Conflicting data exist regarding the relationship between hepatitis C virus genotype 1 and hepatic steatosis as well as the latter's role in the progression of fibrosis and treatment response. We ...assessed factors associated with hepatic steatosis in genotype 1 chronic hepatitis C and the impact of hepatic fat on fibrosis development and interferon responsiveness. Two hundred ninety-one non-diabetic patients with genotype 1 chronic hepatitis C were examined for the presence of steatosis and its correlation with clinical, virological, and biochemical data, including insulin resistance (IR), evaluated by the homeostasis model assessment (HOMA) score. Steatosis was graded as mild (1%-20% of hepatocytes involved), moderate (21%-40% of hepatocytes involved), and severe (>40% of hepatocytes involved). Steatosis was mild in 110 of 291 (37.8%) and moderate/severe in 55 of 291 (18.9%) subjects. By logistic regression, moderate/severe steatosis was independently associated with the female sex (odds ratio OR 2.74; 95% CI 1.40-5.35), high gamma-glutamyltransferase levels (OR 1.52; 95% CI 1.22-1.91), and HOMA-score (OR 1.076; 95% CI 1.001-1.26). By logistic regression, moderate/severe steatosis (OR 2.78; 95% CI 1.21-6.4), and platelet counts (OR 0.97; 95% CI 0.96-0.98) were independent predictors of advanced fibrosis. Patients with moderate/severe steatosis had an OR of 0.52 (95% CI 0.30-0.90) for sustained virological response compared with patients with mild/absent steatosis. In conclusion, in nondiabetic European patients with genotype 1 hepatitis C at low risk for the metabolic syndrome, the prevalence of steatosis was nearly 60%. IR is a risk factor for moderate/severe steatosis, especially in men. Moderate/severe steatosis has clinical relevance, being associated with advanced fibrosis and hyporesponsiveness to antiviral therapy.
The anti-CD33 antibody calicheamicinconjugate gemtuzumab ozogamicin (GO) was used to treat 16 patients with acute promyelocytic leukemia (APL) who had relapsed at the molecular level. Of these ...patients, 8 were experiencing a first, 5 a second, 2 a third, and 1 a fourth relapse. GO was administered at 6 mg/m2 for 2 doses, and patients achieving a new molecular remission (MR) (ie, negativity of the reverse transcriptase–polymerase chain reaction RT-PCR test for PML/RARα) received a third dose. MR was obtained in 9 (91%) of 11 patients tested after 2 doses and in 13 (100%) of 13 patients tested after the third dose. Of the 3 remaining patients, 1 achieved MR after one GO administration and received no further therapy owing to hepatic toxicity, and 2 showed disease progression during treatment. Quantitative RT-PCR studies showed that responding patients experienced a dramatic decline (at least 2 logs) of the PML/RARα transcript after the first GO dose. Of 14 responders, 7 remained in sustained MR for a median of 15 months (range, 7-31 months) while 7 experienced relapse at 3 to 15 months. GO was administered again in 2 patients with relapse, and both obtained a new MR. These data indicate that GO is highly effective as a single treatment for patients with molecularly relapsed APL including those with very advanced disease.
Several studies suggest that the N/OFQ (nociceptin/orphanin FQ)-NOP (N/OFQ peptide) receptor pathway is involved in airway physiology. We previously demonstrated a modulation of the endogenous N/OFQ ...levels in allergen-sensitized mice. Here, we investigated the effects of NOP receptor activation in allergen sensitization using a murine model of allergen-induced airway hyperresponsiveness (AHR). BALB/c mice were intraperitoneally treated with the NOP receptor agonist UFP-112, either during the sensitization phase (30 min before ovalbumin administration) or at the end of sensitization process (15 min before bronchopulmonary reactivity evaluation). At day 21 from the first allergen exposure, bronchopulmonary reactivity and total and differential cell count in bronchoalveolar lavage fluid were evaluated. In a separate set of experiments cell proliferation in lymphocytes, cytokine levels, IgE serum levels, and the effect of UFP-112 on IL-13-induced AHR were evaluated. Pretreatment with UFP-112, during the sensitization phase, caused a significant reduction in allergen-induced AHR and total cell lung infiltration. No effect on allergen-induced AHR was observed when the treatment was performed at the end of sensitization process, on tissues harvested from OVA-sensitized mice and on IL-13-induced AHR. The in vitro proliferative response of lymphocytes was significantly reduced by pretreatment during the sensitization phase with UFP-112. This effect was paralleled by a significant modulation of cytokine secretion in pulmonary tissues and lymphocytes. In conclusion, we demonstrated a role for the NOP receptor and N/OFQ pathway in the AHR induced by allergen, probably through a modulation of the immune response that triggers the development of AHR that involves pro- and anti-inflammatory cytokines.
