Publications by authors named "Vincenzo Martinelli"

31 Publications

A novel ultrasound-based approach to investigate extramedullary haematopoiesis in foetal spleen.

Am J Blood Res 2021 15;11(1):84-92. Epub 2021 Feb 15.

Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise Campobasso, Italy.

Foetal spleen is described as a transient focus of haematopoiesis between the 3 and 5 month of gestation: this function is however entirely replaced by the bone marrow before the end of pregnancy. This study identifies haematopoiesis in foetal spleen by exploring changes of echogenicity during its development throughout gestation. Two intervals of pregnancy were studied: Mid-Pregnancy (Mid-P, 19-23 weeks) and End-Pregnancy (End-P, 37-41 weeks). The foetal spleen was investigated in 80 pregnant women (41 vs 39). Due to quality criteria the comparison was made between 60 images (30 Mid-P vs 30 End-P). The acquisition of splenic parenchyma was followed by clustering segmentation. We identified two new parameters resulted from the clustering segmentation: Dark Ratio (DR) and Light Ratio (LR). These are related to splenic echogenicity expressing the percentage of dark and light signal in the clustered image, influenced by blood cellularity. The mean of DR value was different among the 2 groups (0.0631 vs 0.0483, ), while LR did not show any significant differences. We conclude that DR may represent a reliable radiomic parameter in the determination of extramedullary haematopoiesis in the spleen.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010597PMC
February 2021

Long-term safety and efficacy of givinostat in polycythemia vera: 4-year mean follow up of three phase 1/2 studies and a compassionate use program.

Blood Cancer J 2021 Mar 6;11(3):53. Epub 2021 Mar 6.

Clinical R&D Department, Italfarmaco S.p.A, Cinisello Balsamo, Italy.

Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow, mainly due to a Janus kinase 2 gene mutation (JAK2). Givinostat, a histone-deacetylase inhibitor that selectively targets JAK2 cell growth, has demonstrated good efficacy and safety in three phase 1/2 studies in patients with PV. This manuscript focuses on the 4-year mean (2.8 year median) follow-up of an open-label, long-term study that enrolled 51 patients with PV (out of a total of 54 with MPN) who received clinical benefit from givinostat in these previous studies or on compassionate use, and who continued to receive givinostat at the last effective and tolerated dose. The primary objectives are to determine givinostat's long-term safety and tolerability, and efficacy evaluated by the investigators according to internationally recognized response criteria. During follow-up, only 10% of PV patients reported Grade 3 treatment-related adverse events (AEs), while none had Grade 4 or 5 treatment-related AEs. The overall response rate for the duration of follow-up was always greater than 80% in patients with PV. In conclusion, givinostat demonstrated a good safety and efficacy profile in patients with PV, data supporting long-term use in this population.
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http://dx.doi.org/10.1038/s41408-021-00445-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936975PMC
March 2021

Clinical, Immunological, and Functional Characterization of Six Patients with Very High IgM Levels.

J Clin Med 2020 Mar 17;9(3). Epub 2020 Mar 17.

Department of Translational Medical Sciences-Section of Pediatrics, Federico II University, 80131 Naples, Italy.

Very high IgM levels represent the hallmark of hyper IgM (HIGM) syndromes, a group of primary immunodeficiencies (PIDs) characterized by susceptibility to infections and malignancies. Other PIDs not fulfilling the diagnostic criteria for HIGM syndromes can also be characterized by high IgM levels and susceptibility to malignancies. The aim of this study is to characterize clinical phenotype, immune impairment, and pathogenic mechanism in six patients with very high IgM levels in whom classical HIGM syndromes were ruled out. The immunological analysis included extended B-cell immunophenotyping, evaluation of class switch recombination and somatic hypermutation, and next generation sequencing (NGS). Recurrent or severe infections and chronic lung changes at the diagnosis were reported in five out of six and two out of six patients, respectively. Five out of six patients showed signs of lymphoproliferation and four patients developed malignancies. Four patients showed impaired B-cell homeostasis. Class switch recombination was functional in vivo in all patients. NGS revealed, in one case, a pathogenic mutation in . In a second case, the gene, implicated in B- and T-cell development, survival, and activity was identified as a potential candidate gene. Independent of the genetic basis, very high IgM levels represent a risk factor for the development of recurrent infections leading to chronic lung changes, lymphoproliferation, and high risk of malignancies.
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http://dx.doi.org/10.3390/jcm9030818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141334PMC
March 2020

Combined Oral Fentanyl Citrate and Midazolam as Premedication for Bone Marrow Aspiration and Biopsy in Patients with Hematological Malignancies: A Randomized, Controlled and Patient-Blinded Clinical Trial.

J Clin Med 2020 Feb 1;9(2). Epub 2020 Feb 1.

