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Palumbo A.,University of Turin | Cavallo F.,University of Turin | Gay F.,University of Turin | Di Raimondo F.,University of Catania | And 22 more authors.
New England Journal of Medicine | Year: 2014

Background: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. Methods: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. Results: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P = 0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P = 0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). Conclusions: Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. Copyright © 2014 Massachusetts Medical Society.

Palumbo A.,University of Turin | Bringhen S.,University of Turin | Kumar S.K.,Rochester College | Lupparelli G.,University of Turin | And 23 more authors.
The Lancet Oncology | Year: 2014

Background: Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure. Methods: We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis. Findings: We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6·9% (95% CI 5·3-8·5) in patients who received lenalidomide and 4·8% (2·0-7·6) in those who did not (hazard ratio [HR] 1·55 [95% CI 1·03-2·34]; p=0·037). Cumulative 5-year incidences of solid second primary malignancies were 3·8% (95% CI 2·7-4·9) in patients who received lenalidomide and 3·4% (1·6-5·2) in those that did not (HR 1·1 [95% CI 0·62-2·00]; p=0·72), and of haematological second primary malignancies were 3·1% (95% CI 1·9-4·3) and 1·4% (0·0-3·6), respectively (HR 3·8 [95% CI 1·15-12·62]; p=0·029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4·86 [95% CI 2·79-8·46]; p<0·0001). Exposure to lenalidomide plus cyclophosphamide (HR 1·26 [95% CI 0·30-5·38]; p=0·75) or lenalidomide plus dexamethasone (HR 0·86 [95% CI 0·33-2·24]; p=0·76) did not increase haematological second primary malignancy risk versus melphalan alone. Interpretation: Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma. Funding: Celgene Corporation. © 2014 Elsevier Ltd.

Tartarone A.,Centro Of Riferimento Oncologico Della Basilicata | Lerose R.,Hospital Pharmacy | Lazzari C.,San Raffaele Scientific Institute | Gregorc V.,San Raffaele Scientific Institute | Aieta M.,Centro Of Riferimento Oncologico Della Basilicata
Medical Oncology | Year: 2014

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations derive greater benefits from first- and second-generation tyrosine kinase inhibitors (TKIs) than from chemotherapy, especially in the first-line setting. Thus, main treatment guidelines indicate to test all patients with lung adenocarcinoma for these genetic abnormalities and recommend the employment of TKIs in these patients. However, many unanswered questions about the optimal use of TKIs in lung cancer remain; in particular, an open question is which of the currently available TKIs (gefitinib, erlotinib and afatinib) might be the best choice in untreated NSCLC patients. In the current review, we will analyze the state of EGFR-TKIs therapy in untreated EGFR-mutated NSCLC patients with a focus on both efficacy and toxicity. © Springer Science+Business Media 2014.

Cappello C.,University of Naples Federico II | Tremolaterra F.,Centro Of Riferimento Oncologico Della Basilicata | Pascariello A.,University of Naples Federico II | Ciacci C.,University of Salerno | Iovino P.,University of Salerno
International Journal of Colorectal Disease | Year: 2013

Purpose: The aim of this study is to test in a double-blinded, randomised placebo-controlled study the effects of a commercially available multi-strain symbiotic mixture on symptoms, colonic transit and quality of life in irritable bowel syndrome (IBS) patients who meet Rome III criteria. Background: There is only one other double-blinded RCT on a single-strain symbiotic mixture in IBS. Methods: This is a double-blinded, randomised placebo-controlled study of a symbiotic mixture (Probinul, 5 g bid) over 4 weeks after 2 weeks of run-in. The primary endpoints were global satisfactory relief of abdominal flatulence and bloating. Responders were patients who reported at least 50 % of the weeks of treatment with global satisfactory relief. The secondary endpoints were change in abdominal bloating, flatulence, pain and urgency by a 100-mm visual analog scale, stool frequency and bowel functions on validated adjectival scales (Bristol Scale and sense of incomplete evacuation). Pre- and post-treatment colonic transit time (Metcalf) and quality of life (SF-36) were assessed. Results: Sixty-four IBS patients (symbiotic n = 32, 64 % females, mean age 38.7 ± 12.6 years) were studied. This symbiotic mixture reduced flatulence over a 4-week period of treatment (repeated-measures analysis of covariance, p < 0.05). Proportions of responders were not significantly different between groups. At the end of the treatment, a longer rectosigmoid transit time and a significant improvement in most SF-36 scores were observed in the symbiotic group. Conclusions: This symbiotic mixture has shown a beneficial effect in decreasing the severity of flatulence in IBS patients, a lack of adverse events and a good side-effect profile; however, it failed to achieve an improvement in global satisfactory relief of abdominal flatulence and bloating. Further studies are warranted. © 2012 The Author(s).

