Angelo Vacca

Università degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

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Publications (383)1364.64 Total impact

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    ABSTRACT: Allergic reactions to mannitol have been reported rarely, despite its widespread use as a drug and as a food excipient. This is the first case report in which oral mannitol induces an immediate type hypersensitivity as a drug excipient, in a 42 year old man affected by rhinitis to olive tree pollen. Unusual and undervalued risk factors for mannitol hypersensitivity are examined.
    European annals of allergy and clinical immunology 05/2015; 47(3):99-102.
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    Journal of Allergy and Clinical Immunology 02/2015; 135(4). DOI:10.1016/j.jaci.2014.11.041 · 11.25 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.
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    ABSTRACT: Metronomic chemotherapy (MC) refers to the close administration of a chemotherapeutic drug for a long time with no extended drug-free breaks. It was developed to overcome drug resistance, partly by shifting the therapeutic target from tumor cells to the tumor vasculature, with less toxicity. Because of this peculiar way of administration, MC can be viewed as a form of long-term ‘maintenance’ treatment, and can be integrated with standard and conventional chemotherapy in a “chemo-switching” strategy. Additional mechanisms are involved in its antitumor activity, such as activation of immunity, induction of tumor dormancy, chemotherapy-driven dependency of cancer cells, and the ‘4D effect’. In this paper we report the most important studies that have analysed these processes. In fact, a number of preclinical and clinical studies in solid tumors as well as in multiple myeloma, have been reported regarding several chemotherapy drugs which have been proposed with a metronomic schedule: vinorelbine, cyclophosphamide, capecitabine, methotrexate, bevacizumab, etoposide, gemcitabine, sorafenib, everolimus and temozolomide. The results of these studies have been sometimes conflicting, highlighting the need to develop reliable tools for patient selection and stratification. However, a more precise evaluation of MC strategies with the ongoing randomized phase II/III clinical is fundamental, because of the strict correlation of this approach with translational research and target therapy. Moreover, because of the low toxicity of MC, these studies will also help to better evaluate the clinical benefit of this treatment, with a special focus on elderly and low performance status patients.
    Critical Reviews in Oncology/Hematology 01/2015; 95(1). DOI:10.1016/j.critrevonc.2015.01.008 · 4.05 Impact Factor
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    ABSTRACT: Bone marrow (BM) contains hematopoietic stem cells (HSCs) and nonhematopoietic cells. HSCs give rise to all types of mature blood cells, while the nonhematopoietic component includes osteoblasts/osteoclasts, endothelial cells (ECs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs). These cells form specialized "niches" which are close to the vasculature ("vascular niche") or to the endosteum ("osteoblast niche"). The "vascular niche", rich in blood vessels where ECs and mural cells (pericytes and smooth muscle cells), create a microenvironment affecting the behavior of several stem and progenitor cells. The vessel wall acts as an independent niche for the recruitment of EPCs and MSCs. This chapter will focus on the description of the role of BM niches in the control of angiogenesis occurring during multiple myeloma progression. Copyright © 2015 Elsevier Inc. All rights reserved.
    International review of cell and molecular biology 01/2015; 314:259-82. DOI:10.1016/bs.ircmb.2014.10.004 · 4.52 Impact Factor
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    ABSTRACT: This current retrospective multicenter analysis represents, to our knowledge, the first Italian study evaluating the efficacy and toxicity profile of “lenalidomide plus dexamethasone” as salvage therapy in patients with recurrent-refractory MM in the real life contest. Our study included patients who are usually excluded from clinical trials because of unfavourable baseline characteristics. Median OS was significantly longer in patients receiving “lenalidomide plus dexamethasone” for more than 12 months compared with those who had received “lenalidomide plus dexamethasone” for a shorter interval (P < 0.0001). Median OS was not affected by best response achieved (P 0.4) and age (P 0.3). Quality of response did not correlate with number of previous lines of therapy (P 0.77) and age. Higher ORRs were recorded in the patients group with relapsed MM compared to those with refractory disease, but this difference was not statistically significant (P 0.38).