Hematology, Department of Clinical Medicine and Surgery, AOU Federico II, 80131 Naples, Italy.

Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the routinely used local infiltration anesthesia (LIA) with lidocaine is unable to provide pain relief during the most uncomfortable phases. The primary endpoint of the present randomized, patient-blinded trial was to evaluate the efficacy of an opioid and benzodiazepine combination plus LIA (sedoanalgesia) in patients undergoing BMAB for hematological malignancies. The secondary endpoint was the safety of the procedure in an outpatient setting. Ancillary assessments were anticipatory anxiety related to pain recall in the event of re-biopsy, and adequacy of bone tissue harvested. Patients were randomly assigned to one of 2 arms to receive either sedoanalgesic placebo plus LIA (standard group) or oral fentanyl citrate 200 μg plus oral midazolam 5 mg plus LIA (combo group) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numerical Rating Scale (NRS: 0-10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b and T3) and evaluating the degree of discomfort at each time (T) in both groups. One hundred and sixteen patients were eligible for the study. At T2b (time of biopsy) and T3 (time after biopsy), a significantly lower perception of pain was registered in the combo group. Moreover, there were no significant sedoanalgesia-related side-effects. Finally, histological specimens were higher in quality in the combo group. Sedoanalgesia was highly effective in reducing pain during biopsy, diminished anticipatory anxiety in patients undergoing re-biopsy and led to fewer non-diagnostic specimens being harvested.
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http://dx.doi.org/10.3390/jcm9020395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074337PMC
February 2020

An 1H NMR study of the cytarabine degradation in clinical conditions to avoid drug waste, decrease therapy costs and improve patient compliance in acute leukemia.

Anticancer Drugs 2020 01;31(1):67-72

Hematology, Department of Clinical Medicine and Surgery, AOU Federico II, Naples.

Cytarabine, the 4-amino-1-(β-D-arabinofuranosyl)-2(1H)-pyrimidinone, (ARA-C) is an antimetabolite cytidine analogue used worldwide as key drug in the management of leukaemia. As specified in the manufacturers' instructions, once the components-sterile water and cytarabine powder-are unpackaged and mixed, the solution begins to degrade after 6 hours at room temperature and 12 hours at 4°C. To evaluate how to avoid wasting the drug in short-term, low-dose treatment regimens, the reconstituted samples, stored at 25°C and 4°C, were analyzed every day of the test week by reversed-phase HPLC and high-field NMR spectroscopy. All the samples remained unchanged for the entire week, which corresponds to the time required to administer the entire commercial drug package during low-dose therapeutic regimens. The drug solution was stored in a glass container at 4°C in an ordinary freezer and drawn with sterile plastic syringes; during this period, no bacterial or fungal contamination was observed. Our findings show that an cytarabine solution prepared and stored in the original vials retains its efficacy and safety and can, therefore, be divided into small doses to be administered over more days, thus avoiding unnecessary expensive and harmful waste of the drug preparation. Moreover, patients who require daily administration of the drug could undergo the infusion at home without need to go to hospital. The stability of the aliquots would help decrease hospitalization costs.
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http://dx.doi.org/10.1097/CAD.0000000000000850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903421PMC
January 2020

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis.

Ann Hematol 2019 Aug 14;98(8):1933-1936. Epub 2019 Jun 14.

Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Ruxolitinib is the only commercially available JAK1/2 inhibitor approved for the treatment of myelofibrosis-related splenomegaly and symptoms. During treatment, as rare conditions, leukocytosis and/or thrombocytosis could develop and the management of these situations is not well established. We report here 53 myelofibrosis patients that received a combination of hydroxyurea and ruxolitinib because of uncontrolled myeloproliferation. Both drugs were administered outside clinical trials. At 48 weeks, a significant reduction in leucocyte and platelet counts was observed (p = 0.02 and p = 0.04, respectively). Additionally, the spleen volume decreased from a median value of 10 cm below the left costal margin (range, 0-10) to 6 cm (range, 0-15). The rate of spleen response increased from 14% at the start of the combination to 45% after 48 weeks. The safety profile of the combination was consistent with that observed with ruxolitinib single agent. These data require further confirmation in large cohorts of patients prospectively assessed.
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http://dx.doi.org/10.1007/s00277-019-03727-6DOI Listing
August 2019

Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis.

Cancer Med 2019 06 17;8(6):2802-2809. Epub 2019 Apr 17.

Department of Medicine and Surgery, Hematology and Hematopoietic Stem Cell Transplant Center, University of Naples Federico II, Naples, Italy.

Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi-center study enrolled 20 adult patients with intermediate- or high-risk primary MF, post- polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib-hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow-up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF.
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http://dx.doi.org/10.1002/cam4.2147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558489PMC
June 2019

GATA-1: A potential novel biomarker for the differentiation of essential thrombocythemia and myelofibrosis.