Tiacci E.,University of Perugia | Trifonov V.,Center for Computational Biology and Bioinformatics | Schiavoni G.,University of Perugia | Holmes A.,Center for Computational Biology and Bioinformatics | And 33 more authors.
New England Journal of Medicine | Year: 2011

Background: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. Methods: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. Results: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. Conclusions: The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.) Copyright © 2011 Massachusetts Medical Society.

Conteduca V.,Centro Of Riferimento Oncologico Della Basilicata | Di Lorenzo G.,University of Naples Federico II | Tartarone A.,Centro Of Riferimento Oncologico Della Basilicata | Aieta M.,Centro Of Riferimento Oncologico Della Basilicata
Critical Reviews in Oncology/Hematology | Year: 2013

Gonadotropin-releasing hormone agonists (GnRH) play an important role in the treatment of prostate cancer, improving significantly overall survival. GnRH agonists belong to androgen deprivation therapy (ADT) together with surgical castration and, recently, GnRH antagonists. ADT has several side effects, such as sexual dysfunction and osteoporosis. Recently, changes in body composition, obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension have emerged as complications of ADT, perhaps responsible for cardiovascular events, but discussion is still open. Since the majority of men with prostate cancer die of conditions other than their malignancy, recognition of these adverse effects is important. This review serves to focus attention on the pathogenetic mechanisms of ADT-related cardiovascular toxicity with also reference to the possible direct role of GnRH agonist on the cardiac receptors. Furthermore, this paper would generate recommendations for the management of patients treated with GnRH agonists balancing the potential benefits against the possible risks in prostate cancer men. © 2012 Elsevier Ireland Ltd.

Damiano S.,University of Naples Federico II | Morano A.,Centro Of Riferimento Oncologico Della Basilicata | Ucci V.,University of Naples Federico II | Accetta R.,University of Naples Federico II | And 4 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2015

Dual oxidase 2 enzyme is a member of the reactive oxygen species-generating cell membrane NADPH oxidases involved in mucosal innate immunity. It is not known if the biological activity of dual oxidase 2 is mediated by direct bacterial killing by reactive oxygen species produced by the enzyme or by the same reactive oxygen species acting as second messengers that stimulate novel gene expression. To uncover the role of reactive oxygen species and dual oxidases as signaling molecules, we have dissected the pathway triggered by epidermal growth factor to induce mucins, the principal protective components of gastrointestinal mucus. We show that dual oxidase 2 is essential for selective epidermal growth factor induction of the transmembrane MUC3 and the secreted gel-forming MUC5AC mucins. Reactive oxygen species generated by dual oxidase 2 stabilize tyrosine phosphorylation of epidermal growth factor receptor and induce MUC3 and MUC5AC through persistent activation of extracellular signal-regulated kinases 1/2-protein kinase C. Knocking down dual oxidase 2 by selective RNA targeting (siRNA) reduced epidermal growth factor receptor phosphorylation, and MUC3 and MUC5AC gene expression. Extracellular reactive oxygen species produced by dual oxidase 2, upon stimulation by epidermal growth factor, stabilize epidermal growth factor receptor phosphorylation and activate extracellular signal-regulated kinases 1/2-protein kinase C which induce MUC5AC and MUC3. Extracellular reactive oxygen species produced by dual oxidase 2 that are known to directly kill bacteria, also contribute to the maintenance of the epidermal growth factor-amplification loop, which induces mucins. These data suggest a new function of dual oxidase 2 protein in the luminal protection of the gastrointestinal tract through the induction of mucin expression by growth factors. © 2014 Elsevier Ltd. All rights reserved.

Tartarone A.,Centro Of Riferimento Oncologico Della Basilicata | Lerose R.,Hospital Pharmacy | Aieta M.,Centro Of Riferimento Oncologico Della Basilicata
Seminars in Nuclear Medicine | Year: 2016

Chemotherapy represents the cornerstone of treatment for patients with small cell lung cancer (SCLC); however, standard therapy has reached a plateau in improving patient survival with overall disappointing results. The demonstration that SCLC expresses neuroendocrine markers, such as somatostatin (SST) receptors, has led to use SST analogs or radiolabeled SST analogs in the treatment of SCLC patients. In the current review, we would focus on the possible role of SST analogs in SCLC. © 2016 Elsevier Inc. All rights reserved.

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