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Background. A systematic review of purine analogs revealed heterogeneity between trials in treatment effects on response and progression free survival, but not survival, perhaps partly due to variations in analysis methods. In addition, combination treatments required evaluation. Design and Methods. Individual patient data were sought for all randomized trials in untreated chronic lymphocytic leukemia which involved a purine analog, but not including antibody therapies. Results. Sixteen trials were found, addressing seven comparisons. Eight trials, with 2753 patients, showed that single agent purine analog improved progression free survival (Odds ratio = 0.71; 95% confidence interval =0.63-0.79). Heterogeneity remained substantial. Three trials, with 1403 patients, showed that progression free survival was further improved by the addition of cyclophosphamide (Odds ratio = 0.54; 0.47-0.62). Fewer data were available on the addition of other drugs to purine analog, and none showed clear benefit. Two trials, with 544 patients, suggested cladribine improved progression free survival compared to fludarabine (Odds ratio = 0.77; 0.63-0.95). No differences were seen in overall survival for any comparisons. Conclusions. Purine analogs, particularly combined with cyclophosphamide, significantly improve progression free survival but not survival. Some groups, such as the elderly, may not see the same benefits and maximising doses may be important for all treatments, including chlorambucil. Longer follow-up, consistent definitions and detailed reporting of trials should be encouraged.

EFFECTS OF CHLORAMBUCIL/HYDROXYCHLOROQUINE-LOADED ANTI-CD20 NANOPARTICLES ON A HUMAN/MOUSE MODEL OF BURKITT LYMPHOMA Mezzaroba N,1 Mansilla E,2 Zorzet S,1 Larsen G,3 Tripodo C,4 Núñez L,5 Marín GH,2 Nabergoj M,6 Tedesco F,1 Pozzato G,6 Macor P1 1 Department of Life Science, University of Trieste, Italy; 2 CUCAIBA, Ministry of Health, La Plata, Buenos Aires, Argentina; 3 LNK Chemsolutions, Lincoln Nebraska, USA and Bio-Target, Chicago, USA; 4 Department of Human Pathology, University of Palermo, Italy; 5 University of Chicago, Chicago, USA and BioTarget, Chicago, USA; 6 Department of Medical and Surgical Sciences, University of Trieste, Italy Introduction. In Burkitt lymphoma (BL) chemotherapy shows variable responses since a fraction of younger patients are resistant or relapse and the patients over 40 have difficulties to follow the therapy. In nonresponders/relapsers BL cells often express low level of CD20 and/or mutant/deleted p53. To overcome these problems, we developed a new therapeutic approach in which the efficacy of chemotherapy is associated to the specificity and low side-effects of antibody-based therapy. This approach lies in biodegradable nanoparticles (NP) coated with an antibody to target the neoplastic cells and filled with Hydroxychloroquine (HCQ) (a p53-independent toxic substance) and chlorambucil (CLB) as modern “Trojan Horses” to destroy the cancer cells. Methods. NP were prepared by the copolymerization of polylactic acid and polycaprolactone (diameter:250nm). The NP with HCQ and CLB were prepared by encapsulation at concentrations of 165 µg per mg of polymer inside their core, and then modified by anti-CD20 adsorption. In vitro study: To investigate the ability of NP to kill Burkitt lymphoma cell lines, 5 x 105 BJAB cells were incubated for 48 hours and the number of residual viable cells was determined with MTT assay. Apoptosis was evaluated by analyzing PARP-1 cleavage and Annexin V detection. In vivo study: A xenograft model was developed in SCID mice inoculated i.p. with 2 x 106 labeled or unlabeled BJAB cells; a fraction of mice was treated with NP and all animals examined twice weekly up to 120 days. A small-animal time-domain eXplore Optix pre-clinical imager was used for the invivo and ex-vivo evaluation of labeled BJAB cell dissemination and Ritcy5.5 distribution. At 120 days the animals were sacrificed and peritoneal mass and organs, lymph nodes and bones were collected for immunohistochemical analysis. Results. In vitro study: The binding NP on cell surface and their internalization were documented with confocal microscopy. In BJAB cells, HCQ and CLM as free substances induced cell death in 82% and 38% respectively, while NP containing only 5,4 g of HCQ and CLB killed 100% of cells. This effect is due to the synergic proapoptotic effect as shown by Annexin V detection and by PARP activation. The effects of NP was tested on CD20-negative cell lines CHO, HUVEC, MEL-28, LoVo: No cell cytotoxicity was detectable using NP, whereas free HCQ+CLB induce cell killing between 58 and 71%. In vivo study: The intra-peritoneal injection of BJAB cells induced a fast (within 4 days) tumor cells spread in different organs and, without therapy, all animals died in 50-70 days as well as those receiving free HCQ and CLM. Conversely, survival at 120 days of the mice receiving 4 or 8 i.p. injections of NP was 50 and 90% respectively. Conclusions. These results indicate that NP are able to cure even the highly proliferating BL cell line BJAB in both in vitro and in vivo models. This suggests the introduction of this promising technology into human clinical trial.