J Thromb Haemost 2019 06 25;17(6):896-900. Epub 2019 Apr 25.

School of Life Sciences, University of Lincoln, Lincoln, UK.

Essentials The BCR-ABL negative myeloproliferative neoplasms are subjected to unknown phenotypic modifiers. GATA-1 is upregulated in ET patients, regardless of treatment regimen or mutational status. Myelofibrosis (MF) megakaryocytes displayed decreased GATA-1 staining. GATA-1 may have utility as a diagnostic marker in ET and in its differential diagnosis from MF. ABSTRACT: Background The BCR-ABL-negative myeloproliferative neoplasms, i.e., polycythemia vera, essential thrombocythemia (ET), and myelofibrosis (MF), are characterized by mutations in JAK2, CALR, or MPL. However, an as yet unknown factor drives the precise disease phenotype. The hematopoietic transcription factor GATA-1 and its downstream targets NFE2 and FLI1 are responsible for determining erythroid and megakaryocyte lineages during hematopoietic stem cell differentiation. Previous studies have demonstrated a low level of GATA-1 expression in megakaryocytes from patients with MF. Objectives and methods The expression of GATA-1, NFE2 and FLI1 was studied for changes in the peripheral blood (PB) of ET patients. Peripheral blood samples were obtained from 36 ET patients, 14 MF patients, and seven healthy control donors. Total RNA from PB mononuclear cells (PBMCs) was extracted, and quantitative polymerase chain reaction was used to determine relative changes in gene expression. Protein levels of GATA-1 were also determined in bone marrow sections from ET and MF patients. Results GATA-1 mRNA was upregulated in ET patients, regardless of treatment regimen or mutational status. FLI1 expression was significantly downregulated, whereas NFE2 expression was unaffected by changes in GATA-1 mRNA levels. Megakaryocytes from ET patients showed increased protein levels of GATA-1 as compared with those from MF patients. Conclusions Our results confirmed, in PB, our previous data demonstrating elevated levels of GATA-1 mRNA in total bone marrow of ET patients. GATA-1 mRNA levels are independent of cytoreductive therapies, and may have utility as a diagnostic marker in ET and in its differential diagnosis from MF.
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http://dx.doi.org/10.1111/jth.14433DOI Listing
June 2019

The use of erythropoiesis-stimulating agents is safe and effective in the management of anaemia in myelofibrosis patients treated with ruxolitinib.

Br J Haematol 2018 09 9;182(5):701-704. Epub 2018 Jul 9.

Haematology Division, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Torino, Italy.

Erythropoiesis-stimulating agents (ESAs) were combined with ruxolitinib in 59 anaemic myelofibrosis patients (93% with Dynamic International Prognostic Scoring System [DIPSS] intermediate-2/high risk; 52·5% transfusion-dependent). Anaemia response (AR) rate was 54% and 76% of patients responded at 5 years. A further 15% displayed minor improvement in anaemia and 78% of patients reduced spleen size. Endogenous erythropoietin levels <125 u/l correlated with a higher AR rate (63% vs. 20%, P = 0·008). No thrombotic events or other toxicities occurred. Overall survival was 62% at 4 years, influenced by DIPSS and transfusion dependency. ESAs seem effective in improving anaemia in ruxruxolitinib-treated myelofibrosis patients.
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http://dx.doi.org/10.1111/bjh.15450DOI Listing
September 2018

Lenalidomide at the dose of 25 mg every other day in patients affected by multiple myeloma and renal failure: a real-life experience.

Anticancer Drugs 2018 04;29(4):371-372

Departments of Clinical Medicine, Division of Hematology.

Renal impairment (RI) is a relevant complication of patients affected by multiple myeloma (MM); it can be present in up to 30-35% of newly diagnosed MM and is linked to a poor outcome. However, early recognition and early treatment with novel agents can overcome the negative impact of RI and even reverse kidney damage in most cases. Lenalidomide, available as an oral compound, is an immunomodulatory drug with both antiproliferative and immunomodulatory activity that is largely used in the management of MM. Dose reduction is mandatory in RI; however, there is no theoretical assumption against the possibility that protracting the time of full standard doses can be equally effective and tolerated by patients requiring reduced doses. In this report, we describe our retrospective experience, in 18 patients, with the administration of lenalidomide 25 mg every other day for patients with MM and RI. The overall response ratio was 66.5%. More than half (61.1%) of the patients had a renal response. The median progression-free survival was 8 months (range: 3-18 months). No serious adverse event occurred during treatment, and it was never necessary to disrupt or delay treatment for toxicity. These preliminary observations point to a significant therapeutic effect of lenalidomide, at the dose of 25 mg every other day for 21 days, with logistic and economic advantages. However, these results should be validated by controlled studies involving larger numbers of patients.
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http://dx.doi.org/10.1097/CAD.0000000000000604DOI Listing
April 2018

Secondary syphilis mimicking malignancy: A case report and review of literature.

