0000000000928248
AUTHOR
Salvatrice Mancuso
showing 98 related works from this author
Rituximab for Immune Thrombocytopenia: A Retrospective Analysis on the Role of Prophylaxis Against Pneumocystis Jirovecii and Herpes Zoster Virus
2018
Abstract Introduction and objective of the study Rituximab (RTX) is considered a valid second line treatment option for persistent or chronic Immune Thrombocytopenia (ITP). RTX is known to affect the immune system thus increasing the risk for viral and fungal infections. Although prophylactic treatment to prevent Pneumocystis jirovecii (PJ) and herpes viruses' infections is used in patients with haematological neoplasms receiving RTX, these evidence is lacking in ITP patients candidated to anti-CD20 therapy. We here reported the role of phrophylaxis in a cohort of patients treated with RTX for refractory/relapsed ITP. Methods Data from patients affected by ITP and treated at our Institution…
Cardio-oncology in multiple myeloma: is it time for a specific focus?
2017
It has been known for some time that some oncologic drugs can cause heart damage. The term ‘cardiotoxicity’ just refers to the presence of a cardiac event during therapy or at least related to ther...
Acquired Hemophilia A Associated with Venous Thrombosis and Very High Inhibitor Titer: A Challenging Scenario
2019
Combined Point of Care Tools Are Able to Improve Treatment Adherence and Health-Related Quality of Life in Patients with Severe Hemophilia: An Observ…
2019
Introduction: Ultrasound (US) assessment of joints is an evolving point of care tool for the detection of early joint arthropathy (Napolitano M, Kessler CM. Hemophilia A and B. Consultative Hemostasis and Thrombosis, Kitchens, 4th edition); population pharmacokinetic (pop-PK) studies are adopted as a useful instrument to set the prophylaxis regimen for patients with hemophilia, they may improve adherence (Nagao A.et al. Thromb Res. 2019 Jan; 173:79-84) and reduce the annual bleeding rate (ABR). Adherence to continuous intravenous administrations of factor VIII or Factor IX products is challenging, thus patients may experience breakthrough bleedings while on prophylaxis. Repeated US examinat…
Oral leishmaniasis in an HIV-infected patient.
2000
As in most countries in the Mediterranean basin, leishmaniasis is endemic in Italy, where it has visceral (VL) and cutaneous (CL) forms caused by viscerotropic and dermotropic strains of Leishmania infantum, respectively. With the spread of the acquired immunodeficiency syndrome (AIDS) epidemic, the number of coinfections with Leishmania and human immunodeficiency virus (HIV) is increasing. Between 35% and 50% of the adult VL cases diagnosed annually in Sicily from 1991 to 1995 were related to HIV [1]; although cases of coinfection have been reported in 28 countries worldwide, the majority of these cases (1440 from 1990 to 1998) have been notified in four countries (Spain, Italy, France, Po…
Calculated Whole Blood Viscosity and Albumin/Fibrinogen Ratio in Patients with a New Diagnosis of Multiple Myeloma: Relationships with Some Prognosti…
2023
Background: In this single center study, we retrospectively evaluated the calculated hemorheological profile in patients with a new diagnosis of multiple myeloma, with the aim to evaluate possible relationships with some prognostic predictors, such as ISS, albumin levels, beta2-microglobulin, red cell distribution width, and bone marrow plasma cell infiltration. Methods: In a cohort of 190 patients, we examined the calculated blood viscosity using the de Simone formula, and the albumin/fibrinogen ratio as a surrogate of erythrocyte aggregation, and then we related these parameters to prognostic factors, using the Kruskal–Wallis and the Mann–Whitney tests, respectively. Results: From our ana…
T Cell Large Granular Lymphocytic Leukemia in Association with Sjögren’s Syndrome
2009
T cell large granular lymphocytic (LGL) leukemia is a rare condition accounting for 2–3% of all mature lymphoid leukemias. Here, we present the case of a 73-year-old woman presenting with neutropenia and anemia (hemoglobin 9.9 g/dl). Hematological assessment revealed the presence of a T cell LGL leukemia. At the time of T cell LGL leukemia diagnosis, the patient developed xerophthalmia and xerostomia, and a diagnosis of Sjögren’s syndrome was made following salivary gland biopsy. The finding of large granular lymphocytes in the context of autoimmune disorders is well-known, though it often occurs with rheumatoid arthritis or in association with a positive autoantibody titer in the absence o…
COMPARISON OF CLINICAL AND LABORATORY DATA, INCLUDING JAK-2 46/1 HAPLOTYPE, BETWEEN PATIENTS WITH IDIOPATHIC ERYTHROCYTOSIS AND POLYCYTHEMIA VERA.