    Leukemia Research 12/2014; 39(3). DOI:10.1016/j.leukres.2014.12.007 · 2.69 Impact Factor
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    ABSTRACT: Tumor microenvironment plays an important role in cancer initiation and progression. In hematological malignancies, the bone marrow represents the paradigmatic anatomical site in which tumor microenvironment expresses its morphofunctional features. Among the cells participating in the composition of this microenvironment, cancer associated fibrobasts (CAFs) have received less attention in hematopoietic tumors compared to solid cancers. In this review article, we discuss the involvement of CAFs in progression of hematological malignancies and the potential targeting of CAFs in a therapeutic perspective.
    Oncotarget 11/2014; · 6.63 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) are essential for maintenance of self-tolerance, however tumor cells can exploit the tolerance to escape the immune system. We investigated the Tregs frequency in patients with multiple myeloma (MM) and in those with monoclonal gammopathy of undetermined significance (MGUS), and found that CD4+FoxP3+ and CD8+FoxP3+ Tregs were significantly increased in MM patients and correlated with the active phase. Both Tregs subsets were expanded in cocultures of CD3+ lymphocytes and fresh CD138+ MM plasma cells or RPMI8226 and U266 cell lines, and functioned as natural (n) and inducible (i) Tregs insofar as they inhibited the proliferation of stimulated CD3 lymphocytes via contact-dependent and -independent pathways. Induction of Tregs by MM plasma cells required a contact-dependent pathway, implying antigen recognition by T cells. MM plasma cells acted as immature and tolerogenic antigen-presenting cells (APCs), in that they displayed low CD80/CD86 expression associated with a phagocytic activity. By acting as immature APCs, MM plasma cells plausibly expand (n)Tregs and (i)Tregs both through conversion of CD3+FoxP3- into CD3+FoxP3+ T cells and proliferation of CD3+FoxP3+ T cells, which may suppress the anti-MM immune response.This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 11/2014; 95(1). DOI:10.1111/ejh.12481 · 2.41 Impact Factor
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    ABSTRACT: Bcl-6 translocation is a genetic alteration that is commonly detected in Primary Central Nervous System Lymphoma. The role of this protein in cerebral tumors is unclear. In this study we investigated Bcl-6 translocation and its transcriptional and translational levels in formalin-fixed, paraffin-embedded cerebral tissue sections from Glioblastoma (GBM), low-grade glioma (Astrocytoma grade II and III), and meningioma patients, and correlated them with apoptotic processes and p53 and caspase-3 expression. The results showed a frequency of 36.6% of Bcl-6 translocation in GBM patients and a decreased expression in low-grade glioma patients, correlated with the severity of the disease. Bcl-6 translocation induced an overexpression of both Bcl-6 protein and messenger in GBM, inhibiting apoptotic processes and caspases 3 expression. On the contrary, in low-grade gliomas and meningiomas Bcl-6 expression was reduced, resulting in an increase of apoptotic processes. Finally, p53 expression levels in brain tumors were comparable to Bcl-6 levels. Overall, these data demonstrate, for the first time, that the Bcl-6 gene translocates in GBM patients and that its translocation and expression are correlated with apoptosis inhibition, indicating a key role for this gene in the control of cellular proliferation. This study offers further insights into Glioblastoma biology, and supports Bcl-6 as a new diagnostic marker to evaluate the disease severity.
    Cancer Letters 10/2014; 353(1):41. DOI:10.1016/j.canlet.2014.06.017 · 5.02 Impact Factor
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    ABSTRACT: A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight loss, despite the gluten-free diet, was operated because of a sub-diaphragmatic free air due to a small-bowel pneumatosis cystoides intestinalis (PCI). The jejunum showed granulomatous lesions with a honeycombed appearance of air cysts in the submucosa/subserosa. We found overexpression of peptide YY (PYY) into only the jejunum with PCI, while the expression was very weak or absent in the tissue without cysts. One year after surgery, he had no abdominal pain or PCI recurrence. The above chronic symptoms were plausibly attributable to the PYY.
