Publications by authors named "Giuseppa Penna"

31 Publications

Telomerase and telomere biology in hematological diseases: A new therapeutic target.

Leuk Res 2017 05 7;56:60-74. Epub 2017 Feb 7.

Dipartimento di Patologia Umana dell'Adulto e dell'Età Evolutiva "Gaetano Barresi", University of Messina Via Consolare Valeria, 1, 98125 Messina, Italy.

Telomeres are structures confined at the ends of eukaryotic chromosomes. With each cell division, telomeric repeats are lost because DNA polymerases are incapable to fully duplicate the very ends of linear chromosomes. Loss of repeats causes cell senescence, and apoptosis. Telomerase neutralizes loss of telomeric sequences by adding telomere repeats at the 3' telomeric overhang. Telomere biology is frequently associated with human cancer and dysfunctional telomeres have been proved to participate to genetic instability. This review covers the information on telomerase expression and genetic alterations in the most relevant types of hematological diseases. Telomere erosion hampers the capability of hematopoietic stem cells to effectively replicate, clinically resulting in bone marrow failure. Furthermore, telomerase mutations are genetic risk factors for the occurrence of some hematologic cancers. New discoveries in telomere structure and telomerase functions have led to an increasing interest in targeting telomeres and telomerase in anti-cancer therapy.
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http://dx.doi.org/10.1016/j.leukres.2017.02.002DOI Listing
May 2017

Efficacy of biosimilar granulocyte colony-stimulating factor versus originator granulocyte colony-stimulating factor in peripheral blood stem cell mobilization in de novo multiple myeloma patients.

Cytotherapy 2015 Oct 15;17(10):1485-93. Epub 2015 Jul 15.

Biotechnology Research Unit, Azienda Sanitaria Provinciale di Cosenza, Aprigliano (CS), Italy; Haematology Unit, Azienda Ospedaliera Cosenza, Italy.

Background Aims: Filgrastim and lenograstim are the standard granulocyte colony-stimulating factor (G-CSF) agents for peripheral blood stem cell mobilization (PBSC) in patients who undergo autologous stem cell transplantation.

Methods: To assess whether biosimilars are effective, we conducted a single-center, prospective study that included 40 consecutive de novo multiple myeloma patients who received cyclophosphamide 4 g/m(2) per day plus biosimilar filgrastim G-CSF to mobilize PBSC. These patients were compared with a group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF. The mean number of CD34+ cells/μL in the peripheral blood was 199.6 ± 207.4 in the biosimilar and 192.8 ± 154.7 in the originator group (P = 0.87). The median number of CD34+ cells/kg recipient collected was 11.5 ± 5.8 and 12.3 ± 5.3 in the biosimilar and originator groups, respectively (P = 0.51). The mobilization failure rate was 2.5% and 2.7% in the biosimilar filgrastim and originator filgrastim cohorts (P = NS), respectively.

Results: Twenty-nine patients in the biosimilar group and 28 patients in the originator group underwent autologous transplantation. There were no statistically significant differences between the biosimilar and originator G-CSF cohorts in terms of hematopoietic recovery parameters and transplant-related toxicities.

Conclusions: The efficacy of biosimilar G-CSF appears to be equivalent to the reference G-CSF.
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http://dx.doi.org/10.1016/j.jcyt.2015.05.010DOI Listing
October 2015

Vaccination of multiple myeloma: Current strategies and future prospects.

Crit Rev Oncol Hematol 2015 Nov 18;96(2):339-54. Epub 2015 Jun 18.

Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy-University of Messina, Messina, Italy.

Tumor immunotherapy holds great promise in controlling multiple myeloma (MM) and may provide an alternative treatment modality to conventional chemotherapy for MM patients. For this reason, a major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity. Several antigens that are able to induce specific T-cell responses are involved in different critical mechanisms for cell differentiation, inhibition of apoptosis, demethylation and proliferation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of dendritic cell/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs may synergize with immunotherapies. The task ahead is to evaluate these approaches in appropriate clinical settings, and to couple them with strategies to overcome mechanisms of immunoparesis as a means to induce more robust clinically significant immune responses.
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http://dx.doi.org/10.1016/j.critrevonc.2015.06.003DOI Listing
November 2015

The cancer stem cell hypothesis: a guide to potential molecular targets.

Cancer Invest 2014 Nov 25;32(9):470-95. Epub 2014 Sep 25.

Division of Hematology, University of Messina , Messina , Italy.

Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.
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http://dx.doi.org/10.3109/07357907.2014.958231DOI Listing
November 2014

Long-term results in multiple myeloma after high-dose melphalan and autologous transplantation according to response categories in the era of old drugs.

Clin Lymphoma Myeloma Leuk 2014 Apr 22;14(2):148-54. Epub 2013 Nov 22.

Hematology Unit, Azienda Ospedaliera dell'Annunziata, Cosenza, Italy.

Background: The aim of this study was to investigate the correlation between the long-term prognosis of multiple myeloma (MM) and the quality of response to therapy in a cohort of 173 patients treated with high-dose melphalan (HDM) and autologous transplantation in the era of old drugs.

Patients And Methods: A total of 173 patients with de novo MM who received a transplant between 1994 and 2010 were analyzed. VAD (vincristine, doxorubicin [Adriamycin], dexamethasone) was used as front-line regimen before auto-HPCT. The conditioning was HDM 200 mg/m(2). Patients were evaluated for clinical response using the criteria from the European Group for Blood and Marrow Transplantation, modified to include near complete remission (nCR) and very good partial remission (VGPR).

Results: The response distribution after transplantation in our series was complete remission (CR) in 33 cases (19%), nearly complete remission (nCR) in 38 cases (22%), VGPR in 30 cases (17%), partial remission (PR) in 65 cases (38%), and stable disease (SD) in 7 cases (4%). Patients were followed for 48 ± 36 months. Median overall survival (OS) was not reached for the CR group. Progression-free survival (PFS) was 122 months for CR, 55 months for nCR, 56 months for VGPR, 32 months for PR, and 22 months for SD. Significant differences in PFS and OS were found between the CR and nCR groups (P = .003 and P = .001, respectively), between the CR and VGPR groups (P = .002 and P = .001, respectively), and between the CR and PR groups (P = .000 and P = .001, respectively). Responses were clustered in 3 main categories, ie, CR, nCR + VGPR + PR, and SD. The respective 10-year PFS and OS values were 58% and 70% for CR, 15% and 18% for nCR + VGPR + PR, and 0% and 0% for SD.

Conclusion: The achievement of depth and prolonged response represents the most important prognostic factor. The relapse rate is low for patients in CR after 10 years of follow-up, possibly signifying a cure.
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http://dx.doi.org/10.1016/j.clml.2013.11.009DOI Listing
April 2014

Association of osteonecrosis of the jaws and POEMS syndrome in a patient assuming rituximab.

J Craniomaxillofac Surg 2014 Jun 22;42(4):279-82. Epub 2013 Jun 22.

Division of Hematology, Department of General Surgery and Oncology, AOU Policlinico G. Martino, Via Consolare Valeria, University of Messina, 98185 Messina, Italy.

POEMS syndrome, is a rare condition characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinaemia, and skin lesions. We report a rare case of a patient affected by Waldenström macroglobulinemia, who developed POEMS syndrome and who presented at the time of diagnosis with oral manifestations of the lymphoma and an osteonecrosis of the jaw (ONJ) after rituximab treatment. Although the etiology of ONJ is not known, it is likely that several factors are at play, including endothelial cell damage, decreased angiogenesis, and microvascular compromise. Our patient was treated with rituximab for a long period, and recent studies have demonstrated the possibility that rituximab, a monoclonal antibody directed against the CD20 can exert part of its anti-tumor action, through its action on angiogenesis. Although our report does not allow identification of rituximab as a new risk factor for the onset of the ONJ, further studies seem necessary to exclude a role of the antibody in the alterations of angiogenesis that could lead to the development of the syndrome after rituximab treatment.
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http://dx.doi.org/10.1016/j.jcms.2013.05.014DOI Listing
June 2014

Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma.

Eur J Haematol 2013 Jun 17;90(6):441-68. Epub 2013 Apr 17.

Division of Haematology, University of Messina, Messina, Italy.

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma (MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies (MoAbs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that MoAbs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, MoAbs have shown the ability to overcome resistance to these therapies. It remains to be defined how MoAb therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short-term induction therapy, frontline therapy in patients ineligible for ASCT, or long-term maintenance treatment.
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http://dx.doi.org/10.1111/ejh.12107DOI Listing
June 2013

Evaluation of interleukin-23 plasma levels in patients with polycythemia vera and essential thrombocythemia.

Cell Immunol 2012 Jul-Aug;278(1-2):91-4. Epub 2012 Aug 1.