2017
Buffy coat-derived platelets cryopreserved using a new method: Results from in vitro studies
2018
Abstract Cryopreservation for the long-term storage of platelets (PLTs) is a useful method to overcome the limits of platelet shortage. This is an in vitro prospective study to evaluate the count, viability, and function of buffy coat-derived pooled platelet concentrates (BC-PLTs), treated with dimethyl sulphoxide (DMSO) and cryopreserved (CRY BC-PLTs) at −80 °C with a modified Valeri method. PLTs were stored in 6% DMSO with a patented kit. Overall, 49 BC-PLTs from 245 healthy volunteer donors were prepared, cryopreserved, and analysed before and after 3, 6, and 9 months of storage. In flow cytometry, a statistically significant reduction in CD 42b (92.7 ± 4.29% at T0 vs. 23.6 ± 27.5% at T3…
Single-dose Palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with aggressive non-Hodgkin's lymphoma receiving mode…
2011
PURPOSE: The control of nausea and vomiting induced by chemotherapy is paramount for overall treatment success in cancer patients. Antiemetic therapy during chemotherapy in lymphoma patients generally consists of anti-serotoninergic drugs and dexamethasone. The aim of this trial was to evaluate the efficacy of a single dose of palonosetron, a second-generation serotonin type 3 (5-HT(3)) receptor antagonist, in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy (MEC) containing steroids. METHODS: Patients received a single intravenous bolus of palonosetron (0.25 mg) before administration of chemotherapy. Complete response (CR) defined as no vomiting …
Lymphomas and thyroid: Bridging the gap
2018
The thyroid gland is often involved in the development of neoplastic diseases, including lymphoproliferative disorders. The aim of this paper is to provide a comprehensive overview of the multiple interactions between lymphoma and thyroid. Through an extensive research among the literature, the relationship between lymphomas and thyroid can be established at various levels, and the possible interconnections are here summarized in 5 points: (1) the greater risk of lymphoma development in some thyroid diseases; (2) the primary thyroid lymphoma, with focus on issues related to the diagnosis, differential diagnosis, and treatment; (3) the incidence of thyroid involvement in primitive nodal lymp…
Absolute lymphocyte count is unrelated to overall survival in newly diagnosed elderly patients with multiple myeloma treated with immunomodulatory dr…
2015
The absolute lymphocyte count (ALC) has been widely studied in hematologic and solid malignancies as a marker of host antitumor immunity. Its significance has been evaluated in multiple myeloma (MM...
Cardiovascular risk factor in MPN patients
2020
Genetic Diversity of HIV-1 Non-B Strains in Sicily: Evidence of Intersubtype Recombinants by Sequence Analysis ofgag,pol, andenvGenes
2007
The molecular epidemiology of HIV-1 strains in Sicily (Italy) was phylogenetically investigated by the analysis of HIV-1 gag, pol, and env gene sequences from 11 HIV-1 non-B strains from 408 HIV-1-seropositive patients observed from September 2001 to August 2006. Sequences suggestive of recombination were further investigated by bootscanning analysis of various fragments. Overall, we identified several second-generation recombinant (SGRs) strains, which contained genetic material of CRF02_AG in at least one gene. Notably, three individuals were found to be infected with subsubtype A3, and one of them showed genetic recombination with subsubtype A4. The current study emphasizes the genetic a…
Comparison between whole blood viscosity measured and calculated in subjects with monoclonal gammopathy of undetermined significance and in patients …
2021
BACKGROUND: in this study, with a re-evaluation of the hemorheological determinants previously described in MGUS subjects and in MM patients, we have detected the calculated whole blood viscosity, according whether to the hematocrit and total plasma protein concentration (de Simone formula) or to the haematocrit and plasma fibrinogen level (Merrill formula), and a marker of the erythrocyte aggregation (albumin/fibrinogen level). METHODS: data were expressed as means±standard deviation. Student’s t test for unpaired data was used to compare MGUS subjects and MM patients. The correlation coefficient between mean erythrocyte aggregation (MEA) and hematocrit (Ht) was evaluated in MGUS, MM and M…
The Essential Thrombocythemia in 2020: What We Know and Where We Still Have to Dig Deep
2020
The Essential Thrombocythemia is a Chronic Philadelphia-negative Myeloproliferative Neoplasm characterized by a survival curve that is only slightly worse than that of age- and sex-adjusted healthy population. The criteria for diagnosis were reviewed in 2016 by WHO. The incidence varies from 0.2 to 2.5:100 000 people per year, with a prevalence of 38 to 57 cases per 100 000 people. The main characteristics of ET are the marked thrombocytosis and the high frequency of thrombosis. The spectrum of symptoms is quite wide, but fatigue results to be the most frequent. Thrombosis is frequently observed, often occurring before or at the time of diagnosis. The classification of thrombotic risk has …
The difference of free light chains as a predictor of kidney damage in patients with Multiple Myeloma
2022

 Background: Multiple myeloma (MM) is a malignant neoplasm characterized by the clonal expansion of plasma cells that can release monoclonal immunoglobulins (monoclonal component) or part of theme. Since 2001, the k and λ serum free light chains (sFLC) evaluation and their ratio (rFLC) have made up the laboratory analysis more sensitive and precise in MM patients. The role of rFLC has been widely studied and discussed and now it is validated in the literature. Instead, the value of free light chains difference (dFLC), especially in MM is less known yet. The aim of this study is to evaluate the relationship between the dFLC and the kidney damage parameters in patients with MM, in compa…
Presence of human papillomavirus and Epstein-Barr virus in the cervix of women infected with the human immunodeficiency virus
2001
The presence of human papillomavirus (HPV) and Epstein-Barr virus (EBV) was sought in cervical scrapings from 110 human immunodeficiency virus (HIV)-infected women to evaluate the role of these viruses as risk factors for squamous intraepithelial lesions of the cervix. By using PCR, presence of HPV-DNA and EBV-DNA was found in 60.9% (67/110) and in 10% (11/110) of clinical samples, respectively. Identification of oncogenic group of HPV by hybrid capture (HC II, Murex-Digene) indicated the presence of low-risk HPV in 13 (19.4%) patients, high-risk HPV in 28 (41.8%), and both types of HPV in 26 (38.8%) patients. Squamous intraepithelial lesions were present in 59 cases, being low-grade (n = 5…
Isolated Nodal TBC Reactivation in a Patient with Post-Thrombocythemia Myelofibrosis Treated with Ruxolitinib: Case Report and Review of the Literatu…
2021
Ruxolitinib side effects include the most frequent hematological toxicity along with a more recently evidenced immunosuppressive activity, interfering both with the innate and adaptive immunity, and several cases of reactivation of latent infections by opportunistic agents in patients in treatment with ruxolitinib have been published in the last years. Several pathophysiological mechanisms may explain an association between ruxolitinib and opportunistic infections. From what we know, the only case of an isolated lymph node TBC reactivation in a ruxolitinib-treated myelofibrosis (MF) patient was reported by Patil et al. in 2016 [Int J Med Sci Public Health. 2017;6(3):1]. Other 10 cases descr…
Monocyte and lymphocyte apoptosis resistance in acute and chronic brucellosis and its possible implications in clinical management.