    Clinical and Experimental Medicine 10/2014; DOI:10.1007/s10238-014-0314-5 · 2.82 Impact Factor
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    ABSTRACT: Conventional radiographic skeletal survey has been for many years the gold standard to detect the occurrence of osteolytic lesions in patients with multiple myeloma (MM). However, the introduction of more sensitive imaging procedures has resulted in an updated anatomic and functional Durie and Salmon "plus" staging system and has remarkably changed the diagnostic and prognostic approach to this tumor. It is now established that (18)fluorine-fluorodeoxyglucose ((18)F-FDG) positron-emission tomography (PET) combined with low-dose computed tomography (CT), shortly designated PET/CT, exhibits a higher screening and diagnostic sensitivity and specificity over the skeleton X-ray. In patients with monoclonal gammopathy of undetermined significance and in those with smoldering MM, PET/CT is consistently unable to detect focal and/or diffuse marrow abnormalities. Conversely, based on a systematic review of 18 studies comprising almost 800 MM patients, PET/CT was able to detect MM osteolytic lesions with a sensitivity of approximately 80-90 % and a specificity of 80-100 %. Importantly, a poor degree of concordance has also been emphasized between PET/CT and whole-body magnetic resonance imaging (WB-MRI) in that when both techniques were applied to the same patients, double-positive results were recorded in approximately 30 % of the cases, but in the majority of them, a higher number of lesions were revealed with PET/CT than with MRI. Double-negative results, on the other hand, were found in about 22 % of the patients. Because PET/CT is able to identify tumor foci throughout the body, it can be usefully applied to the study of solitary bone plasmacytoma and extra-medullary plasmacytoma: In both conditions, the detection of additional, previously overlooked sites of skeletal involvement would falsify the diagnosis of single-district disease, upstage the tumor, and therefore require a different therapeutic approach. In addition, although PET/CT is poorly sensitive to diffuse bone marrow infiltration, it can anticipate a site of impending fracture throughout the body and can discriminate old from new pathologic fractures. MRI should, however, be preferred when vertebral bodies are suspected to be involved and the risk of vertebral fracture is to be assessed. PET/CT is a sensitive and reliable procedure to evaluate the response to chemotherapy and/or radiotherapy, which is shown by a remarkable reduction and sometimes total disappearance of FDG accumulation in the involved bony structures, although these structures remain morphologically abnormal. Conversely, an increased focal uptake of FDG in apparent remission patients often precedes clinically overt relapse. PET/CT should be preferred to other imaging techniques to assess the remission status after autologous stem cell transplantation. In patients with primary and remission-induced non-secretory MM, the use of PET/CT may help to early detect single or multiple districts of focal non-secretory relapse. Osteonecrosis of the jaw, its location, and extent in MM patients receiving bis-phosphonates are better defined by both PET/CT and contrast-enhanced MRI compared with dental panoramic views derived from cone beam CT imaging. Little is known as to the possible role of PET/CT in the assessment of disease extension, tumor load, and response to therapy in patients with Waldenström's macroglobulinemia (WM). In a study conducted on 35 WM patients, comparative PET/CT before and after therapy was able to detect positive findings in 83 % of the patients, in contrast with the previous results achieved with conventional imaging that reported visceral involvement in much lower percentages. Similarly scanty are the data on the use of PET/CT in localized and systemic amyloidosis, given the small number of patients studied so far. A retrospective study has shown that, at variance from (123)Iodine-serum amyloid P component ((123)I-SAP) scintigraphy, which was found to be positive in about one-third of the patients with localized amyloidosis, an increased FDG uptake was detected at the amyloid site in virtually all of them. On the contrary, none of the patients with systemic amyloidosis showed an increased FDG uptake in sites of known deposition, whereas (123)I-SAP scintigraphy tested positive in the large majority of them. In another study, however, no such remarkable difference of positive PET/CT scans between localized and systemic amyloidosis was reported. Finally, false-positive and false-negative PET/CT findings can occur in different conditions that should be kept in mind to avoid wrong or omitted diagnoses.
