Publications by authors named "Marianna Greco"

27 Publications

  • Page 1 of 1

Bortezomib-Loaded Mesoporous Silica Nanoparticles Selectively Alter Metabolism and Induce Death in Multiple Myeloma Cells.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.

A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative (FR-) normal cells. FOL-MSN-BTZ efficacy studies were conducted by means of growth experiments, TEM, TUNEL assay and Western Blotting analysis (WB). Metabolic investigations were performed to assess cells metabolic response to MSNs treatments. FOL-MSN-BTZ exclusively killed FR+ MM cells, leading to an apoptotic rate that was comparable to that induced by free BTZ, and the effect was accompanied by metabolic dysfunction and oxidative stress. Importantly, FOL-MSN-BTZ treated FR- normal cells did not show any significant sign of injury or metabolic perturbation, while free BTZ was still highly toxic. Notably, the vehicle alone (MSN-FOL) did not affect any biological process in both tested cell models. These data show the striking specificity of FOL-MSN-BTZ toward FR+ tumor cells and the outstanding safety of the MSN-FOL vehicle, paving the way for a future exploitation of FOL-MSN-BTZ in MM target therapy.
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http://dx.doi.org/10.3390/cancers12092709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565423PMC
September 2020

Systemic Mastocytosis with Associated Primary Myelofibrosis.

Indian J Hematol Blood Transfus 2020 Apr 28;36(2):442-443. Epub 2019 Oct 28.

2Dipartimento di Scienze Mediche e Sanità Pubblica, SC Ematologia e CTMO, Ospedale Businco, P.O. Businco, Università di Cagliari, Azienda Ospedaliera Brotzu, Via Jenner, sn, 09124 Cagliari, Italy.

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http://dx.doi.org/10.1007/s12288-019-01225-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229127PMC
April 2020

Metabolomic Analysis of Patients with Chronic Myeloid Leukemia and Cardiovascular Adverse Events after Treatment with Tyrosine Kinase Inhibitors.

J Clin Med 2020 Apr 20;9(4). Epub 2020 Apr 20.

Department of Medical Sciences and Public Health, University of Cagliari, 09042 Cagliari, Italy.

Background: Cardiovascular adverse events (CV-AEs) are considered critical complications in chronic myeloid leukemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (TKIs). The aim of our study was to assess the correlation between metabolic profiles and CV-AEs in CML patients treated with TKIs.

Methods: We investigated 39 adult CML patients in chronic-phase (mean age 49 years, range 24-70 years), with no comorbidities evidenced at baseline, who were consecutively identified with CML and treated with imatinib, nilotinib, dasatinib, and ponatinib. All patients performed Gas-Chromatography-Mass-Spectrometry-based metabolomic analysis and were divided into two groups (with and without CV-AEs).

Results: Ten CV-AEs were documented. Seven CV-AEs were rated as 3 according to the Common Toxicity Criteria, and one patient died of a dissecting aneurysm of the aorta. The patients' samples were clearly separated into two groups after analysis and the main discriminant metabolites were tyrosine, lysine, glutamic acid, ornithine, 2-piperdinecarboxylic acid, citric acid, proline, phenylalanine, threonine, mannitol, leucine, serine, creatine, alanine, and 4-hydroxyproline, which were more abundant in the CV-AE group. Conversely, myristic acid, oxalic acid, arabitol, 4-deoxy rithronic acid, ribose, and elaidic acid were less represented in the CV-AE group.

Conclusions: CML patients with CV-AEs show a different metabolic profile, suggesting probable mechanisms of endothelial damage.
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http://dx.doi.org/10.3390/jcm9041180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231160PMC
April 2020

Systemic mastocytosis with associated BCRABL1-negative atypical chronic myeloid leukemia.

Ann Hematol 2020 Feb 6;99(2):363-365. Epub 2019 Dec 6.

SC Ematologia e CTMO Dipartimento di Scienze Mediche e Sanità Pubblica, P.O. Businco, Azienda Ospedaliera Brotzu, Università di Cagliari, Cagliari, Italy.