2003
This study evaluated the level of susceptibility of monocytes and lymphocytes to spontaneously induced and CH11-induced apoptosis in 16 patients with Brucella infection. The expression of some immunological and apoptotic markers was evaluated. Before therapy, monocytes showed a high level of resistance to spontaneously induced or CH11-induced apoptosis in all patients. In patients with acute infection, this resistance persisted for 10-20 days after treatment was initiated, then decreased; in chronically infected patients, it persisted after 45 days of treatment. Lymphocytes were also more resistant to CH 11-induced apoptosis. The level of activated CD8++ T lymphocytes was high in patients w…
Comprehensive geriatric assessment is an essential tool to support treatment decisions in elderly patients with diffuse large B-cell lymphoma: A pros…
2015
We performed a multicenter study to validate the concept that a simple comprehensive geriatric assessment (CGA) can identify elderly, non-fit patients with diffuse large B-cell lymphoma (DLBCL) in whom curative treatment is not better then palliation, and to analyze potential benefits of treatment modulation after further subdividing the non-fit category by CGA criteria. One hundred and seventy-three patients aged > 69 treated with curative or palliative intent by clinical judgement only were grouped according to CGA into fit (46%), unfit (16%) and frail (38%) categories. Two-year overall survival (OS) was significantly better in fit than in non-fit patients (84% vs. 47%; p < 0.0001).…
JAK2 ALLELE BURDEN IN PATIENTS WITH PHILADELPHIA NEGATIVE MYELOPROLIFERATIVE NEOPLASMS
2017
Familial essential thrombocythemia: 6 cases from a mono‐institutional series
2022
Rarely essential thrombocythemia (ET) is diagnosed in more than one person within a family. Familial myeloproliferative neoplasms are underdiagnosed. In this report, we describe 6 couples of familial ET, evaluating the heterogeneity of the mutational state and the clinical presentation.
Buffy coat-derived platelets cryopreserved using a new method: Results from a pivotal clinical trial on thrombocytopenic patients with acute leukaemia
2019
Abstract The administration of cryopreserved platelets (PLTs) may overcome the limits of platelet shortage and availability, especially during some seasons or in specific contexts like rural areas. After in vitro validation studies, ad hoc prepared buffy coat-derived pooled platelet concentrates (BC-PLTs), treated with dimethyl sulphoxide (DMSO) and cryopreserved (CRY BC-PLTs) at -80 °C with a modified Valeri method, were transfused in patients with severe thrombocytopenia secondary to chemotherapy for acute leukaemia (AL). Five inpatients were enrolled in the pivotal clinical trial NCT02032134: 4 males and 1 female with a mean age of 71 years (range: 65–80). Four patients were diagnosed wi…
Immunosenescence and lymphomagenesis
2018
Abstract One of the most important determinants of aging-related changes is a complex biological process emerged recently and called “immunosenescence”. Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way. This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of t…
Synthesis and induction of G0–G1 phase arrest with apoptosis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazep…
2007
The multistep synthesis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one 15 has been carried out. The compound showed antiproliferative and apoptotic effects against K562, K562-R (imatinib mesilate resistant), HL60 and multidrug resistant (MDR) HL60 cell lines. Compound 15 showed a pro-apoptotic activity against HL60 and K562 resistant cell lines markedly higher than etoposide and busulfan, respectively. Flow cytometry studies carried out on K562 cells allowed to establish that 15 induces G0-G1 phase arrest followed by apoptosis.
Late onset of unilateral optic disk edema secondary to treatment with imatinib mesylate
2017
Key Clinical Message Prompt ophthalmology evaluation and immediate imatinib suspension should be suggested at any time of tyrosine kinase inhibitor therapy in patients with visual deficit, as it may be a clinical manifestation of optic disk edema, and suspension may help in prompt recovery.
Clinical utility and physician perceptions of a digital platform for electronic patient-reported outcomes monitoring in patients with hematologic mal…
2021
Abstract Background There is now great interest in using digital health tools to monitor patients' health status in real-world practice. Such tools often include electronic-patient-reported outcome (ePRO) systems in which symptoms questions are included into online interfaces for patient self-reporting, with real-time alerts triggered to the treating physician if severe symptoms or problems are reported. However, there is little information about the clinical utility and user perceptions of these systems, and this is particularly true in the area of hematology. Objectives This study investigates physicians' perceptions of usability and clinical utility of using remote ePROs in routine pract…
Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy
2022
B-cell lymphoma and lymphoproliferative diseases represent a heterogeneous and complex group of neoplasms that are accompanied by a broad range of immune regulatory disorder phenotypes. Clinical features of autoimmunity, hyperinflammation, immunodeficiency and infection can variously dominate, depending on the immune pathway most involved. Immunological imbalance can play a role in lymphomagenesis, also supporting the progression of the disease, while on the other hand, lymphoma acts on the immune system to weaken immunosurveillance and facilitate immunoevasion. Therefore, the modulation of immunity can have a profound effect on disease progression or resolution, which makes the immune syst…
Cancer-Associated Deep Vein Thrombosis: The Role of Residual Vein Thrombosis for Assessing the Duration of Low Molecular Weight Heparin (the EXTENDED…
2014
Abstract Introduction. The optimal duration of Low Molecular Weight Heparin (LMWH) after cancer associated deep vein thrombosis (DVT) is unknown; current guidelines suggest to prolong anticoagulation until cancer is active. We have recently demonstrated, in a randomized trial, that detection of Residual Vein Thrombosis (RVT) after 6 months of LMWH identify patients who require or not extension of therapy with anticoagulants (JCO in press). Now we present data of a prospective study evaluating a RVT-based management of patients with cancer-associated DVT, in whom LMWH has been extended up to 2 years in patients considered at high-risk for recurrent DVT because of persistence of RVT. Material…
HIV Infection in 403 Female Prostitutes in Italy
1991
Since the beginning of HIV epidemic, it became clear that the modality of transmission was different between Western Countries and Africa (1). Infact, in Africa heterosexual contact is the most important factor in the spread of HIV infection and female prostitutes are considered to be the major reservoir of HIVinfection (2).