This study evaluated the sealing capacity and safety of a new fibrin sealant (FS) to reduce alveolar air leaks (AALs) after pulmonary resections in a randomized controlled clinical trial conducted in ...3 Italian centers.
The study randomized (1:1) 185 patients with an intraoperative AAL graded 1 to 3 according to the Macchiarini scale: 91 received FS and 94 had standard lung closure. The primary outcomes were the length of postoperative AAL duration and the mean time to chest drain removal. Other end points included the percentage of patients without AAL, the development of serum antibodies against bovine aprotinin, and any adverse event related to FS. Chest drains were removed when fluid output was 100 mL/day or less, with no air leak.
The study groups were comparable with respect to demographic variables and surgical procedures. The FS group showed a statistically significant reduction in duration of postoperative AALs (9.52 vs 35.8 hours; p < 0.005) and in the percentage of patients with AALs at wound closure (81.11% vs 100%; p < 0.001); the difference in time to chest drain removal was not significant. Pleural empyema developed in 1 patient with FS treatment vs in 4 with standard treatment, and antibodies against bovine aprotinin were found in 34 of 91 FS-treated patients.
The present study showed that the new FS is safe and effective in preventing AALs after lung resections and in shortening the duration of postoperative AALs.
Background: Over the last two decades several phenotypic, molecular, and chromosomal markers have been identified that are significantly associated with the prognosis of CLL patients. Therefore, ...clinicians managing CLL patients would benefit from a simplified prognostic index.
Methods: We analyzed prospectively collected data from 337 Binet A CLL patients enrolled in Italian the O-CLL1-GISL protocol with the aim of developing scores capable of predicting treatment free survival (TFS). Factors independently associated with TFS were included in the prognostic indexes. To account for differences in the magnitude of the association between the individual independent factors and TFS, we assigned a weighted risk score to each factor based on ranges of their corresponding hazard ratios (HRs) (i.e., 1 point for HR 1.1-1.9; 2 points for HR 2.0-2.9, etc.). The total risk score was then calculated by the sum of the ratings of each factor on individual basis. Risk groups were identified combining risk categories with a non-statistically different TFS.
Results: We developed two scores based on weighted multivariable models: the first included clinical and laboratory parameters clinical score (c-score), while the second was based on biological markers biological score (b-score) (Table 1). The c-score allowed to predict the TFS of patients through the combination of Rai stage, b2-microglobulin and absolute lymphocyte count (ALC), while the b-score predicted TFS by IGHV mutational status and CD38 expression. The c-score showed a C-statistic of 0.72, while the b-score was 0.67, although cases stratified according to the b-score showed a more specific mRNA/microRNA profile. When the two scores were forced in a multivariate analysis, both showed an independent predictive value on TFS with a similar HR, demonstrating their complementarity. Thus, we attempted to integrate the two scores performing a further multivariate analysis in which all parameters, significantly associated with TFS at univariate analysis, were tested (Table 1). ALC, Rai stage, b2-microglobulin together with IGHV mutational status, resulted independently associated with TFS. We constructed a weighted score comprehensive score (co-score), including all the above 4 variables, which allowed the identification of 3 different risk groups with significantly different TFS (Figure 1). The C-statistic of the g-score was 0.75, showing a better concordance than the other two scores. Moreover, its validity was externally validated in a series of 297 newly diagnosed Binet A CLL patients from the Mayo Clinic, USA.
Conclusions: Using this multistep process and external validation, we developed a score with high discriminatory power and predictive significance on the individual patient level.
Table 1Univariate and multivariate Cox proportional Hazards ModelsVariableUnivariate analysisMultivariate analysisClinical modelBiological modelComprehensive modelHR (95% CI)PHR (95% CI)PscoreHR (95% CI)PscoreHR (95% CI)PscoreAge (years) 601.12 (0.73-1.74)0.59---Sex Male/Female0.93 (0.6-1.44)0.93---Rai stage 0/I-II2.30 (1.47-3.50)<0.00012.13 (1.24-3.03)0.0040/2---1.76 (1.11-2.78)0.0150/1ALC (109/L) 103.43 (1.99-5.92)<0.00012.91 (1.85-5.20)<0.00010/2---2.70 (1.54-4.72)0.0010/2b-2 microglobulin normal/elevated3.04 (1.96-4.70)<0.00012.78 (1.79-4.30)<0.00010/2---2.65 (1.66-4.21)<0.00010/2LDH normal/elevated1.25 (0.57-2.71)0.57---CD38 negative/positive3.22 (2.06-5.02)<0.0001---2.11 (1.15-3.16)0.020/21.40 (0.80-2.42)0.24-ZAP-70 negative/positive2.34 (1.51-3.61)<0.0001---1.21 (0.70-2.16)0.485-1.0 (0.98-1.01)0.72-IGHVmutated/unmutated3.57 (2.32-5.50)<0.0001---2.10 (1.12-3.90)0.0190/22.39 (1.27-4.50)0.0070/2FISH risk low+int/high2.93 (1.46-5.90)0.002---1.65 (0.76-3.34)0.216-1.80 (0.84-3.88)0.13-Abbreviations: ALC: absolute lymphocyte count; CI: confidential interval; HR: hazard ratio.
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Shanafelt:Cephalon: Research Funding; Glaxo-Smith-Kline: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding. Kay:Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Tolero Pharma: Research Funding; Pharmacyclics: Research Funding.
Time-lapse live cell imaging is a powerful tool for studying the responses of cells to drugs. Zoledronic acid (ZOL) is the most potent aminobiphosphonate able to induce cell growth inhibition at very ...low concentrations. The lack of clear evidence of ZOL-induced anti-cancer effects is likely due to its unfavorable pharmacokinetic profile. The use of nanotechnology-based formulations allows overcoming these limitations in ZOL pharmaco-distribution. Recently, stealth liposomes (LIPOs) and new self-assembly PEGylated nanoparticles (NPs) encapsulating ZOL were developed. Both the delivery systems showed promising anticancer activity in vitro and in vivo.
In this work, we investigated the cytostatic effect of these novel formulations (LIPOs and NPs) compared with free ZOL on 2 different prostate cancer cell lines, PC 3 and DU 145 and on prostate epithelial primary cells EPN using time lapse video-microscopy (TLVM). In PC3 cells, free ZOL showed a significant anti-proliferative effect but this effect was lower than that induced by LIPOs and NPs encapsulating ZOL; moreover, LIPO-ZOL was more potent in inducing growth inhibition than NP-ZOL. On the other hand, LIPO-ZOL slightly enhanced the free ZOL activity on growth inhibition of DU 145, while the anti-proliferative effect of NP-ZOL was not statistically relevant. These novel formulations did not induce anti-proliferative effects on EPN cells. Finally, we evaluated cytotoxic effects on DU145 where, LIPO-ZOL induced the highest cytotoxicity compared with NP-ZOL and free ZOL. In conclusion, ZOL can be transformed in a powerful anticancer agent, if administered with nanotechnology-based formulations without damaging the healthy tissues.
To evaluate the difference at different steps of follow-up of the postoperative quality of life (QoL) in patients who had undergone radical cystectomy and ileal orthotopic neobladder derivation.
A ...multicentric, cross-qualitative study was performed in 5 Italian centers of reference for the treatment of bladder cancer. One hundred seventy one patients who underwent radical cystectomy and creation of ileal orthotopic neobladder according to 'Vescica Ileale Padovana' between 2006 and 2011 have been analyzed. The validated and dedicated questionnaires EORTC QLQ-C30, IOB-PRO and EORTC QLQ-BLM30 were used.
All data gathered were then processed, specifically means ± SD were included for comparison during 4 periods of follow-up (quartile): the first ranging from 1 to 18 months; the second ranging from 19 to 36 months; the third from 37 to 72 months and the fourth >72 months. Cancer-specific and health-related factors were analyzed separately, and the change was determined during follow-up.
The global QoL, highlighted by validated cancer-specific and health-related questionnaires, is certainly on a satisfactory level. Thus, the education of the patient, the exploration of the pros and cons of an orthotopic neobladder and the active participation in treatment decision seem to be the keys to better improve the post-operative QoL during the follow-up period.
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