DEVELOPMENT OF CHLORAMBUCIL/HYDROXYCHLOROQUINE-LOADED ANTI-CD20 NANOPARTICLES FOR THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA : IN VITRO MODEL Mezzaroba N,1 Mansilla E,2 Zorzet S,1 Calvaruso M,3 Tripodo C,3 Núñez L,4 Tedesco F,1 Nabergoj M,6 Sblattero D,5 Granzotto M,7 Pozzato G,6 Macor P1 1 Department of Life Science, University of Trieste, Italy; 2 CUCAIBA, Ministry of Health, La Plata, Buenos Aires, Argentina; 3 Department of Human Pathology, University of Palermo, Italy; 4 University of Chicago, Chicago, USA and BioTarget, Chicago, USA; 5 Department of Medical Sciences, University of Eastern Piedmont, Novara, Italy; 6 Department of Medical and Surgical Sciences, University of Trieste; 7 Department of Molecular and Laboratory Medicine, IRCCSS Burlo Garofolo, Trieste, Italy Introduction. The actual challenge of tumor therapy is to design new therapeutic agents able to maximize the efficacy minimizing the adverse effects. Nanoparticles (NP) have emerged as important tools to modify the release profile for a large number of drugs. The aim of this study was to determine whether anti-CD20-coated biocompatible FDA-approved NP loaded with Chlorambucil (CLB) and Hydroxychloroquine (HCQ) could induce apoptosis of the B-Chronic Lymphocytic Leukemia (CLL) cell line MEC-1, as well as of circulating neoplastic B-cells isolated from patients with B-CLL. Methods. Nanoparticles were prepared by the copolymerization of polylactic acid and polycaprolactone and had an diameter of 250 nm. The NP with HCQ and CLB were prepared by encapsulation of the two drugs at concentrations of 165 µg per mg of polymer inside their core, and then modified by anti-CD20 adsorption. The NP were resuspended in PBS with 10% Bovine Serum Albumin (BSA) and maintained at 4°C before use. To investigate the ability of NP to affect cell viability and induce cellular apoptosis, MEC-1 cells (2 x 105) were incubated with anti-CD20 coated and CLB-HCQ loaded NP for 48 hours and the residual viable cells was determined with MTT assay. Cell death program activation was also evaluated by analyzing PARP-1 cleavage and Annexin V detection. Monoclonal B-cells were obtained from 44 patients affected by CLL. In each case the IGHV gene mutational status was assessed using standard methods and CD38 and ZAP-70 expressions were determined by flow cytometry. Interphase FISH was performed on nuclei preparations of PBMC and each case was investigated for 13q deletion, 11q deletion, 17p deletion or presence of trisomy 12. Results. Anti-CD20 NP with HCQ and CLB were able to induce a strong reduction (95%) in cell viability of MEC-1 cells. The cytotoxicity was present in a dose-dependent manner and was apoptosis-dependent as confirmed by the PARP- 1 activation and by the binding of Annexin V on cell surface. The same high cytotoxicity rate (>90%) was found also in patient-derived B-cells. The killing rate was independent from IGVH mutational status or from ZAP70 and CD38 expression or from the presence of 17p deletion. An efficient cytotoxicity was present even in CLL B-lymphocytes expressing low CD20 antigen levels on cell surface. The effects of NP were also tested on CD20-negative human and animal cells (CHO, HUVEC, MEL- 28, LoVo cell lines) and no specific cytotoxicity was obtained. On the contrary, incubation of CD20-negative cells with free HCQ + CLB induced cell killing between 58 and 71%. Conclusions. These results indicate that anti-CD20 coated and CLB-HCQ loaded NP show a high toxicity rate in CLL cell line as well as in B-cell obtained from CLL patients. The toxic effect is present also in 17p deleted cases, usually resistant to chemo-immuno-therapy. These results should be confirmed in animal models in order to introduce this promising technology into human clinical trials

OBJECTIVES: The aim of the present study is to provide information on clinical outcome of the patients affected by HCV-positive mixed cryoglobulinemia (MC) treated with PEG-IFN and Ribavirin for 6 or 12 months according to the HCV genotype. METHODS: Eighty-six patients (42 women and 44 men) were enrolled in 8 Italian centres. All the patients had MC in the active phase of the disease. The patients received Peginterferon alfa-2b 1.5 mcg/kg/once a week (QW) and daily oral Ribavirin (800/1,000/1,200) according to their body weight for 48 weeks for genotype 1 and 4 and for 24 weeks for genotypes 2 and 3. RESULTS: In the 44 patients who underwent 12 months of therapy, 17 cases (39%) could be considered as 'non-responders' and 11 relapsed, therefore only 16 patients (36%) obtained a sustained virological response. In the 42 patients who underwent six months of therapy only 7 cases (17%) could be considered as 'non-responders' and 8 relapsed, therefore 27 patients (64%) obtained a sustained virological response. Purpura score dropped in both group (p