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http://dx.doi.org/10.1007/s00277-019-03875-9DOI Listing
February 2020

Dealing with Skin and Blood-Brain Barriers: The Unconventional Challenges of Mesoporous Silica Nanoparticles.

Pharmaceutics 2018 Dec 1;10(4). Epub 2018 Dec 1.

Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.

Advances in nanotechnology for drug delivery are fostering significant progress in medicine and diagnostics. The multidisciplinary nature of the nanotechnology field encouraged the development of innovative strategies and materials to treat a wide range of diseases in a highly specific way, which allows reducing the drug dosage and, consequently, improving the patient's compliance. Due to their good biocompatibility, easy synthesis, and high versatility, inorganic frameworks represent a valid tool to achieve this aim. In this context, Mesoporous Silica Nanoparticles (MSNs) are emerging in the biomedical field. For their ordered porosity and high functionalizable surface, achievable with an inexpensive synthesis process and being non-hazardous to biological tissues, MSNs offer ideal solutions to host, protect, and transport drugs to specific target sites. Extensive literature exists on the use of MSNs as targeted vehicles for systemic (chemo) therapy and for imaging/diagnostic purposes. However, the aim of this review is to give an overview of the last updates on the potential applications of the MSNs for Topical Drug Delivery (TDD) and as drug delivery systems into the brain, discussing their performances and advantages in dealing with these intriguing biological barriers.
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http://dx.doi.org/10.3390/pharmaceutics10040250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320758PMC
December 2018

Alternative formation of amides and β-enaminones from aroyl chlorides using the TiCl-trialkylamine reagent system.

Org Biomol Chem 2018 08;16(31):5677-5683

Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria Edificio Polifunzionale, I-87036 Arcavacata di Rende (CS), Italy.

The TiCl4/NR3 reagent system has been successfully employed for the synthesis of amides and β-enaminones. The reaction of variously substituted benzoyl chlorides with the TiCl4/NR3 reagent system, by using two different experimental procedures (Method A and Method B), afforded alternatively the corresponding amides and β-enaminones as unique or major products. The two developed protocols were investigated with a series of tertiary amines. The reactions, modulated by the presence of TiCl4, provided the corresponding amides or β-enaminones with satisfactory yields. This paper reports a new method for carbon-carbon bond formation via the reaction of aroyl chlorides with the TiCl4/NR3 reagent system.
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http://dx.doi.org/10.1039/c8ob01536hDOI Listing
August 2018

The and polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia.

Oncotarget 2017 Oct 30;8(50):88021-88033. Epub 2017 Sep 30.

Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of (rs683369 [c.480C>G]) and (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, and polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, n contrast to data obtained in patients treated with imatinib, and polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.
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http://dx.doi.org/10.18632/oncotarget.21406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675690PMC
October 2017

Formation of amides: one-pot condensation of carboxylic acids and amines mediated by TiCl.

Chem Cent J 2017 Sep 15;11(1):87. Epub 2017 Sep 15.

Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria Edificio Polifunzionale, 87036, Arcavacata, CS, Italy.

A general procedure for the synthesis of amides via the direct condensation of carboxylic acids and amines in the presence of TiCl is reported. The amidation reaction was performed in pyridine at 85 °C with a wide range of substrates providing the corresponding amide products in moderate to excellent yields and high purity. The reaction proceeds with low yields when both the carboxylic acid and the amine are sterically hindered. The process takes place with nearly complete preservation of the stereochemical integrity of chiral substrates.
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http://dx.doi.org/10.1186/s13065-017-0318-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602818PMC
September 2017

HLA-G molecules and clinical outcome in Chronic Myeloid Leukemia.

Leuk Res 2017 10 18;61:1-5. Epub 2017 Aug 18.

Hematology Unit, Department of Medical Sciences and Public Health, Bone Marrow Transplant Center, R. Binaghi Hospital, University of Cagliari, Cagliari, Italy.