J Infect Chemother 2017 Aug 26;23(8):576-578. Epub 2017 Apr 26.

Department of Advanced Biomedical Sciences, University of Naples "Federico II", Italy.

A 56-year-old man developed disseminate lymphadenopathies, associated with hepato-splenomegaly, fever, nocturnal sweating and weight loss. Imaging studies in particular FDG-PET/CT raised the suspicion of a malignant disease. But blood flow cytometry assay for B/T cell clonality was negative and fine-needle biopsy of enlarged laterocervical lymph node showed a not specific "reactive hyperplasia". Four months later, the patient developed a non-itching rash; since a further anamnestic investigation revealed an history of high-risk sexual intercourse, the patient underwent serological tests for Treponema pallidum that were positive at high titer, after a first negative screening. Made the diagnosis of secondary syphilis, the patient responded to the treatment with benzyl penicillin with complete resolution of symptoms. This case highlights the importance of carefully screening the patients with suspected lymphoadenopathies also for lue, particularly in presence of behavioral risk factors.
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http://dx.doi.org/10.1016/j.jiac.2017.03.003DOI Listing
August 2017

Unbiased pro-thrombotic features at diagnosis in 977 thrombocythemic patients with Philadelphia-negative chronic myeloproliferative neoplasms.

Leuk Res 2016 07 7;46:18-25. Epub 2016 Apr 7.

Hematology Dept., University Hospital, Firenze, Italy.

In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thrombotic and/or cytoreductive treatment in the follow-up may affect the evaluation of the pro-thrombotic weight of the clinical and biological characteristics at diagnosis. In order to avoid this potential confounding effect, we investigated the relationship between prior thrombosis (PrTh: thrombosis occurred before diagnosis and before treatment) and the characteristics at diagnosis in 977 thrombocythemic patients with MPN, reclassified according to the WHO 2008 criteria. PrTh occurred in 194 (19.9%) patients, with similar rates in the different MPNs. In multivariate analysis, PrTh rate was significantly related to minor thrombocytosis (platelets ≤700×10(9)/L), leukocytosis (leukocytes >10×10(9)/L), higher hematocrit (HCT >45%), JAK2 V617F mutation, older age, and cardiovascular risk factors (CVRFs). The highest PrTh rate (33.9%) was associated with the coexistence of minor thrombocytosis and leukocytosis. Of note, the inverse relationship between PrTh rate and platelet count is consistent with the hemostatic paradox of thrombocytosis. In conclusion, this analysis in MPN patients disclosed the unbiased characteristics at diagnosis with a pro-thrombotic effect. Moreover, it suggests that the optimal control of blood cells counts, and CVRFs might be of utmost importance in the prevention of thrombosis during the follow-up.
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http://dx.doi.org/10.1016/j.leukres.2016.04.004DOI Listing
July 2016

A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy.

Br J Haematol 2013 Jun 10;161(5):688-94. Epub 2013 Apr 10.

Haematology, Ospedale Papa Giovanni XXIII, Bergamo, Italy.

Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients.
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http://dx.doi.org/10.1111/bjh.12332DOI Listing
June 2013

Erythrocytosis after liver transplantation: the experience of a university hospital.

Liver Transpl 2013 Apr 20;19(4):420-4. Epub 2013 Mar 20.

Hepatology Unit, AORN A. Cardarelli, Naples, Italy.

The prevalence and causes of erythrocytosis after liver transplantation have never been studied, even though this condition is known to predispose patients to thrombosis leading to graft failure or death. Erythrocytosis after orthotopic liver transplantation (OLT) can be defined as an increase in the red cell mass >125% in patients without a pre-OLT history of this condition. The study population was composed of 96 patients: 33 had undergone transplantation for a hepatitis B virus (HBV) infection (18 had a hepatitis D virus coinfection), 43 had undergone transplantation for a hepatitis C virus infection, 9 had undergone transplantation for alcohol abuse, and 11 had undergone transplantation for other causes [autoimmune liver disease (6), Wilson's syndrome (1), or cryptogenetic liver cirrhosis (4)]. Idiopathic erythrocytosis was reported in 11 male patients with a history of HBV infection. Patients with the diagnosis of erythrocytosis underwent phlebotomy every 3 weeks until the hematocrit level reached 45%, and this was repeated if the level exceeded 49%, so no patient presented with cardiovascular accidents during the follow-up. In conclusion, a history of HBV infection, male sex, and hepatitis B immune globulin therapy are all possible cofactors for an increased risk of erythrocytosis in OLT patients.
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http://dx.doi.org/10.1002/lt.23606DOI Listing
April 2013

Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN.

Am J Hematol 2012 May 4;87(5):552-4. Epub 2012 Apr 4.