School and Division of Allergy and Clinical Immunology, Department of Human Pathology, University of Messina, Italy.

Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis share the same acquired genetic lesion, JAK2V617F. It is believed that cytokines participate in the activation of JAK2V617F. In this study, we analyzed the plasma levels of interleukin (IL)-23, IL-10 and IL-22 in patients with PV and ET. In the same subjects we also performed analysis of the JAK2(V617F) mutation, and evaluated a possible relationship between interleukin levels and thrombotic complications or with the symptom pruritus. Plasma levels of IL-23 were significantly increased in all patients with MPN in comparison to controls. Moreover, there was a significant difference between the levels of IL-23 in patients affected by PV and those measured in controls (8.57±3.69pg/mL vs. 6.55±4.125pg/mL; p<0.03). No difference was found between IL-23 levels in ET patients and controls. No statistically significant differences were found between the levels of IL-23, Il-22 or IL-10 in PV or ET subjects with or without thrombosis, in patients with or without pruritus, or according the JAK2V617F burden. In PV patients the JAK2 burden and Hb levels correlated with occurrence of pruritus. Our study seems to point out a possible involvement of IL-23 in the pathogenesis of PV.
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http://dx.doi.org/10.1016/j.cellimm.2012.07.003DOI Listing
January 2013

Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review).

Int J Oncol 2012 Dec 1;41(6):1897-912. Epub 2012 Oct 1.

Division of Hematology, University of Messina, I-98125 Messina, Italy.

MicroRNAs (miRNAs) are small non-coding, endogenous, single-stranded RNAs. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and cancer. However, while the majority of miRNAs are found intracellularly, a significant number of miRNAs have been observed outside of cells, including various body fluids. Circulating miRNAs function as 'extracellular communication RNAs' that play an important role in cell proliferation and differentiation. MiRNA regulation is essential to many cellular processes, and escape from this regulatory network seems to be a common characteristic of several disease processes and malignant transformation. The interest in circulating miRNAs reflects in fact their central role in regulation of gene expression and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, metabolic, neurologic, immune-related diseases as well as others. In our review we aimed to summarize the data related to the action of cellular miRNAs on the onset of various diseases, thus bringing together some of the latest information available on the role of circulating miRNAs. Additionally, the role of circulating miRNAs could be particularly relevant in the context of neoplastic diseases. At least 79 miRNAs have been reported as plasma or serum miRNA biomarkers of solid and hematologic tumors. Circulating miRNA profiling could improve the diagnosis of cancer, and could predict outcome for cancer patients, while the profiling of alterations in circulating miRNA that may signal a predisposition to cancer, could also be a therapeutic target in these patients.
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http://dx.doi.org/10.3892/ijo.2012.1647DOI Listing
December 2012

Changes in advanced oxidation protein products, advanced glycation end products, and s-nitrosylated proteins, in patients affected by polycythemia vera and essential thrombocythemia.

Clin Biochem 2012 Nov 28;45(16-17):1439-43. Epub 2012 Jul 28.

Division of Haematology, University of Messina, Messina, Italy.

Objectives: Oxidative stress has a clear pro tumoral effect in myeloproliferative neoplasms (MPDs). In this study, we analyzed oxidative stress in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Design and methods We analyzed serum levels of advanced oxidation protein products (AOPPs) degradation, advanced glycation end products (AGEs), and protein nitrosylation in ET and PV patients. We also evaluated neutrophil gelatinase-associated lipocalin (NGAL) levels, an acute phase protein isolated in human neutrophils, the activation status of platelets and leukocytes, and the JAK2 (V617F) mutation status.

Results: AOPPs and s-nitrosylated proteins were significantly higher in PV and ET subjects as compared to healthy volunteers, while AGEs were higher in ET subjects with respect to controls. Moreover, in PV patients we found a correlation between s-nitrosylated proteins and Hb value. In ET patients AGEs were significantly higher in patients with thrombosis compared with those without thrombotic events.

Conclusions: Our results suggest that oxidative stress could play a role in the physiopathology of MPDs and in the onset of myeloproliferative associated thrombotic risk.
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http://dx.doi.org/10.1016/j.clinbiochem.2012.07.100DOI Listing
November 2012

Increase of novel biomarkers for oxidative stress in patients with plasma cell disorders and in multiple myeloma patients with bone lesions.

Inflamm Res 2012 Oct 7;61(10):1063-7. Epub 2012 Jun 7.