The human leukocyte antigen-G (HLA-G) gene encodes a tolerogenic protein known to promote tumor immune-escape. We investigated HLA-G polymorphisms and soluble molecules (sHLA-G) in 68 chronic myeloid leukemia (CML) patients. Patients with G*01:01:01 or G*01:01:02 allele had higher value of sHLA-G compared to G*01:01:03 (109.2±39.5 vs 39.9±8.8 units/ml; p=0.03), and showed lower event free survival (EFS) (62.3% vs 90.0%; p=0.02). The G*01:01:03 allele was associated with higher rates and earlier achievement of deep molecular response (MR) (100% vs 65%, median of 8 vs 58 months, p=0.001). HLA-G alleles with higher secretion of sHLA-G seem associated with lower EFS, possibly because of an inhibitory effect on the immune system. Conversely, lower levels of sHLA-G promoted achievement of MR, suggesting increased cooperation with immune system.
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http://dx.doi.org/10.1016/j.leukres.2017.08.005DOI Listing
October 2017

Genetic risk of prediabetes and diabetes development in chronic myeloid leukemia patients treated with nilotinib.

Exp Hematol 2017 11 28;55:71-75. Epub 2017 Jul 28.

Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. Electronic address:

Impaired fasting glucose and type 2 diabetes represent adverse events in patients with chronic myeloid leukemia (CML) treated with the second generation tyrosine kinase inhibitor nilotinib. An unweighted genetic risk score (uGRS) for the prediction of insulin resistance, consisting of 10 multiple single-nucleotide polymorphisms, has been proposed. We evaluated uGRS predictivity in 61 CML patients treated with nilotinib. Patients were genotyped for IRS1, GRB14, ARL15, PPARG, PEPD, ANKRD55/MAP3K1, PDGFC, LYPLAL1, RSPO3, and FAM13A1 genes. The uGRS was based on the sum of the risk alleles within the set of selected single-nucleotide polymorphisms. Molecular response (MR) and MR were achieved in 90% and 79% of patients, respectively. Before treatment, none of the patients had abnormal blood glucose. During treatment and subsequent follow-up at 80.2 months (range: 1-298), seven patients (11.5%) had developed diabetes that required oral treatment, a median of 14 months (range: 3-98) after starting nilotinib treatment. Twelve patients (19.7%) had developed prediabetes. Prediabetes/diabetes-free survival was significantly higher in patients with a uGRS <10 than in those with higher scores (100% vs. 22.8 ± 12.4%, p <0.001). Each increment of one unit in the uGRS caused a 42% increase in the prediabetes/diabetes risk (hazard ratio = 1.42, confidence interval: 1.04-1.94, p = 0.026). The presence of more than 10 allelic variants associated with insulin secretion, processing, sensitivity, and clearance is predictive of prediabetes/diabetes development in CML patients treated with nilotinib. In clinical practice, uGRS could help tailor the best tyrosine kinase inhibitor therapy.
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http://dx.doi.org/10.1016/j.exphem.2017.07.007DOI Listing
November 2017

Bone Marrow Homing and Engraftment Defects of Human Hematopoietic Stem and Progenitor Cells.

Mediterr J Hematol Infect Dis 2017 19;9(1):e2017032. Epub 2017 Apr 19.

Hematology Unit, Bone Marrow Transplant Center, R. Binaghi Hospital, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

Homing of hematopoietic stem cells (HSC) to their microenvironment niches in the bone marrow is a complex process with a critical role in repopulation of the bone marrow after transplantation. This active process allows for migration of HSC from peripheral blood and their successful anchoring in bone marrow before proliferation. The process of engraftment starts with the onset of proliferation and must, therefore, be functionally dissociated from the former process. In this overview, we analyze the characteristics of stem cells (SCs) with particular emphasis on their plasticity and ability to find their way home to the bone marrow. We also address the problem of graft failure which remains a significant contributor to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Within this context, we discuss non-malignant and malignant hematological disorders treated with reduced-intensity conditioning regimens or grafts from human leukocyte antigen (HLA)-mismatched donors.
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http://dx.doi.org/10.4084/MJHID.2017.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419183PMC
April 2017

What Unrelated Hematopoietic Stem Cell Transplantation in Thalassemia Taught us about Transplant Immunogenetics.