Hematology Unit, AOU Careggi Largo Brambilla 3, Firenze, IT.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of "intolerance" to HU have been described;patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.
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http://dx.doi.org/10.1002/ajh.23160DOI Listing
May 2012

Low impact of cardiovascular adverse events on anagrelide treatment discontinuation in a cohort of 232 patients with essential thrombocythemia.

Leuk Res 2011 Dec 20;35(12):1557-63. Epub 2011 Jul 20.

Hematology Institute L e A Seragnoli, University Hospital, Bologna, Italy.

This retrospective study of the thrombocythemia Italian registry (RIT) documented that 71 (30.6%) out of 232 ET patients experienced 88 cardiovascular adverse events (CV-AEs) during anagrelide treatment (522 pt-y). The rate of CV-AEs was: 24.1% for palpitations, 4.3% for angina, 3.5% for arterial hypertension, 3.0% for congestive heart failure, 1.8% for arrhythmia, 0.9% for AMI, 0.4% for pericardial effusion. CV-AEs led to treatment discontinuation in nine (3.9%) patients, while in the remaining cases they were managed by pharmacological intervention and/or patient life style improvement. CV-AEs had no relationship with patient characteristics (including older age). A significant relationship was found only with a higher anagrelide induction dose. In the absence of any agreed protocol, a cardiovascular instrumental evaluation (CV-IE) was performed in 102 (44%) patients before commencement of anagrelide (with higher rate after the anagrelide/Xagrid EMA approval of 2004), and in 84 (36%) patients during treatment. Patients with and without CV-IEs, who resulted completely balanced for all their characteristics, did not significantly differ in the occurrence of CV-AEs. In conclusion, this study on ET patients treated with anagrelide shows that CV-AEs, equally distributed in younger and older subjects, were mostly mild and easily manageable, allowing safe treatment continuation in the majority of cases. Moreover, routinely performing a CV-IE did not appear to anticipate the occurrence of CV-AEs.
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http://dx.doi.org/10.1016/j.leukres.2011.06.030DOI Listing
December 2011

Preferential nuclear accumulation of JAK2V617F in CD34+ but not in granulocytic, megakaryocytic, or erythroid cells of patients with Philadelphia-negative myeloproliferative neoplasia.

Blood 2010 Dec 22;116(26):6023-6. Epub 2010 Sep 22.

Hematology Division, Department of Biochemistry and Medical Biotechnology, University Federico II, Naples, Italy.

Recently, Dawson et al identified a previously unrecognized nuclear role of JAK2 in the phosphorylation of histone H3 in hematopoietic cell lines. We searched nuclear JAK2 in total bone marrow (BM) cells and in 4 sorted BM cell populations (CD34(+), CD15(+), CD41(+), and CD71(+)) of 10 myeloproliferative neoplasia (MPN) patients with JAK2V617F mutation and 5 patients with wild-type JAK2 MPN. Confocal immunofluorescent images and Western blot analyses of nuclear and cytoplasmic fractions found nuclear JAK2 in CD34(+) cells of 10 of 10 JAK2-mutated patients but not in patients with wild-type JAK2. JAK2 was predominantly in the cytoplasmic fraction of differentiated granulocytic, megakaryocytic, or erythroid cells obtained from all patients. JAK2V617F up-regulates LMO2 in K562 and in JAK2V617F-positive CD34(+) cells. The selective JAK2 inhibitor AG490 normalizes the LMO2 levels in V617F-positive K562 and restores the cyto-plasmic localization of JAK2.
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http://dx.doi.org/10.1182/blood-2010-08-302265DOI Listing
December 2010

[Italian nursing survey of cardiological intensive care units].

G Ital Cardiol (Rome) 2010 May;11(5):412-24

Dipartimento di Anestesia e Rianimazione, Ospedale S. Chiara, APSS, Trento.

Background: The recent evolution of nursing management of cardiovascular disease has led to significant changes in specific healthcare processes. The aim of this study is to present the first nursing survey of Italian intensive cardiac care units (ICCUs).

Methods: In March and April 2007, a questionnaire investigating the main problems concerning ICCU organization, specifically addressed to nursing care, has been mailed to all the operative Italian ICCUs. The questionnaire investigated staff characteristics, education and training, daily work organization, risk management strategies, and nursing research.

Results: For a more detailed analysis, the ICCUs were divided into three levels (standard, medium and high) based on their technological equipment, and in particular mechanical ventilatory assistance and intra-aortic balloon pumping availability. A high proportion of ICCUs (347/385, 90%) answered to the questionnaire and an analysis of the responses revealed no significant differences between the three main geographical areas of Italy (North, Center, South).