Department of Human Pathology, School and Division of Allergy and Clinical Immunology, University of Messina, Messina, Italy.

Objectives: Protein oxidation plays a key role in the pathogenesis of oncological diseases. In this study, we analyzed the oxidative stress in untreated multiple myeloma (MM) patients and in patients affected by monoclonal gammopathy of uncertain significance (MGUS).

Methods: We evaluated serum levels of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and protein nitrosylation in patients with monoclonal gammopathy and in control subjects.

Results: Serum levels of AOPPs and S-nitrosylated proteins were significantly increased in MM patients in comparison to controls and to MGUS subjects. Moreover, in MM patients the levels of AOPPs, AGEs and S-nitrosylated proteins were significantly higher in patients with bone lesions compared with those without lytic bone lesions.

Conclusions: MM is closely associated with oxidative stress and further investigation might provide an insight to understand a putative causal link between oxidative stress and MM disease onset and progression or MM complications.
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http://dx.doi.org/10.1007/s00011-012-0498-7DOI Listing
October 2012

Imatinib mesylate therapy induces reduction in neutrophil gelatinase-associated lipocalin serum levels and increase in leptin concentrations in chronic myeloid leukemia patients in molecular remission.

Acta Haematol 2012 4;127(1):1-6. Epub 2011 Oct 4.

Division of Hematology, Medicinal Chemistry Section, University of Messina, Italy.

The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.
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http://dx.doi.org/10.1159/000330948DOI Listing
February 2012

Nanoparticles in oncology: the new theragnostic molecules.

Anticancer Agents Med Chem 2011 Sep;11(7):669-86

Division of Haematology, University of Messina, Italy.

Cancer nanotherapeutics have shown promise in resolving some of the limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, low therapeutic indices, and poor oral bioavailability. Moreover, cancer nanotechnology has the potential of improving current approaches to cancer detection, diagnosis, and imaging. Recently, nanotechnology and molecular imaging have been combined to generate nanoparticles that simultaneously facilitate cancer therapy and diagnosis, the so called theragnostic nanoparticles. The aim of our review is to highlight recent developments within the context of the current knowledge of nanotechnology, to recall the experimental steps that have brought to the clinical development and application of nanoparticles, and explain the biological rationale for their use with oncologic patients. In particular, we summarize recent findings with respect to possible new applications for therapy and diagnosis, and their specific properties. Moreover, we report the more recent prospects in gene therapy, the possibility of using new drug delivery methods, the action of nanoparticles on the immune system and apoptosis, and the concrete possibility of detecting and characterizing circulating tumor cells or of developing new technologies in drug discovery.
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http://dx.doi.org/10.2174/187152011796817682DOI Listing
September 2011

Stevens-Johnson syndrome after lenalidomide therapy for multiple myeloma: a case report and a review of treatment options.

Hematol Oncol 2012 Mar 23;30(1):41-5. Epub 2011 Jun 23.

Division of Haematology, University of Messina, Messina, Italy.

Stevens- Johnson syndrome (SJS) is a severe and life-threatening condition. Although allopurinol, an antihyperuricemia drug, is the drug most commonly associated with SJS, more than 100 different causative drugs have been reported. Among hematologic drugs recently introduced into the market, drugs such as rituximab, imatinib, and bortezomib are reported. Here, we describe a patient with SJS while receiving lenalidomide in combination with prednisolone for treatment-naïve multiple myeloma. Although SJS has been reported rarely as an adverse reaction to Lenalidomide, this drug should be considered in the etiology of SJS, and the increased number of prescriptions of Lenalidomide for the therapy of multiple myeloma has to stress the awareness of its potentially serious side-effects.
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http://dx.doi.org/10.1002/hon.1000DOI Listing
March 2012

MDR-1 gene polymorphisms G2677T and C3435T in a case of Hodgkin's variant of Richter's syndrome.

Oncol Lett 2011 Mar 20;2(2):379-381. Epub 2011 Jan 20.

Division of Hematology, Policlinico G. Martino, University of Messina, Messina, Italy.