Paroxysmal nocturnal hemoglobinuria-like phenotype and thrombotic risk in several clinical disorders.
2021
High Output Heart Failure in Multiple Myeloma: Pathogenetic Considerations.
2022
The high output heart failure is a clinical condition in which the systemic congestion is associated to a high output state, and it can be observed in a non-negligible percentage of hematological diseases, particularly in multiple myeloma, a condition in which the risk of adverse cardiovascular events may increase, with a worse prognosis for patients. For this reason, though an accurate literature search, we provided in this review a complete overview of different pathogenetic mechanisms responsible for high output heart failure in multiple myeloma. Indeed, this clinical finding is present in the 8% of multiple myeloma patients, and it may be caused by artero-venous shunts, enhanced angioge…
Cardiovascular Issues in Tyrosine Kinase Inhibitors Treatments for Chronic Myeloid Leukemia: A Review
2021
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by a fusion gene, encoding for the chimeric protein BCR-ABL, with constitutive tyrosine kinase activity. The use of tyrosine kinase inhibitors (TKIs) has drastically improved survival, but there are significant concerns about cardiovascular toxicity. Cardiovascular risk can be lowered with appropriate baseline evaluation, accurate choice of TKI therapy, improvement of modifiable cardiovascular risk factors through lifestyle modifications, and prescription of drugs for primary or secondary prevention. Which examinations are necessary, and when do they have to be scheduled? How often should a TKI-treated patient undergo wh…
Comparison between thrombotic risk scores in essential thrombocythemia and survival implications.
2019
The conventional thrombotic risk stratification in essential thrombocythemia (ET) distinguishes patients in two risk groups based on previous thrombosis and age (< or >60). The IPSET-thrombosis takes into account four risk factors: age greater than 60 years and the presence of CV risk factors, thrombosis history and JAK2 V617F presence. The revised IPSET-thrombosis uses three adverse variables to delineate four risk categories: age greater than 60, thrombosis history, and JAK2 V617F presence. We compared different risk models in the estimation of thrombotic risk in 191 patients with ET and the role of specific driver mutations affecting overall survival, according to thrombotic risk. …
Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone as first-line treatment for splenic marginal zone ly…
2015
Rituximab ® provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in patients with SMZL who were either untreated or were splenectomized but had shown disease progression within 1 year after splenectomy. Treatment consisted of six courses of Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-year progression-free survival and overall survival were 54% and 72%, respectively. Toxicity was substantial (grade ≥ 3 neutropenia: 26%; grade ≥ 3 infections: 8%).…
Efficacy of ruxolitinib retreatment in a patient with high-risk myelofibrosis using the international prognostic scoring system
2019
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm in which clonal proliferation of hematopoietic stem cells and bone marrow fibrosis coexist.1 Patients may eventually die due to leukemic progression, which occurs in up to 20% of cases, or because of cardiovascular comorbidities or cytopenia, which causes susceptibility to infections and bleeding.2 Myelofibrosis diagnosis relies upon the evaluation of several clinical and laboratory criteria suggested by the World Health Organization (WHO) in 2016.3 The major mutations leading to myelofibrosis usually occur in the JAK2, CALR, and MPL genes. However, in almost 10% of the cases, none of the above-mentioned mutations can be detected …
Mitochondrial disruption and apoptosis in lymphocytes of an HIV infected patient affected by lactic acidosis after treatment with highly active antir…
2003
Aims: Highly active antiretroviral therapy (HAART) can induce an increase in lactic acid concentrations that seems to be caused by mitochondrial dysfunction induced by the interaction of nucleoside reverse transcriptase inhibitors (NRTIs) with DNA polymerase γ in the mitochondria. Mitochondrial alterations have been described in liver and muscle cells of NRTI treated human immunodeficiency virus (HIV) infected patients. Because lymphocytes are the main target for HIV and because mitochondria are involved in apoptosis, we studied mitochondrial morphology and apoptosis in the lymphocytes of an HIV infected patient with severe lactic acidosis after treatment with stavudine, didanosine, and ind…
Triple-Negativity Identifies a Subgroup of Patients with Better Overall Survival in Essential Thrombocythemia
2022
Essential thrombocythemia, as defined by the WHO in 2016, is a Philadelphia-negative chronic myeloproliferative neoplasm showing a better prognosis than polycythemia vera and myelofibrosis. In a variable percentage, patients with essential thrombocythemia show none of the known driver-gene mutations that may occur on JAK2, CALR, and MPL genes. Such patients are classified as triple-negative and their clinical features and prognosis have not been described with precision yet. In this study, we evaluated some of the characteristics of this population by comparing them with those of patients with driver-gene mutated ET. Data from 266 consecutive essential thrombocythemia patients were analysed…
Prevention of venous thromboembolic events occurring in myeloma patients treated with second-generation novel agents
2021
Thrombosis and neoplasms are strictly linked, and the diagnosis of a malignancy is a relevant risk factor for venous thromboembolism (VTE). In particular, between gammopathies, the VTE risk is known to be increased in both monoclonal gammopathy of uncertain significance and in multiple myeloma, with a 3- and 9-fold increase respectively, when compared to the general population. The risk appears to be further increased in patients treated with immunomodulating drugs, such as thalidomide, especially when in combination with dexamethasone or conventional cytotoxic chemotherapies, and lenalidomide. In 2008 the International Myeloma Working Group put out thrombosis prophylaxis recommendations fo…
Thrombotic risk in paroxysmal nocturnal hemoglobinuria-like (PNH-like) phenotype
2020
The complement system is an essential component of the innate immune defence that, if overly activated, may damage organs and tissues. For this reason, there is a fine complement regulatory system. The complement modulation system includes two proteins with important regulatory activity, CD55 or decay accelerating factor (DAF) and CD59 or membrane inhibitor of reactive lysis (MIRL). The paroxysmal nocturnal hemoglobinuria (PNH) is a clonal and non-neoplastic disease characterized by intravascular haemolysis, occurrence of thrombosis and bone marrow failure. In clinical practice, in opposition to PNH, a variety of pathological conditions have been observed with an acquired and non-genetic de…
CARDIOVASCULAR RISK IN ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA: THROMBOTIC RISK AND SURVIVAL
2019
Thromboembolic and bleeding events pose a severe risk for patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET). Many factors can contribute to promoting the thrombotic event due to the interaction between platelets, leukocytes, and endothelium alterations. Moreover, a significant role can be played by cardiovascular risk factors (CV.R) such as cigarette smoking habits, hypertension, diabetes, obesity and dyslipidemia. In this study, we evaluated the impact that CV.R plays on thrombotic risk and survival in patients with PV and ET .