Conclusions: Despite some organizational and staffing problems, the survey confirmed the high level of routine nursing care, the strong tendency towards the integration of different professional competencies among the staff, and the high degree of standardization.
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May 2010

Outcome of 122 pregnancies in essential thrombocythemia patients: A report from the Italian registry.

Am J Hematol 2009 Oct;84(10):636-40

Hematology Unit, San Giovanni Rotondo, Italy.

Pregnancy is a high-risk event in women with essential thrombocythemia (ET). This observational study evaluated pregnancy outcome in ET patients focusing on the potential impact of aspirin (ASA) or interferon alpha (IFN) treatment during pregnancy. We retrospectively analyzed 122 pregnancies in 92 women consecutively observed in the last 10 years in 17 centers of the Italian thrombocythemia registry (RIT). The live birth rate was 75.4% (92/122 pregnancies). The risk of spontaneous abortion was 2.5-fold higher than in the control population (P < 0.01). ASA did not affect the live birth rate (71/93, 76.3% vs. 21/29, 72.4%, P = 0.67). However, IFN treatment during pregnancy was associated with a better outcome than was management without IFN (live births 19/20, 95% vs. 73/102, 71.6%, P = 0.025), and this finding was supported by multivariate analysis (OR: 0.10; 95% CI: 0.013-0.846, P = 0.034). The JAK2 V617F mutation was associated with a poorer outcome (fetal losses JAK2 V617F positive 9/25, 36% vs. wild type 2/24, 8.3%, P = 0.037), and this association was still significant after multivariate analysis (OR: 6.19; 95% CI: 1.17-32.61; P = 0.038). No outcome concordance between first and second pregnancies was found (P = 0.30). Maternal complications occurred in 8% of cases. In this retrospective study, in consecutively observed pregnant ET patients, IFN treatment was associated with a higher live birth rate, while ASA treatment was not. In addition, the JAK2 V617F mutation was confirmed to be an adverse prognostic factor.
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http://dx.doi.org/10.1002/ajh.21504DOI Listing
October 2009

Spectroscopical and mechanical characterization of normal and thalassemic red blood cells by Raman Tweezers.

Opt Express 2008 May;16(11):7943-57

Dipartimento di Scienze Fisiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cinthia, 80126 Napoli, Italy.

In this work, the effects of thalassemia, a blood disease quite diffuse in the Mediterranean sea region, have been investigated at single cell level using a Raman Tweezers system. By resonant excitation of hemoglobin Raman bands, we have examined the oxygenation capability of beta-thalassemic erythrocytes. A reduction of this fundamental erythrocyte function has been found. The measurements have been performed on a significant number of red blood cells; the relative statistical analysis is presented. Moreover, the response to photo-induced oxidative stress of diseased cells with respect to the normal ones has been analyzed. Finally, the deformability of thalassemic erythrocytes has been quantified by measuring the membrane shear modulus by using a double-trap system: the measurements have revealed an increase in membrane rigidity of more than 40%, giving evidence that the genetic defect associated to thalassemia, which manly relies on hemoglobin structure, also strongly affects the erythrocyte mechanical properties. Our results demonstrate that the developed set-up may have potential for the monitoring of blood diseases and their response to drug therapies.
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http://dx.doi.org/10.1364/oe.16.007943DOI Listing
May 2008

A methodology to study the deformability of red blood cells flowing in microcapillaries in vitro.

Ann Ist Super Sanita 2007 ;43(2):186-92

Dipartimento di Ingegneria Chimica, Facoltà di Medicina e Chirurgia, Università degli Studi Federico II, Naples, Italy.

The deformability of red blood cells flowing in microvessels is essential to maintain optimal blood circulation and to allow gas transfer between blood and tissues. Here, we report on an experimental methodology to investigate the deformability of RBCs flowing in microcapillaries having diameter close to the average cell size. The microcapillaries are placed in a rectangular flow cell, where a suspension of RBCs, properly diluted in albumin-additioned ACD, is fed through a syringe under the action of a liquid head in the physiological range. Video microscopy images of the flowing RBCs are acquired at high magnification and later processed by an automated image analysis macro. It was found that RBCs from healthy donors exhibit the classical parachute shape observed in vivo. Furthermore, all the data of healthy RBC velocity vs liquid head are well represented by the same linear regression, independently on the donor. Preliminary results on beta-thalassemia RBCs are also presented and show, on the average, a reduced velocity compared to healthy samples.
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September 2008

Ramipril in post-renal transplant erythrocytosis.

J Nephrol 2007 Jan-Feb;20(1):57-62

Department of Nephrology, School of Medicine, University of Naples Federico II, Naples - Italy.