Complementary and alternative medicine (CAM) is common in patients with cancer and its use is steadily increasing over time. We performed a multicenter survey in which the use of CAM in 442 Italian patients with chronic lymphocytic leukemia (CLL), the commonest form of leukemia in Western countries, was assessed. Data were collected by means of a face-to-face standardized questionnaire with several items. Mean age was 69 years; 258 patients (58%) were male and 184 (42%) female. Seventy-three patients (16.5%) were found to be CAM users. The most common CAM therapies were green tea, aloe formulations and high dose vitamins. Predictors of CAM use were female gender, younger age, higher education level, internet availability and newspaper reading. The reasons for CAM popularity among these patients are complex. Given the number of patients combining therapy with CAM and its possible drug interactions, doctor interest as well as patient education about CAM should be improved.

We define a notion of rational closure for the logic SHIQ, which does not enjoys the finite model property, building on the notion of rational closure introduced by Lehmann and Magidor in [23]. We provide a semantic characterization of rational closure in SHIQ in terms of a preferential semantics, based on a finite rank characterization of minimal models. We show that the rational closure of a TBox can be computed in EXPTIME using entailment in SHIQ., Comment: 30 pages, extended version of paper accepted to DL2014

Lymphoproliferative disorders are heterogeneous malignancy characterized by the expansion of a lymphoid clone more or less differentiated. At the level of the oral cavity, the lymphoproliferative disorder can occur in various ways, most commonly as lymphoid lesions with extranodal externalization, but sometimes, oral lesions may represent a localization of a disease spread. With regard to the primary localizations of lymphoproliferative disorders, a careful examination of the head and neck, oral, and oropharyngeal area is necessary in order to identify suspicious lesions, and their early detection results in a better prognosis for the patient. Numerous complications have been described and frequently found at oral level, due to pathology or different therapeutic strategies. These complications require precise diagnosis and measures to oral health care. In all this, oral pathologists, as well as dental practitioners, have a central role in the treatment and long-term monitoring of these patients.

International audience; no abstract

After consuming comparable amounts of ethanol, women have higher blood ethanol concentrations than men, even with allowance for differences in size, and are more susceptible to alcoholic liver disease. Recently, we documented significant "first-pass metabolism" of ethanol due to its oxidation by gastric tissue. We report a study of the possible contribution of this metabolism to the sex-related difference in blood alcohol concentrations in 20 men and 23 women. Six in each group were alcoholics. The first-pass metabolism was determined on the basis of the difference in areas under the curves of blood alcohol concentrations after intravenous and oral administration of ethanol (0.3 g per kilogram of body weight). Alcohol dehydrogenase activity was also measured in endoscopic gastric biopsies. In nonalcoholic subjects, the first-pass metabolism and gastric alcohol dehydrogenase activity of the women were 23 and 59 percent, respectively, of those in the men, and there was a significant correlation (rs = 0.659) between first-pass metabolism and gastric mucosal alcohol dehydrogenase activity. In the alcoholic men, the first-pass metabolism and gastric alcohol dehydrogenase activity were about half those in the nonalcoholic men; in the alcoholic women, the gastric mucosal alcohol dehydrogenase activity was even lower than in the alcoholic men, and first-pass metabolism was virtually abolished. We conclude that the increased bioavailability of ethanol resulting from decreased gastric oxidation of ethanol may contribute to the enhanced vulnerability of women to acute and chronic complications of alcoholism.

The etiology of non-Hodgkin's lymphomas (NHL) remains a controversial matter, but, in the last few years, considerable evidence suggests that aberrations of the immune system and viruses may act as etiologic agents, in at least some cases of NHL. In fact, patients with primary immuno-deficiencies, or those suffering from diseases characterized by autoimmune dysfunction, show an increased risk for the development of NHL. Several viruses have been identified as possible etiologic agents for NHL; one of the best studied is the Epstein-Barr virus, which was detected in cultures of tumor cells from patients with Burkitt's lymphoma. The pathogenetic potential of this virus is illustrated by its association with an increasing number of malignant diseases. In addition, the human T-cell lymphotropic virus family (HTLV), was also recognized as possible etiologic agents for several lymphomas, such as cutaneous T-cell lymphoma and T-cell leukemia-lymphoma syndrome (HTLV-I), and T-cell hairy cell leukemia (HTLV-II). Recently, the presence of hepatitis C virus infection has also been recognized in several hematological malignancies such as mixed cryoglobulinemia, low-grade malignant lymphomas and Waldenström's disease. The possible etiopathogenetic role of this virus in non-Hodgkin's lymphomas is discussed on the basis of molecular, clinical, and epidemiological considerations.