The Essential Thrombocythemia, Thrombotic Risk Stratification, and Cardiovascular Risk Factors
2020
Essential thrombocythemia is a rare hematological malignancy with good overall survival, but moderate to high risk of developing arterial or venous thrombosis lifelong. Different thrombotic risk scores for patients with essential thrombocythemia have been proposed, but only one of them (the IPSET-t scoring system) takes into account the classical cardiovascular risk factors as one of the scoring items. Currently, in clinical practice, the presence of cardiovascular risk factors in patients with diagnosis of ET rarely determines the decision to initiate cytoreductive therapies. In our study, we compared different risk models to estimate the thrombotic risk of 233 ET patients and the role of …
Evaluation of Bone Marrow CD8+ tissue-Resident Memory T Cells in Multiple Myeloma
2019
Background: CD8+ T cell responses are an essential component of the adaptive immune system. After resolution of infection a small population of memory cells is formed. In relation to circulatory patterns, different subsets of memory CD8+ T cells can be identified: the central memory (CM) and the effector memory T cells (EM) (Martin MD, et al., Front Immunol. 2018). In addition, it has been described a subset of resident memory T cells (TRM) permanently living in peripheral tissues, including the bone marrow (BM) (Di Rosa F., et al., Nat Rev Immunol. 2016). It is conceivable that these cells can contribute to the defence toward haematological tumours infiltrating the BM. Therefore, we perfor…
Functional In Vitro Studies Of Buffy Coat Pooled Platelets Cryopreserved In Dimethyl-Sulphoxide With a New System
2013
Abstract Introduction Cryopreservation for long term storage of platelets (PLTs) represents a clinical useful method for avoiding platelet shortage. Many studies have tried to define, in vitro and in vivo, the entity and weight of storage-related PLTs lesions with discordant results related to different methods. We have performed an in vitro prospective study to evaluate PLTs count, viability and function of buffy coat derived pooled platelet concentrates (BC-PLTs) treated with dimethyl-sulphoxide (DMSO) and cryopreserved at -80°C with an innovative patented system not requiring laminal flow hoods and external manipulations. Materials and methods Each BC-PLTs was obtained from 5 buffy coats…
ChemInform Abstract: Synthesis and Induction of G0-G1 Phase Arrest with Apoptosis of 3,5-Dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,…
2009
The multistep synthesis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one 15 has been carried out. The compound showed antiproliferative and apoptotic effects against K562, K562-R (imatinib mesilate resistant), HL60 and multidrug resistant (MDR) HL60 cell lines. Compound 15 showed a pro-apoptotic activity against HL60 and K562 resistant cell lines markedly higher than etoposide and busulfan, respectively. Flow cytometry studies carried out on K562 cells allowed to establish that 15 induces G0-G1 phase arrest followed by apoptosis.
Paroxysmal nocturnal haemoglobinuria: When delay in diagnosis and long therapy occurs
2017
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder characterized by hemolytic anemia, bone marrow failure and thrombosis, caused by a somaticmutation in PIG-A gene that results in theabsence of CD55 and CD59, two important complement regulatory proteins. In thispaper, a case of PNH is retrospectively examined looking for clinical and laboratory features, and the entire course of the disease from the onset of the symptoms isdescribed, together with an adequate follow-up over a 7-years treatment period. Inthis case, the not specificity and the limited clinical relevance of the symptoms led to adelay in diagnosis. After thrombosis, Eculizumab therapy has been shown to be effec…
Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study.
2018
Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revis…
Coexistence of Von Willebrand disease and gastrointestinal stromal tumor (G.I.S.T): Case report of a rare and challenge association
2019
Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by a quantitative (type 1 and 3) or qualitative (type 2) defect of Von Willebrand factor (VWF). Bleeding from the gastrointestinal (GI) tract is not uncommon in VWD and is usually associated with angiodysplasia. We report herein on the management of a patient affected by VWD2B with severe GI bleeding secondary to gastrointestinal stromal tumor (GIST) complicated by deep vein thrombosis (DVT). The current case demonstrated that the hemostatic balance, in RBDs under specific circumstances, can range from a tendency toward a hemorrhagic to normal or prothrombotic state. In these patients, a close collabor…
Plasma HIV-1 RNA and route of transmission in oral candidiasis and oral hairy leukoplakia
2000
Erythrocyte deformability profile evaluated by laser diffractometry in patients with multiple myeloma: Re-examination of our cases.