Background: Posttransplant erythrocytosis (PTE; i.e., hematocrit [Ht] >=51%) may be responsible for cardiovascular events. Angiotensin-converting enzyme inhibitors (ACEIs) are increasingly employed in PTE treatment. Diverse ACEIs have been administered at variable doses and with erratic follow-up. In addition, guidelines recommend the administration of ACEIs as first-line therapy for PTE but do not give information on dosage. In this study the dose-response of a single ACEI was assessed, and patients were followed up for 1 year. The role of ACE gene polymorphism in both prevalence of PTE and successful response to ACEI therapy was also tested.

Methods: At study entry, blood chemistry and ACE-gene polymorphism were measured. ACEI (ramipril) was initiated at 1.25 mg/day; if Ht was still >=51%, ramipril was increased every 6 weeks to ensuing greater dosages. Scheduled dosages were 1.25, 2.5, 5.0, 7.5 and 10 mg/day. Blood chemistry was repeated every 6 weeks. Serum erythropoietin (EPO) concentration was assayed at the start and end of the study. Follow-up was extended for 1 year.

Results: PTE developed 12.6 +/- 16.0 months after transplantation in 40 out of 400 patients; 27 patients completed the study. Initial Ht was not correlated with any variable. Final Ht appeared normalized in 26 out of 27 patients. Mean dose (+/- SD) of ramipril was 4.6 +/- 3.6 mg. Mean time for correction of PTE was 135 days, and was not dependent on baseline Ht, hemoglobin or EPO. PTE relapsed in 4 patients. Prevalence of PTE and successful response to ramipril was not dependent on ACE-gene polymorphism.

Conclusion: Ramipril was effective in PTE; low doses normalized Ht in most patients. No clinical characteristics or biochemical variables predicted the response to ramipril. PTE may relapse; thus long-term follow-up is mandatory.
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July 2007

Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.

Blood 2006 Jan 6;107(2):514-9. Epub 2005 Oct 6.

Department of Pediatrics, Second University of Naples, Via Luigi De Crecchio, 4, Naples, Italy.

Chuvash polycythemia (MIM 263400) is an autosomal recessive disorder characterized by a high hemoglobin level, relatively high serum erythropoietin, and early death. It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1alpha activity and erythrocyte production in the face of normoxia. This polycythemia is endemic in Chuvashia, whereas its worldwide frequency is very low. We investigated the incidence of the Chuvash-type VHL mutation in Campania (South Italy) and identified 14 affected subjects (5 families). Twelve live on the island of Ischia (Bay of Naples). From analysis of the mutated allele, we found that the disease was more frequent on Ischia (0.070) than in Chuvashia (0.057). The haplotype of all patients matched that identified in the Chuvash cluster, thereby supporting the single-founder hypothesis. We also found that nonaffected heterozygotes had increased HIF-1alpha activity, which might confer a biochemical advantage for mutation maintenance. In conclusion, we have identified the first large cluster of Chuvash erythrocytosis outside Chuvashia, which suggests that this familial polycythemia might be endemic in other regions of the world.
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http://dx.doi.org/10.1182/blood-2005-06-2422DOI Listing
January 2006

High number of circulating CD34+ cells in patients with myelophthisis.

Haematologica 2005 Jul;90(7):976-7

Six patients with bone marrow micrometastases from solid cancers presented with increased numbers of circulating CD34+ cells; the CD34+ cell counts were very high in some cases. By contrast, no patient with metastatic cancer without bone marrow involvement showed raised numbers of circulating hemopoietic progenitors.
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July 2005

Interferon alfa treatment for pregnant women affected by essential thrombocythemia: case reports and a review.

Am J Obstet Gynecol 2004 Dec;191(6):2016-20

Dept. of Gynecology and Obstetrics, Federico II, University of Naples, via Pansini 5, Naples, Italy.

Objectives: In the past essential thrombocythemia was considered a disease of the elderly. At present, the number of young people suffering from this disease is growing, with a slightly higher frequency in females. We investigated the effects of interferon alfa therapy in these patients.

Study Design: We describe 9 pregnancies in 4 women affected by essential thrombocythemia.

Results: Four pregnancies were carried out without interferon alfa therapy, and resulted in 2 intrauterine deaths, 1 spontaneous abortion, and 1 neonatal death. Interferon alfa was given during another 5 pregnancies; among them, 2 ended in preterm deliveries with normal infants, and 3 in full-term deliveries. The literature is reviewed.

Conclusion: Our cases and published series suggest that fetal outcome is improved by therapy, and that interferon alfa may be the best therapeutic option.
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http://dx.doi.org/10.1016/j.ajog.2004.05.001DOI Listing
December 2004

Randomized comparison of power Doppler ultrasound-directed excisional biopsy with standard excisional biopsy for the characterization of lymphadenopathies in patients with suspected lymphoma.

J Clin Oncol 2004 Sep;22(18):3733-40

Department of Clinical and Experimental Medicine, CEINGE-Biotecnologie Avanzate, Federico II University Medical School, Naples, Italy.