Richter's syndrome is defined as the transformation of low-grade lymphoma to a more aggressive high-grade malignant form, usually diffuse large B-cell lymphoma. Hodgkin's lymphoma variant of Richter transformation is relatively rare, and only approximately 100 cases have been reported in the literature. This study examined a case of a 53-year-old woman who developed Hodgkin's lymphoma almost 5 years after the diagnosis of chronic lymphocytic leukemia (CLL). The major points of interest regarding CLL with Hodgkin's transformation were also considered, such as the potential role of MDR-1 gene polymorphisms. The patient was evaluated for two MDR-1 gene polymorphisms, G2677T polymorphism in exon 21 and silent C3435T polymorphism in exon 26, to ascertain whether polymorphisms affect the risk of Hodgkin's lymphoma variant of Richter transformation and whether genomic polymorphisms provide prognostic information on the clinical progression of the disease. According to the data obtained, the analysis of polymorphisms in the MDR1 gene exons 21 and 26 revealed that the T2677T and T3435T alleles are not a predisposing factor to Richter transformation, while the presence of the wild-type genotype may be associated with a more favorable response to therapy.
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http://dx.doi.org/10.3892/ol.2011.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410599PMC
March 2011

Increased serum levels of neutrophil gelatinase-associated lipocalin in patients with essential thrombocythemia and polycythemia vera.

Leuk Lymphoma 2011 Jan 6;52(1):101-7. Epub 2010 Dec 6.

Division of Hematology, University of Messina, Messina, Italy.

Neutrophil gelatinaase-associated lipocalin (NGAL) is a glycoprotein bound with matrix metalloproteinase-9 (MMP-9) in human neutrophils, and elevated tissue NGAL expression has been documented in different infectious and inflammatory conditions. Recent evidence suggests that NGAL expression is induced in many types of human cancer. Moreover, NGAL is required for BCR-ABL-induced tumorigenesis. The aim of the present study was to measure serum levels of NGAL in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We also evaluated NGAL levels in patients with ET and PV with and without thrombotic events, to explore a possible correlation of NGAL with platelet and leukocyte activation, and in patients with sepsis. Serum NGAL levels in the study population were significantly higher than in healthy adults and in subjects with sepsis. A correlation between NGAL and the number of white cells and neutrophils was found in patients with PV and ET. NGAL serum levels were not different depending on the presence or not of the JAK2 mutation, and a mutant allele dosage effect was not observed for NGAL levels. Patients with PV and ET with thrombosis did not have significantly higher levels of NGAL. We were unable to demonstrate a significant association between serum NGAL levels and CD11b or CD62 expression. In conclusion, our study reports evidence demonstrating that increased levels of NGAL appear to be a characteristic of patients with PV and ET.
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http://dx.doi.org/10.3109/10428194.2010.531413DOI Listing
January 2011

Novel therapeutic strategies in multiple myeloma: role of the heat shock protein inhibitors.

Eur J Haematol 2011 Feb 20;86(2):93-110. Epub 2010 Dec 20.

Division of Haematology, University of Messina, Messina, Italy.

Despite advances in understanding the molecular pathogenesis of multiple myeloma and promising new therapies, almost all patients eventually relapse with resistant disease. There is therefore a strong rationale for combining novel therapies that target intrinsic molecular pathways mediating multiple myeloma cell resistance. One such protein family is the heat shock proteins (HSP), especially the HSP90 family. Heat shock protein inhibitors have been identified as promising cancer treatments as, while they only inhibit a single biologic function, the chaperone-protein association, their effect is widespread as it results in the destruction of numerous client proteins. This article reviews the preclinical and clinical data, which support the testing of HSP90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of HSP90 inhibitors in multiple myeloma.
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http://dx.doi.org/10.1111/j.1600-0609.2010.01558.xDOI Listing
February 2011

Cardiac involvement in patients with hematologic malignancies.

J Investig Med 2010 Oct;58(7):859-74

Division of Hematology, University of Messina, Messina, Italy.

Authors have reviewed literature about the management of patients with cardiologic disease occurring secondary to hematologic pathology itself or its therapy, with a focus on infiltration of myocardium in acute and chronic leukemia, lymphoma, multiple myeloma, and hypereosinophilic syndrome. Moreover, they evaluated chemotherapy-associated toxicity, particularly for new drugs such as monoclonal antibody therapy, tyrosine kinase inhibitors, arsenic trioxide, bortezomib, and epigenetic therapy. In fact, cardiac toxicity may range from asymptomatic subclinical abnormalities, such as electrocardiographic changes and left ventricular ejection decline, to life-threatening events and lead to chemotherapy dose reduction and delay and, in some cases, for patients with severe side effects, discontinuation of treatment. Finally, they discussed on the identification of early markers of cardiac injury and on cardiac stem cell therapy as a promising approach to facilitate myocardial regeneration.
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http://dx.doi.org/10.231/JIM.0b013e3181efbc4eDOI Listing
October 2010

Bisphosphonates induce apoptosis of circulating endothelial cells in multiple myeloma patients and in subjects with bisphosphonate-induced osteonecrosis of the jaws.