2023
Background: Multiple myeloma is a complex pathology which represents about 10 % of all hematological neo-plasms. It can often present changes in the hemorheological profile and, in relation to this last topic, our aim is to evaluate the hemorheological profile in a group of multiple myeloma patients, with reference to erythrocyte deformability. Methods: We have examined the profile of the erythrocyte deformability in multiple myeloma enrolling 29 pa-tients; this profile, expressed as elongation index at several shear stress, has been obtained using the diffracto-metric method. Results: By comparing normal controls and MM patients, a significant decrease in erythrocyte deformability, especia…
Optimal duration of low molecular weight heparin for the treatment of cancer-related deep vein thrombosis. The ”CANCER DACUS” study
2014
Purpose We evaluated the role of residual vein thrombosis (RVT) to assess the optimal duration of anticoagulants in patients with cancer who have deep vein thrombosis (DVT) of the lower limbs. Patients and Methods Patients with active cancer and a first episode of DVT treated with low molecular weight heparin (LMWH) for 6 months were eligible. Patients were managed according to RVT findings: those with RVT were randomly assigned to continue LMWH for an additional 6 months (group A1) or to discontinue it (group A2), and patients without RVT stopped LMWH (group B). The primary end point was recurrent venous thromboembolism (VTE) during the 1 year after disconinuation of LMWH, and the secondar…
<p>Clinical Phenotype and Response to Different Lines of Therapy in Elderly with Immune Thrombocytopenia: A Retrospective Study</p>
2020
Purpose Insufficient knowledge of primary immune thrombocytopenia purpura (ITP) in the elderly, together with a lack of clinical trial data, has resulted in wide variation in treatments. Here, we present a study focused on clinical characteristics of ITP in older subjects at diagnosis integrated with the subsequent course of the disease and treatment history. Methods In a retrospective monoinstitutional study, we evaluated >65-year-old patients with primary ITP. Clinical characteristics at the time of diagnosis were described and analyzed. We aimed to delineate whether subsequent lines of therapy influenced the number of relapses. In addition to initial regimens, we reported subsequent trea…
Gender differences in human immunodeficiency virus–related oral lesions: An Italian study
2001
Abstract Objective: The purpose of this study was to investigate the relationship between oral lesions and gender, age, CD4+ cell count, human immunodeficiency virus-1 (HIV-1) viral load, antiretroviral therapy, and route of transmission in a group of HIV-infected (HIV+) persons from the Mediterranean region. Study Design: The participants in this study were HIV+ adults who sought dental care between January 1999 and June 1999 in the Department of Oral Medicine (University of Palermo, Italy). Results: One hundred thirty-six HIV+ adults came in for an initial oral examination. Their mean age was 35.2 years (SD ± 7.97), and 33% were women. Their mean CD4+ cell count was 325.3 × 106 /L (SD ± 2…
Candidal carriage in the oral cavity of human immunodeficiency virus–infected subjects
2002
Abstract Objectives. We sought to assess asymptomatic oral carriage of Candida species and relative density in human immunodeficiency virus-infected (HIV+) subjects, as well as to determine whether yeast carriage is associated with CD4+cell count, HIV-1 RNA quantity, gender, route of HIV transmission, antiretroviral therapy, or smoking. Study Design. A cross-sectional analysis of oral rinses from HIV+ and healthy subjects was undertaken. Oral candidal carriage and relative species were investigated in 42 HIV+ and 41 healthy individuals, all of whom were seen at the Palermo University Department of Oral Sciences, Italy. Data were managed and analyzed by means of the computer software package…
Detection of a new 3-base pair insertion mutation in the protease gene of human immunodeficiency virus type 1 during highly active antiretroviral the…
2005
To investigate a new insertion mutation in the protease (PR) gene of human immunodeficiency virus type 1 (HIV-1) in a patient extensively pretreated with antiretroviral drugs, genotypic analyses of plasma-derived viruses were performed by sequencing segments of 1302 nucleotides in the pol gene of HIV-1. Despite optimal compliance to highly active antiretroviral therapy (HAART) the patient showed poor virological success. Nucleotide sequences of retrospective available plasma samples exhibited a previously unknown 3-bp insertion mutation, corresponding to a leucine, between codons 31 and 32 of the PR gene. This kind of mutation appears to be very rare and it does not seem to be associated wi…
Presence of Epstein-Barr virus, cytomegalovirus and human papillomavirus in normal oral mucosa of HIV-infected and renal transplant patients
2001
OBJECTIVES: To determine the prevalence of EBV-DNA,CMV-DNA and HPV-DNA in oral healthy mucosa of HIV-infected and renal transplant patients. To associate the detection of viral genomes with laboratory parameters of immunodeficiency, gender, antiretroviral and immunosuppressive therapy. DESIGN: A cross-sectional analysis of lingual and buccal cytobrushings from HIV-infected and renal transplant patients. SUBJECTS AND METHODS: Lingual and buccal cytobrushings were obtained from clinically normal oral mucosa of 57 HIV+, 40 renal transplant patients and 30 healthy uninfected controls, all matched for age at baseline of examination. Presence of EBV-, CMV- and HPV-DNA was assessed by polymerase c…
Cardiovascular Risk in Polycythemia Vera: Thrombotic Risk and Survival: Can Cytoreductive Therapy Be Useful in Patients with Low-Risk Polycythemia Ve…
2019
<b><i>Background/Aims:</i></b> Cardiovascular risk factors are not considered in the current scores for evaluation of the thrombotic risk in myeloproliferative neoplasms, and in polycythemia vera (PV) in particular. Cytoreduction is currently not indicated in low-risk patients with PV, despite the absence or presence of cardiovascular risk factors. Our purpose is to highlight how cardiovascular risk factors in patients with PV increase the thrombotic risk both in low- and high-risk patients. <b><i>Methods:</i></b> We collected and analyzed data from 165 consecutive patients with a diagnosis of PV followed at our institution and compared the fr…
Long Term Results of Stanford V Regimen and Highly Active Antiretroviral Therapy (HAART) In 59 Patients (pts) with HD and HIV Infection (HD-HIV)
2010
Abstract Abstract 4827 Background: The introduction of HAART has significantly improved the outcome of pts with HD-HIV. However there are no data on the long term follow-up of HD-HIV pts treated with conventional chemotherapy (CT) regimens. In 2002, we reported the results of a prospective phase II study with the intensive 12-week CT with adjuvant radiotherapy (Stanford V) and concomitant HAART in 59 pts (Spina et al. Blood 2002;100:1984-1988). Methods: To analyze the long term outcome of patients included in the Stanford V and HAART protocol. Results: The median follow-up is 67months (range 3–156 months The 5-yr overall survival (OS), freedom from progression (FFP), disease free survival a…
