5-Aza (75 mg/mq daily for 5 consecutive days every 28 days) was given to low-risk MDS pts in order to evaluate its efficacy and tolerability and to identify biological markers to predict the response. Methods: From September 2008 to February 2010, 34 patients were enrolled into the study. Fifteen patients had refractory anemia (RA), 5 patients refractory anemia with ringed sideroblasts (RARS), 7 patients refractory cytopenia with multilineage dysplasia (RCMD) and 7 patients refractory anemia with excess blasts-1 (RAEB-1). All patients failed previously EPO therapy and were in chronic red blood cell (RBC) supportive care with a median transfusions requirement of 4 units/monthly. The response treatment criteria was according to IWG 2006. Results: At present time 31 out of 34 pts are evaluable: 12/31 pts (39%) completed the treatment plan (8 courses), 7/31 pts (22%) performed the first 4 courses, 8/31 (26%) made 1 to 3 courses and 4/31 (13%) died during the treatment period. Out of 12 pts who completed the 8 courses of therapy 10 (83%) obtained an HI, 2/12 (17%) maintained a stable disease. Out of 10 pts who obtained HI, 4 pts (40%) achieved a CR. Generally the drug was very well tolerated. The most commonly reported hematologic toxicities were neutropenia (55%) and thrombocytopenia (19%) but they were transitory and usually no delay of treatment was necessary. 2/4 pts died early after the 1th cycle for septic shock and gastrointestinal hemorrage respectively whereas 2/4 pts died in a condition of stable disease after the 4th cycle for pneumonia and respiratory distress. Samples for biologic studies have been collected from the pts before starting the therapy and at the end of 4th and 8th course. Preliminary data on the lipid signalling pathways suggested a direct correlation between PI-PLC-β1 gene expression and 5-Aza responsiveness. Conclusion: Interim analysis of our study based on the small number of cases who completed the treatment program, shows that 83% of pts obtain an HI and 40% obtain a CR. 4 patients died during the treatment and even if the causes were reported as no related to the therapy it has been considered that caution has to be reserved in given 5-Aza in these pts who are elderly and frail. Preliminary data of PI-PLC-β1 gene expression suggest that this and probably other biological markers could help us to know a priori who are the patients who have more chances to respond.

Studio di marcatori biologici prognostici nel linfoma di Hodgkin

Recent reports showed that early-interim PET-scan is the only tool predicting treatment outcome in advanced-stage classical Hodgkin lymphoma (asCHL). We evaluated the prognostic impact of a series of immunohistochemical markers, mentioned in literature as prognostic factors, on tissue microarrays assembled from biopsies of 220 patients: STAT1, SAP, TOP2A, PCNA and CD20, both in neoplastic (HRSC) and microenvironment cells (MC); RRM2, MAD2, CDC2, BCL2, P53, BCL11A and EBER in HRSC; ALDH1A1, TIA-1, granzyme B, perforin, FOXP3, and PD-1 in MC. All patients had been treated with standard ABVD ± Rx therapy. Interim-PET after 2 ABVD courses was evaluated according to the criteria indicated by Gallamini in his study (Journal of Clinical Oncology, 2007). The survival analysis has been performed in a subset of 138 patients whose complete clinical information were available: the mean age was 33.3 years (14-79), the stage III-IVB in 98 and IIB in 40, and the mean follow-up 38.1 months (7.6-71.9). Histopathology review showed: NS-I 75, NS-II 22, MC 20, DL 3, and CHL/nos 18 cases. Interim-PET was positive in 30 patients, while treatment failure was recorded in 32. In univariate analysis the factors related to treatment outcome were BCL2 on HRSC (cut-off value 50%), STAT1/SAP on MC, and PET (Log-rank 6.9, 7.9 and 93.9 respectively). The combined expression of STAT1 and SAP was scored in three levels depending on the architectural pattern: score 0 for expression of both with a diffuse/rosetting pattern; score 1 for discordant combination of diffuse/rosetting and scattered patterns; score 2 for both markers with a scattered pattern; the 3y-PFS were 87.4%, 69.9% and 61.9% respectively. In multivariate analysis PET, BCL2 and STAT1/SAP remained significant (HR: 24.8, 4.6, 7.5 and 5.6, respectively; p<.01). The proposed model is able to predict treatment response in AsCHL, even if with a lower efficacy than PET. However, unlike PET, it can be applied upfront therapy.

L'evoluzione della tutela cautelare nel processo amministrativo

L’effettività della tutela cautelare, intesa come tutela tempestiva, adeguata e piena, è stata la linea cardine dell’evoluzione della giustizia amministrativa, che, nel corso di un periodo durato più di un secolo, grazie all’opera della giurisprudenza e della dottrina, si è strutturata oggi su un vero processo. Approdo recente, e allo stesso tempo, simbolo di questa evoluzione, è sicuramente il Codice del processo amministrativo emanato con il d. lgs. 2 luglio 2010, n. 104. La ricerca, di cui questo contributo costituisce un resoconto, è iniziata contestualmente all’entrata in vigore del nuovo testo, e quindi è stata anche l’occasione per vederne le prime applicazioni giurisprudenziali. In particolare la lettura del Codice, prescindendo da una mera ricognizione di tutto il suo lungo articolato, è stata fatta alla luce di una ponderazione, nell’attualità, non solo del principio di effettività, ma anche del principio di strumentalità che lega tradizionalmente la fase cautelare con la fase di merito. I risultati della ricerca manifestano la volontà del legislatore di confermare questo rapporto strumentale, per fronteggiare una deriva incontrollata verso una cautela dagli effetti alle volte irreversibili, quale verificatasi nell’applicazione giurisprudenziale, ma contestualmente evidenziano la volontà di estendere la portata della tutela cautelare. Guardando a cosa sia diventata oggi la tutela cautelare, si è assistito ad un rafforzamento degli effetti conformativi, tipici delle sentenze di merito ma che si sono estesi alla fase cautelare. I giudici, pur consapevoli che la tutela cautelare non sia una risposta a cognizione piena, bensì sommaria, intendono comunque garantire una tutela tempestiva ed effettiva, anche per il tramite di tecniche processuali particolari, come quella del remand, cui, all’interno della ricerca, viene dedicato ampio spazio. Nella sua ultima parte la ricerca si è focalizzata, sempre volendo guardare in maniera globale agli effetti della tutela cautelare, sul momento dell’esecuzione e quindi sul giudizio di ottemperanza.