Purpose: The sensitivity of lymph node excisional biopsy requires validation. Power Doppler ultrasound (US) helps predict the malignant status of lymphadenopathies. We used power Doppler US to select for biopsy the lymph node most suspected of malignancy.

Patients And Methods: One hundred fifty-two patients having lymphadenopathies with clinical suspicion of lymphoma were divided into two well-matched groups and randomly assigned to undergo either standard or power Doppler US-directed lymph node excisional biopsy.

Results: Histology showed a malignancy in 64% of patients in the standard group (lymphoma, 49 patients; carcinoma, two patients) and in 87% of patients in the US-assisted group (lymphoma, 62 patients; carcinoma, one patient). There were significantly fewer biopsy-related complications in the assisted group than in the standard group. During the follow-up of the patients with lymph nodes reported as being reactive, 14 of 29 patients in the standard group were rebiopsied and were found to have lymphoma (13 patients) or carcinoma at the subsequent lymph node histology, whereas none of the patients in the assisted group (nine patients) required a second biopsy. Thus, biopsy provided false-negative results for malignancy in 21% of patients affected by lymphoma in the standard group and never in the assisted group (P <.01).

Conclusion: Power Doppler US is an accurate tool for screening lymphadenopathies to be removed by excisional biopsy in patients with suspected lymphoma.
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http://dx.doi.org/10.1200/JCO.2004.02.171DOI Listing
September 2004

Spleen enlargement following recombinant human granulocyte colony-stimulating factor administration for peripheral blood stem cell mobilization.

Haematologica 2003 Jul;88(7):794-800

Division of Hematology, Federico II University Medical School, Naples, Italy.

Background And Objectives: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to mobilize peripheral blood stem cells (PBSC) for autologous or allogeneic transplants. Such treatment may cause spleen enlargement; exceptionally, spontaneous spleen rupture has been reported. We investigated changes in spleen size during stem cell mobilization.

Design And Methods: We evaluated spleen size, comparing palpation with ultrasound (US)-evaluated longitudinal diameter and volume, in 13 healthy donors and 22 patients with a hematological malignancy who were undergoing PBSC mobilization with rhG-CSF-including regimens.

Results: Intraobserver and interobserver variability of US-calculated spleen volume was very low; the correlation between the volume calculated by US and that measured by 3-dimensional computed tomography was excellent. During mobilization, spleen enlargement was detected by palpation in 17% of subjects, by US-measured longitudinal diameter in 60%, and by US-calculated volume in 91%. The median increase in spleen volume was 300 mL (range, 54-820; p<0.001) in healthy donors and 135 mL (range, 0-413; p=0.004) in the group of patients; the enlargement correlated with white blood cell count elevation (p=0.016) but not with circulating CD34+ cells. One month after the last administration of rhG-CSF, the median decrease was 160 mL (range, 35-800) in healthy donors and 58 mL (range, 0-310) in patients.

Interpretation And Conclusions: When evaluated by sensitive methods, rhG-CSF caused spleen enlargement in almost all individuals treated. US-calculated volume proved to be an excellent method, much better than longitudinal diameter, for detecting non-palpable splenomegaly induced by rhG-CSF.
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July 2003

Lymphnode localization of extramedullary myeloid cell tumor in myelodysplastic syndrome: report of one case diagnosed by fine-needle cytology.

Diagn Cytopathol 2003 Mar;28(3):136-9

Dipartimento di Scienze Biomorfologiche e Funzionali, Sezione di Anatomia Patologica e Citopatologia, Università degli Studi di Napoli Federico II, Naples, Italy.

Trilineage extramedullary myeloid tumor (EMT) is an uncommon medical condition mostly diagnosed in patients affected by acute or chronic myeloid leukemia or, more rarely, by a myelodysplastic syndrome, among which the most frequent is refractory anemia with excess of blasts in transformation (RAEB-t). The prognostic significance of EMT is still unclear, although the appearance of trilineage EMT is often considered to affect the outcome adversely. A 70-year-old lady with previous history of intestinal resection for colonic adenocarcinoma in 1995 and subsequently treated with 5-fuorouracyl developed a refractory anemia with excess of blasts (RAEB) in 1998. During the follow-up, a progression to RAEB-t was recorded. During chemotherapy for this condition, slight enlargement of left supraclavicular and right submandibular nodes was noticed. Fine-needle biopsy was performed with ancillary studies. A diagnosis of trilineage extramedullary myeloid tumor was reached. The patient was treated with low doses of chemotherapy with a good response lasting 12 months. The peculiar cytologic picture of this condition when corroborated by ancillary studies (immunocytochemistry and flow cytometry) is diagnostic of this rare condition. Furthermore, the extramedullary myeloid tumor in this case did not significantly affect the response to the chemotherapy of RAEB-t.
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http://dx.doi.org/10.1002/dc.10256DOI Listing
March 2003