Host-related factors and cancer: Malnutrition and non-Hodgkin lymphoma
2022
Assessment of host-related factors is a crucial aspect in the comprehensive management of cancer patients. A distinct nutritional disturbance linked to cancer has been recognized to be associated with negative outcomes. However, compared to solid tumors, only a limited number of studies have looked specifically at nutritional issues in the field of lymphoma. The aim of this review is to integrate the current knowledge on interactions between malnutrition and lymphoma and address most relevant and pertinent questions. We first provide a literature review on the mutual biological relationship between malnutrition and lymphoma. Next, we explore the overlap between malnutrition, sarcopenia, cac…
Antimicorbial prophylaxis in patients with immune thrombocytopenia treated with rituximab:a retrospective analysis
2019
Antibodies to human herpes virus type 8 (HHV8) in general population and in individuals at risk for sexually transmitted diseases in Western Sicily.
2000
Human herpes virus 8 (HHV8) appears to be the primary aetiologic agent of Kaposi sarcoma (KS). To study the distribution of HHV8, a seroepidemiological study was carried out in western Sicily, where a high incidence rate of classical KS is well documented.A total of 970 sera of healthy human immunodeficiency virus (HIV) negative individuals of general population (1-70 years old) and 742 sera of individuals in different risk groups for HIV infection were evaluated by means of an indirect immunofluorescence assay able to detect antibodies to lytic and latent HHV8 antigens.Crude seroprevalence to HHV8 antigens was 11.5% in the general population, and it increased significantly with age from 6%…
Acquired haemophilia in cancer: A systematic and critical literature review
2017
Aim There is a paucity of data on the clinical presentation and management of cancer patients with acquired haemophilia (AH), we here report a systematic literature review on acquired haemophilia in the context of cancer. Methods Treatment outcomes of AH were defined as complete response (CR), partial response (PR) or no response (NR), based on inhibitor eradication, coagulation factor VIII levels and bleeding control. Reported deaths were either related to cancer or bleeding. Results Overall, 105 cases were collected and analyzed according to classification of cancer and efficacy of treatments for inhibitor and malignancy. The mean age was 68 years for both males (range 37-86 years) and fe…
Management of Ponatinib in Patients with Chronic Myeloid Leukemia with Cardiovascular Risk Factors
2019
Cardiovascular (CV) adverse events are considered common complications of ponatinib treatment. Recently, it has been demonstrated that ponatinib dose reductions in definite settings can obtain optimal responses and lower ponatinib-related CV events. In this study, we describe the management of 5 patients with chronic myeloid leukemia treated with ponatinib, from second to fourth line of tyrosine kinase inhibitor therapy, carrying high pre-ponatinib CV risk, who obtained optimal molecular response and developed no CV adverse event during follow-up. Among these 5 patients, 2 had diagnosis of ischemic heart disease and underwent percutaneous angioplasty, 2 had type 2 diabetes and arterial hype…
Bendamustin in association with Rituximab (BR) in the treatment of patients with relapsed/refractory lymphoid neoplasm. A GISL retrospective study
2009
Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi
2014
PREDICTORS OF RESIDUAL VEIN THROMBOSIS AFTER CANCER-RELATED DEEP VEIN THROMBOSIS OF THE LOWER LIMBS
2012
A Case of Fatal Drug Rash Eosinophilia and Systemic Symptoms from Allopurinol
2015
Hypereosinophilia is a systemic condition that has several possible etiologies: allergies, medications, infectious, autoimmune or other systemic diseases, and finally idiopathic forms. Skin involvement seems to relate to subcutaneous inflammatory infiltration in this condition, as can be observed in parasitic, autoimmune and bullous diseases, as well as in drug reactions. Generalizing, a severe adverse drug-induced reaction may cause a systemic inflammatory disease: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Its diagnosis requires the application of a complex diagnostic algorithm and immediate identification to prevent inauspicious evolution. The prognosis is severe; drug di…
Clinical Phenotype and Response to Different Lines of Therapy in Elderly with Immune Thrombocytopenia: A Retrospective Study
2020
Salvatrice Mancuso,1 Melania Carlisi,1 Nicola Serra,2,3 Mariasanta Napolitano,1 Simona Raso,3 Ugo Consoli,4 Roberto Palazzolo,5 Maria Rosa Lanza Cariccio,6 Sergio Siragusa1 1Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE) Department, University of Palermo, Palermo, Italy; 2Department of Molecular Medicine and Medical Biotechnology, University Federico II of Naples, Naples, Italy; 3Department of Surgical, Oncological and Stomatological Disciplines, University of Palermo, Palermo, Italy; 4UOC Ematologia ARNAS Garibaldi, Catania, Italy; 5UOS Ematologia, Asst Valtellina e Alto Lario, Sondrio, Italy; 6Dipartimento Oncologico, La Maddalena,…
Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials
2023
The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton’s tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complet…
Screening sierologico per Leishmania infantum su donatori di sangue e HIV+ asintomatici residenti in area endemica [Serological screening for Leishma…
2008
Visceral leishmaniasis (VL) is endemic in Sicily (48 new cases in 2004, of which nine were in Agrigento). In southern Europe between 25-70 per cent of adult VL cases are related to HIV infection. The HIV cases have a high risk (1.5-9%) of developing VL either as a new infection or as the revival of a latent infection. We therefore carried out serologic screening to detect antibodies against L. infantum by IFAT in 1449 blood donors in Agrigento and the surrounding area (May-December 2005) and in 120 HIV+ in western Sicily, all of whom were asymptomatic and had no history of VL. L. DNA was assessed by nested PCR in blood samples of some seropositive donors. Of the 1449 blood donors, 11 (0.75%…
ABSOLUTE LYMPHOCYTE COUNT IS NOT A PREDICTOR FOR SURVIVAL IN NEWLY DIAGNOSED ELDERLY PATIENTS WITH MULTIPLE MYELOMA. FINAL RESULTS OF A MULTICENTER S…
2012
CANCER AS A PREDICTOR FOR INCREASED PERIPROCEDURAL BLEEDING DURING SURGERY OR PLATELET-INDUCED CHEMOTHERAPY IN CHRONICALLY ANTICOAGULATED PATIENTS
2012
Molecular epidemiology of HIV type 1 (HIV-1) non-B subtypes in SIcily
2004
INFEZIONE DA HIV E IMMIGRATI NEGLI ULTIMI CINQUE ANNI DI ATTIVITA' DEL NOSTRO CENTRO
2006
Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis.