    Clinical and Experimental Medicine 09/2014; 15(1). DOI:10.1007/s10238-014-0308-3 · 2.82 Impact Factor
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    ABSTRACT: Purpose: To investigate the angiogenic role of the HGF/cMET pathway and its inhibition in bone marrow (BM) endothelial cells (ECs) from patients with multiple myeloma (MM) vs those with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (controls). Experimental Design: The HGF/cMET pathway was evaluated in ECs from MM patients (MMECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, in ECs from patients with MGUS (MGECs), and in those from controls. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on the MMECs angiogenic activities were studied in vitro and in vivo. Results: MMECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein level vs MGECs and control ECs. MMECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, while treatment with anti-HGF and anti-cMET neutralizing antibodies (Abs) is able to inhibit the cMET activation. The cMET pathway regulates several MMECs activities including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo. Conclusions: An autocrine HGF/cMET loop sustains MM angiogenesis, and represents an appealing new target to potentiate the antiangiogenic management of MM patients.
    Clinical Cancer Research 09/2014; DOI:10.1158/1078-0432.CCR-14-0847 · 8.19 Impact Factor
  • Journal of Biotechnology 09/2014; 185:S14. DOI:10.1016/j.jbiotec.2014.07.051 · 2.88 Impact Factor
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    ABSTRACT: Tumour pathogenesis in multiple myeloma (MM) correlates with a high vascular index. Therefore, targeting angiogenesis is an important therapeutic tool to reduce MM progression. This study aimed to investigate the role of invariant natural killer T (iNKT) cells in angiogenesis and the mechanisms behind the stimulation by α-Galactosylceramide (α-GalCer). We have previously found that α-GalCer could increase the survival of 5T33MM mice and here we demonstrate that α-GalCer reduces the microvessel density. We performed both in vivo and in vitro angiogenic assays to confirm this observation. We found that conditioned medium of α-GalCer stimulated iNKT cells reduced neovascularization in the chick chorioallantoic membrane and in matrigel plug assays. Moreover, we observed a reduction in proliferation, migration and network formation and an induction of apoptosis upon exposure of murine endothelial cell lines to this conditioned medium. We furthermore observed that the JAK-STAT signaling pathway was highly activated in endothelial cells in response to stimulated iNKT cells, indicating the possible role of IFN-γ in the anti-angiogenic process. In conclusion, these results highlight the possibility of recruiting iNKT cells to target MM and angiogenesis. This gives a rationale for combining immunotherapy with conventional anti-tumour treatments in view of increasing their therapeutic potential.
    British Journal of Haematology 08/2014; 167(5). DOI:10.1111/bjh.13092 · 4.96 Impact Factor
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    ABSTRACT: The aim of this study was to identify the main features of a cohort of Caucasian patients with idiopathic (I) and systemic disease-associated (SDA) autoimmune uveitis (AU) who were followed up at a single tertiary reference center. The study consisted of a retrospective analysis of the demographic, clinical, and laboratory features and the response to treatment of 104 patients with AU evaluated between 2004 and 2013, with a median follow-up of 4.8 years. The primary outcome measure was the response to systemic treatment after 24 months of therapy. The data are expressed as the range, percentage, or mean ± standard error. Categorical variables were assessed by Fisher's exact test.
    07/2014; 4:17. DOI:10.1186/s12348-014-0017-9
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    ABSTRACT: Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease.
    06/2014; 6(3):1363-1381. DOI:10.3390/cancers6031363
  • Roberto Ria, Antonia Reale, Angelo Vacca
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    ABSTRACT: This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents (bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality responses with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials.
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    ABSTRACT: Background: Tryptase is a serin protease stored and released from mast cells (MCs) that plays a role in tumour angiogenesis. In this study we aimed to evaluate serum tryptase levels in colo-rectal cancer (CRC) patients before (STLBS) and after (STLAS) radical surgical resection. We also evaluated mast cell density positive to tryptase (MCDPT) and microvascular density (MVD) in primary tumour tissue. Methods: A series of 61 patients with stage B and C CRC (according to the Astler and Coller staging system) were selected. Serum blood samples were collected from patients one day before and one day after surgery. Tryptase levels were measured using the UniCAP Tryptase Fluoroenzymeimmunoassay (Pharmacia, Uppsala, Sweden). Tumour sections were immunostained with a primary anti-tryptase antibody (clone AA1; Dako, Glostrup, Denmark) and an anti CD-34 antibody (QB-END 10; Bio-Optica Milan, Italy) by means of immunohistochemistry and then evaluated by image analysis methods. Results: The mean +/- s.d. STLBS and STLAS was 5.63 +/- 2.61 mu g/L, and 3.39 +/- 1.47 mu g/L respectively and a significant difference between mean levels was found: p = 0.000 by t-test. The mean +/- s.d. of MCDPT and MVD was 8.13 +/- 3.28 and 29.16 +/- 7.39 respectively. A strong correlation between STLBS and MVD (r = 0.83, p = 0.000); STLBS and MCDPT (r = 0.60, p = 0.003); and MCDPT and MVD (r = 0.73; p = 0.001) was found. Conclusion: Results demonstrated higher STLBS in CRC patients, indicating an involvement of MC tryptase in CRC angiogenesis. Data also indicated lower STLAS, suggesting the release of tryptase from tumour-infiltrating MCs. Serum tryptase levels may therefore play a role as a novel bio-marker predictive of response to radical surgery. In this context tryptase inhibitors such as Gabexate and Nafamostat Mesilate might be evaluated in adjuvant clinical trials as a new anti-angiogenic approach.
    PLoS ONE 06/2014; 9(6):e99512. DOI:10.1371/journal.pone.0099512 · 3.53 Impact Factor
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    ABSTRACT: Primary tumors of the inferior vena cava are rare, with leiomyosarcoma representing the vast majority.
    Phlebology 05/2014; DOI:10.1177/0268355514535928 · 1.92 Impact Factor
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    ABSTRACT: In patients with multiple myeloma (MM), the bone marrow (BM) contains hematopoietic stem cells (HSCs) and non-hematopoietic cells. HSCs are able to give rise to all types of mature blood cells, while the non hematopoietic component includes mesenchymal stem cells (MSCs), fibroblasts, osteoblasts, osteoclasts, chondroclasts, endothelial cells, endothelial progenitor cells (EPCs), B and T lymphocytes, NK cells, erythrocytes, megakaryocytes, platelets, macrophages and mast cells. All of these cells form specialized "niches" in the BM microenvironment which are close to the vasculature ("vascular niche") or to the endosteum ("osteoblast niche"). The "vascular niche" is rich in blood vessels where endothelial cells and mural cells (pericytes and smooth muscle cells) create a microenvironment that affects the behavior of several stem and progenitor cells. The vessel wall serves as an independent niche for the recruitment of endothelial progenitor cells, MSCs and HSCs. The activation by angiogenic factors and inflammatory cytokines switch the "vascular niche" to promote MM tumor growth and spread. This review will focus on the mechanisms involved in the generation of signals released by endothelial cells in the "vascular niche" that promote tumor growth and spread in MM. © 2014 Elsevier Ltd. All rights reserved.
    Thrombosis Research 05/2014; 133 Suppl 2:S102-6. DOI:10.1016/S0049-3848(14)50017-5 · 2.43 Impact Factor

Publication Stats

10k Citations
1,364.64 Total Impact Points

Institutions

  • 1984–2015
    • Università degli Studi di Bari Aldo Moro
      • Dipartimento di Scienze Biomediche ed Oncologia Umana (DIMO)
      Bari, Apulia, Italy
  • 2003–2014
    • Policlinico di Bari
      • Department of Allergy and Clinical Immunology
      Bari, Apulia, Italy
  • 2011
    • Ospedali Vito Fazzi
      Lecce, Apulia, Italy
  • 2006–2008
    • Università degli studi di Foggia
      • Department of Medical and Surgical Sciences
      Foggia, Apulia, Italy
  • 2005
    • CRO Centro di Riferimento Oncologico di Aviano
      • Division of Experimental and Clinical Pharmacology
      Aviano, Friuli Venezia Giulia, Italy