Acta Haematol 2010 15;124(2):79-85. Epub 2010 Jul 15.

Division of Hematology, University of Messina, Messina, Italy.

Bisphosphonates (BPs) are the current standard of care for bone lesions in patients with multiple myeloma (MM) but they are associated with a number of side effects such as osteonecrosis of the jaw. The exact mechanisms of osteonecrosis are not elucidated, and its physiopathology is based on several hypotheses such as a decrease in bone remodeling or an inhibitory effect on angiogenesis. The aim of our study was to investigate the mechanism involved in the pathogenesis of osteonecrosis. We examined the apoptosis of circulating endothelial progenitor cells in MM subjects before and after BP treatment and in osteonecrosis patients using a flow-cytometric analysis. Our data showed an increase in endothelial cell apoptosis in MM patients after BP administration and in osteonecrosis subjects. Our study seems in agreement with the hypothesis that BPs can inhibit angiogenesis interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis.
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http://dx.doi.org/10.1159/000313787DOI Listing
October 2010

Immunohistochemial evaluation of sarcoglycans and integrins in gingival epithelium of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw.

Oncol Rep 2010 Jul;24(1):129-34

Division of Maxillofacial Surgery, University of Messina, Messina, Italy.

Osteonecrosis of the jaw (ONJ) is an adverse outcome associated to bisphosphonate treatment. However, it is not known whether the ONJ lesion originates in the bone, or whether it may initiate in the oral mucosa. The aim of our study was to evaluate the pattern of basal lamina of oral mucosa after bisphosphonate administration and to analyze the structural damage of the mucosa in ONJ patients, and in subjects treated with bisphosphonates without osteonecrosis. By immunohistochemistry, we evaluated changes in basement membrane by expression of signalling proteins, laminin, and type IV collagen. All tested proteins were almost absent in basal lamina and mucosa of subjects treated with bisphosphonates without osteonecrosis, whereas in mucosa of patients with ONJ, they showed a clearly detectable pattern of the same proteins, specifically in basal lamina, but less in comparison to control samples. Moreover, in pathological mucosa, the clearly detectable staining pattern for VEGF indicated a massive neoangiogenesis. Bisphosphonates induce changes in expression of proteins also in oral mucosa. The increase of these proteins in basal lamina, and the neo-angiogenesis, concomitant with formation of the lesion, could indicate a compensative behaviour in the remodelling of the gingival mucosa in order to restore the epithelial architecture.
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http://dx.doi.org/10.3892/or_00000837DOI Listing
July 2010

Epigenetic therapy in myelodysplastic syndromes.

Eur J Haematol 2010 Jun 23;84(6):463-73. Epub 2010 Feb 23.

Division of Hematology, University of Messina, Messina, Italy.

The wide spectrum of clonal hematopoietic disorders that fall under the broad diagnostic category of myelodysplastic syndromes (MDS) consist of a family of bone marrow malignancies - with ineffective, inadequate, and dysplastic hematopoiesis, and with an increased risk of life-threatening infections, bleeding, and progression to acute myeloid leukemia (AML) - that are characterized by a deep heterogeneity on the clinical, biologic and prognostic level. The intrinsic complexity of this group of disorders and the frequent association with one or more comorbidities have limited for many years the number of effective treatment options available: most patients are, indeed, still managed by supportive care measures, with just a minority of them being eligible for allogeneic stem cell transplantation, which is still the only potentially curative modality. In the last two decades, the progressively better understanding of MDS biology has shown how an abnormal epigenetic modulation might play a crucial part in the pathogenesis and in the process of biologic evolution of these disorders. Moreover, pharmacological agents that target the so-called epigenome have shown a significant clinical activity for diverse hematologic malignancies, including MDS. The aim of this review is to highlight recent developments within the context of current knowledge of MDS and its altered epigenetic regulation and to recall the experimental steps that have brought to the clinical development and application of epigenetic modifiers, such as azacytidine and decitabine, trying to explain the biologic rationale for their use in this setting.
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http://dx.doi.org/10.1111/j.1600-0609.2010.01433.xDOI Listing
June 2010

Absence of the V617F JAK2 mutation in the lymphoid compartment in a patient with essential thrombocythemia and B-chronic lymphocytic leukemia and in two relatives with lymphoproliferative disorders.