2012
Introduction: This study aimed at defining protease (PR) resistance mutations associated with darunavir (DRV) failure and PR resistance evolution at DRV failure in a large database of treatment-experienced human immunodeficiency virus (HIV) patients. Results: Overall, 1,104 patients were included: 118 (10.7%) failed at a median observation time of 16 months. The mean number of PR mutations at baseline was 2.7, but it was higher in patients who subsequently failed DRV. In addition, the number of PR mutations increased at failure. The increase in the mean number of mutations was completely related to mutations considered to be associated with DRV resistance following the indications of the ma…
Prevalence of Giardia, Cryptosporidium and Isospora in HIv-seropositive individuals in Sicily.
2004
ABSOLUTE LYMPHOCYTE COUNT IS NOT A PREDICTOR FOR SURVIVAL IN NEWLY DIAGNOSED ELDERLY PATIENTS WITH MULTIPLE MYELOMA
2012
VALIDITA' DEL METODO DI IMMUNOFLUORESCENZA DIRETTA NELLA DIAGNOSI DI GIARDIASI IN UN SOGGETTO HIV+
2006
Screening sierologico per l'infantum in soggetti HIV+ in area endemica Sicilia occidentale
2006
Clinical history of thrombosis before diagnosis of overt myeloproliferative neoplasms in triple negative patients
2017
Thromboses are the most important preventable risk factors for morbidity and mortality in myeloproliferative neoplasms (MPN). We here performed a retrospective cross sectional study of patients with a diagnosis of Philadelphia negative MPN and a prior history of thrombosis, analyzed from electronic charts. Among a cohort of 260 patients with MPNs (78PV, 102ET, 80 MF), forty four were found triple negative for JAK-2, calreticulin and MPL gene mutations. Sixty-nine (26.54%) patients (29F, 40M) had a personal past clinical history of arterial or venous thrombosis. Among patients with thrombosis, 13(18.8%) cases (11ET, 2MF) were triple negative (median age:60 years). Most events, in particular …
Chronic myeloid leukemia as second malignancy; a retrospective multicentrico study
2009
Dimagrimento e diarrea: oltre la "wasting syndrome"
2007
Thrombotic complications in paroxysmal nocturnal haemoglobinuria: a literature review.
2012
BENDAMUSTINE IN ASSOCIATION WITH RITUXIMAB AS SALVAGE THERAPY FOR SPLENIC MARGINAL ZONE LYMPHOMA
2010
At present, a prospectively validated treatment for SMZL is lacking. Despite this fact, splenectomy is still deemed to be the best choice for patients requiring treatment. Nevertheless, the high fraction of patients achieving a clinical response following splenectomy eventually relapses or progresses
Synthesis and induction of G0-G1 phase arrest with apoptosis of 3,5-dimethyl-6-phenyl-8-trifluoromethyl-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin…
2007
Lymphonodal amyloidosis: case report
2009
VEBEP REGIMEN IN PATIENTS (PTS) WITH HD AND HIV INFECTION(HD-HIV): FINAL RESULTS OF A PHASE II STUDY OF THE ITALIAN COOPERATIVE GROUP ON AIDS AND TUM…
2011
DETECTION OF HIV TYPE 1 (HIV-1) NON-B SUBTYPES IN SICILY, ITALY
2004
To evaluate the presence of HIV-1 non-B subtypes in Sicily, we sequenced and genotyped HIV-1 PR and RT regions of the pol gene using plasma from 169 HIV-1-infected adult patients. All samples were obtained from a study of antiretroviral-associated resistance mutations resulting in virological failure during highly active antiretroviral therapy (HAART). Eight (4.7%) patients had the non-B HIV-1 subtype including some circulating recombinant forms (CRFs). All of these individuals acquired the infection by heterosexual transmission. The detection of HIV-1 non-B strains was significantly associated with younger age of HIV-1 acquisition. Our findings indicate, for the first time, the presence of…
ABSOLUTE LYMPHOCYTE COUNT AS PREDICTOR FOR SURVIVAL IN NEWLY DIAGNOSED ELDERLY PATIENTS WITH MULTIPLE MYELOMA
2011
Chronic myeloid leukemia as second malignancy; restrospective multicentric study
2009
Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-co…
2008
Background: Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients. Methods: We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely…