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Caraffa di Catanzaro, Italy

Lionetti M.,University of Milan | Fabris S.,University of Milan | Cutrona G.,SS Molecular Diagnostics | Agnelli L.,University of Milan | And 18 more authors.
British Journal of Haematology | Year: 2014

NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia (CLL). We performed deep next generation sequencing of the NOTCH1 mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis (MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O-CLL1 multicentre trial. The NOTCH1 c.7541_7542delCT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction-based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the NOTCH1 mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the NOTCH1 mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. NOTCH1-mutated cases, even at low clonal level, displayed a significant reduction in median progression-free survival, although NOTCH1 mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, IGHV mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure NOTCH1 mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches. © 2014 John Wiley & Sons Ltd.

Cantiello F.,University of Catanzaro | Cicione A.,University of Catanzaro | Salonia A.,Vita-Salute San Raffaele University | Autorino R.,Cleveland Clinic | And 4 more authors.
Urology | Year: 2013

Objective: To investigate the role periurethral fibrosis secondary to chronic prostatic inflammation as a potential contributing factor to the etiology of lower urinary tract symptoms (LUTS) in male patients. Methods: Periurethral prostate tissue from 30 consecutive patients who underwent retropubic radical prostatectomy for prostate cancer was analyzed. We circumferentially performed 16 periurethral core bench biopsies on each radical prostatectomy specimen to evaluate the extent of periurethral inflammatory infiltrate and collagen and elastin amount. The clinical and urodynamic findings and the collagen and elastin periurethral amount in patients with or without inflammation were compared using the Mann-Whitney U test and the Pearson χ2 test. Spearman correlation analysis tested the association between variables. Results: Of the 30 patients, 21 (70%) presented with inflammatory infiltration and 9 (30%) had no inflammation. A significant difference was found between the 2 groups in International Prostate Symptom Score (IPSS; P =.03) and in urodymanics findings by Schafer class (P =.01) and Abrams Griffiths number (P =.002). The histologic evaluation showed a higher collagen quantity (P =.04) and lower, albeit not statistically significant, elastin amount (P =.19) in the inflammation group. A positive association was observed between IPSS with inflammation grading (r = 0.507; P =.004) and collagen content (r = 0.649; P <.001), whereas IPSS was correlated negatively with elastin content (r = -0.565; P =.001). Conclusion: Prostate inflammation may induce fibrotic changes in periurethral prostatic tissues, and this may eventually promote urethral stiffness and LUTS. Patients experiencing prostate-related LUTS could benefit from anti-inflammatory therapies, used alone or combined with the currently prescribed regimen. © 2013 Elsevier Inc. All Rights Reserved.

Cantiello F.,University of Catanzaro | Cicione A.,University of Catanzaro | Salonia A.,University of Catanzaro | Salonia A.,Vita-Salute San Raffaele University | And 6 more authors.
International Journal of Urology | Year: 2014

Objectives: To investigate the pathological relationship between metabolic syndrome and peri-urethral fibrosis status secondary to chronic prostate inflammation. Methods: Peri-urethral prostate tissue from 80 consecutive patients who underwent retropubic radical prostatectomy for prostate cancer was analyzed. Patients were divided in two groups according to whether or not they had a diagnosis of metabolic syndrome. A 16-peri-urethral core bench biopsy was carried out on each radical prostatectomy specimen to evaluate the extent of peri-urethral inflammatory infiltrate, and collagen and elastin amount. Spearman's correlation analysis was used to test the association between variables. Furthermore, the data were used to define a bivariate logistic regression model in which the presence (>50% collagen amount for each patients) or absence (≤50% collagen amount) of fibrosis was analyzed after adjusting for clinical and pathological variables. Results: A significant difference was found between the two groups in terms of International Prostatic Symptoms Score (P<0.05) and urodynamics findings (all P<0.05). Patients with metabolic syndrome showed a more extended inflammatory infiltrate and higher peri-urethral collagen amount, along with a lower peri-urethral elastin amount (all P<0.05). A positive correlation was observed between inflammation, International Prostatic Symptoms Score, Bladder Outlet Obstruction Index and collagen amount, whereas inflammation was inversely correlated with elastin amount. On multivariate logistic regression analysis, prostate inflammation and metabolic syndrome were the only independent predictors of peri-urethral fibrosis (OR 1.73, 1.52, respectively). Conclusions: The present findings suggest that metabolic syndrome might represent an independent risk factor for prostate inflammation and fibrotic changes secondary to inflammation within the peri-urethral prostatic tissue. © 2013 The Japanese Urological Association.

Blotta S.,Dana-Farber Cancer Institute | Blotta S.,Harvard University | Blotta S.,University of Catanzaro | Jakubikova J.,Dana-Farber Cancer Institute | And 18 more authors.
Blood | Year: 2012

The Hedgehog (Hh) pathway is required for cell-fate determination during the embryonic life, as well as cell growth and differentiation in the adult organism, where the inappropriate activation has been implicated in several cancers. Here we demonstrate that Hh signaling plays a significant role in growth and survival of multiple myeloma (MM) cells. We observed that CD138 + MM cells express Hh genes and confirmed Smoothened (Smo)-dependent Hh signaling in MM using a novel synthetic Smo inhibitor, NVPLDE225 (Novartis), which decreased MM cell viability by inducing specific downregulation of Gli1 and Ptch1, hallmarks of Hh activity. In addition, we detected a nuclear localization of Gli1 in MM cells, which is completely abrogated by Forskolin, a Gli1-modulating compound, confirming Smo-independent mechanisms leading to Hh activation in MM. Finally, we identified that bone marrow stromal cells are a source of the Shh ligand, although they are resistant to the Hh inhibitor because of defective Smo expression and Ptch1 up-regulation. Further in vitro as well as in vivo studies showed antitumor efficacy of NVP-LDE225 in combination with bortezomib. Altogether, our data demonstrate activation of both canonical and noncanonical Hh pathway in MM, thus providing the rationale for testing Hh inhibitors in clinical trials to improve MM patient outcome. © 2012 by The American Society of Hematology.

Talarico V.,University of Catanzaro | Aloe M.,University of Catanzaro | Barreca M.,Pugliese Ciaccio Hospital | Galati M.C.,Pugliese Ciaccio Hospital | Raiola G.,Pugliese Ciaccio Hospital
Clinica Terapeutica | Year: 2014

Scurvy, a disease caused by a deficiency of ascorbic acid (vitamin C), is not very common disease especially in pediatric age. In the late nineteenth century, instead, we assisted to increase incidence of this problem for the use of heated milk and convenience foods. We report two cases of scurvy: a child of 3 years old came to our observation for an important gums' stomatitis, fever, widespread petechiae and ecchymosis on the skin of the lower limbs; in the second moment he had pain in upper and lower limbs with difficulty in walking; a second child of 4 years came to our observation for pain lower limbs and maintained the posture of the legs down, inability to walking, with reduced muscle tone and trophism in all limbs; at the instrumental examination he had an alveolar hemorrhage. The two boys had a history of a diet completely lacking in fruits and vegetables; they were drinking almost only milk. They carried various laboratory and instrumental tests, in particular X-ray of lower limbs that showed "a thick sclerotic metaphyseal line with beak-like excrescences of tibiae and femur". The characteristic radiological appearance, the particular clinical aspects, the dietary history and the dosage of vitamin C, have led us to the diagnosis of scurvy. They started therapy with vitamin C and they had a progressive improvement in general condition. © 2014. Società Editrice Universo (SEU).

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