Acta Haematol 2009 7;122(1):46-9. Epub 2009 Oct 7.

Division of Hematology, University of Messina, Policlinico G. Martino, Messina, Italy.

Background: Myeloproliferative neoplasms likely involve both myeloid and lymphoid lineages. Nevertheless, the coincidence of chronic myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon.

Methods: We report a case of a patient having essential thrombocythemia (ET) and B-chronic lymphocytic leukemia (B-CLL). In this patient and in 2 relatives with lymphoproliferative disorders, we searched for JAK2(V617F) mutation in lymphocytes.

Results: In the patient with ET and B-CLL, we identified homozygous JAK2(V617F) mutation in the granulocytic compartment. Both relatives were heterozygous for JAK2(V617F) mutation, whereas no mutation signal could be detected in the lymphoid compartment of all 3 patients.

Conclusion: Our results seem to confirm that CLL cases are negative for JAK2(V617F) mutation in B- and T-lymphocyte populations.Presence of JAK2(V617F) mutation in subjects without myeloproliferative diseases could indicate an increased risk of a future myeloproliferative neoplasm development.
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http://dx.doi.org/10.1159/000243721DOI Listing
November 2009

Exacerbation of chronic idiopathic thrombocytopenic purpura following reactivation of an occult hepatitis B.

Med Oncol 2010 Sep 23;27(3):912-4. Epub 2009 Sep 23.

Division of Hematology, University of Messina, Messina, Italy.

Immune thrombocytopenia is a disease mediated by platelet autoantibodies that accelerate platelet destruction and inhibit their production. Most cases are considered idiopathic, whereas others are secondary to coexisting conditions such as infectious diseases. All hepatotropic viruses seem able to cause thrombocytopenia. The advent of molecular techniques has revealed the possible persistence of hepatitis B virus genome in HBsAg-negative individuals with or without serologic markers of previous infection. This form of infection is named occult. We report a case of autoimmune thrombocytopenia associated with acute reverse seroconversion of hepatitis B in a patient who was initially hepatitis B virus surface antigen negative and hepatitis B virus surface antibody positive. The search for occult HBV infection before immunosuppressive therapy and monitoring for reactivation is today diagnostic standard and several reports have been presented in literature about HBV reactivation following immunosuppressive therapy. In our patient, reactivation of dormant HBV happened prior to any immunosuppressive therapy. The case we report offers the occasion to emphasize the importance of medium-term and long-term hemovigilance also in other kind of patients than in subjects on immunosuppressive therapy. A deeper follow-up is advisable even in patients showing an unexplainable worsening of their hematological conditions.
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http://dx.doi.org/10.1007/s12032-009-9305-xDOI Listing
September 2010

JAK2 V617F-positive latent essential thrombocythemia and splanchnic vein thrombosis: the role of bone marrow biopsy for the diagnosis of myeloproliferative disease.

Acta Haematol 2009 29;121(4):218-20. Epub 2009 May 29.

Division of Haematology, University of Messina, Via Colapesce 20, Messina, Italy.

Background: Splanchnic vein thrombosis (SVT) is a severe complication of essential thrombocythemia (ET). No clear explanation has been given for the occurrence of thrombosis in this unusual site in patients with ET, but the existence of a specific association between unexplained SVT and the JAK2 mutation has been reported.

Methods And Results: The present study describes SVT (portal and splenic vein thrombosis) in a young woman as the first presenting symptom of latent ET. Extensive screening for thrombophilia was negative. Our patient in fact did not fulfill the WHO diagnostic criteria for myeloproliferative disease (MPD), while she had splenomegaly and developed features suggestive of latent ET during follow-up.

Conclusions: In these patients with SVT, the detection of JAK2(V617F) mutation is diagnostic for masked MPD as could be documented by bone marrow histopathology. The presence of JAK2(V617F) mutation should be considered per se a prothrombotic state for cerebral, coronary and peripheral microvascular disturbances and for SVT but not for deep vein thrombosis. Anticoagulation is the treatment of choice for all SVT and proper treatment of the MPD is recommended in patients with SVT associated with the JAK2(V617F) mutation.
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http://dx.doi.org/10.1159/000221962DOI Listing
August 2009