Mediterr J Hematol Infect Dis 2016 20;8(1):e2016048. Epub 2016 Oct 20.

Bone Marrow Transplant Center, R. Binaghi Hospital - ASL 8, Cagliari, Italy; Hematology Unit, Department of Medical Sciences, University of Cagliari, Italy.

Although the past few decades have shown an improvement in the survival and complication-free survival rates in patients with beta-thalassemia major and gene therapy is already at an advanced stage of experimentation, hematopoietic stem cell transplantation (HSCT) continues to be the only effective and realistic approach to the cure of this chronic non-malignant disease. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with HSCT from other sources. Nowadays, the availability of an international network of voluntary stem cell donor registries and cord blood banks has significantly increased the odds of finding a suitable HLA matched donor. Stringent immunogenetic criteria for donor selection have made it possible to achieve overall survival (OS) and thalassemia-free survival (TFS) rates comparable to those of sibling transplants. However, acute and chronic graft-versus-host disease (GVHD) remains the most important complication in unrelated HSCT in thalassemia, leading to significant rates of morbidity and mortality for a chronic non-malignant disease. A careful immunogenetic assessment of donors and recipients makes it possible to individualize appropriate strategies for its prevention and management. This review provides an overview of recent insights about immunogenetic factors involved in GVHD, which seem to have a potential role in the outcome of transplantation for thalassemia.
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http://dx.doi.org/10.4084/MJHID.2016.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111522PMC
October 2016

FGF2 and EGF Are Required for Self-Renewal and Organoid Formation of Canine Normal and Tumor Breast Stem Cells.

J Cell Biochem 2017 03 28;118(3):570-584. Epub 2016 Nov 28.

Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.

Recent studies suggest that human tumors are generated from cancer cells with stem cell (SC) properties. Spontaneously occurring cancers in dogs contain a diversity of cells that like for human tumors suggest that certain canine tumors are also generated from cancer stem cells (CSCs). CSCs, like normal SCs, have the capacity for self-renewal as mammospheres in suspension cultures. To understand how cells with SC properties contribute to canine mammary gland tumor development and progression, comparative analysis between normal SCs and CSCs, obtained from the same individual, is essential. We have utilized the property of sphere formation to develop culture conditions for propagating stem/progenitor cells from canine normal and tumor tissue. We show that cells from dissociated mammospheres retain sphere reformation capacity for several serial passages and have the capacity to generate organoid structures ex situ. Utilizing various culture conditions for passaging SCs and CSCs, fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) were found to positively or negatively regulate mammosphere regeneration, organoid formation, and multi-lineage differentiation potential. The response of FGF2 and EGF on SCs and CSCs was different, with increased FGF2 and EGF self-renewal promoted in SCs and repressed in CSCs. Our protocol for propagating SCs from normal and tumor canine breast tissue will provide new opportunities in comparative mammary gland stem cell analysis between species and anticancer treatment and therapies for dogs. J. Cell. Biochem. 118: 570-584, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25737DOI Listing
March 2017

RNA-Generated and Gene-Edited Induced Pluripotent Stem Cells for Disease Modeling and Therapy.

J Cell Physiol 2017 Jun 20;232(6):1262-1269. Epub 2016 Dec 20.

Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania.

Cellular reprogramming by epigenomic remodeling of chromatin holds great promise in the field of human regenerative medicine. As an example, human-induced Pluripotent Stem Cells (iPSCs) obtained by reprograming of patient somatic cells are sufficiently similar to embryonic stem cells (ESCs) and can generate all cell types of the human body. Clinical use of iPSCs is dependent on methods that do not utilize genome altering transgenic technologies that are potentially unsafe and ethically unacceptable. Transient delivery of exogenous RNA into cells provides a safer reprogramming system to transgenic approaches that rely on exogenous DNA or viral vectors. RNA reprogramming may prove to be more suitable for clinical applications and provide stable starting cell lines for gene-editing, isolation, and characterization of patient iPSC lines. The introduction and rapid evolution of CRISPR/Cas9 gene-editing systems has provided a readily accessible research tool to perform functional human genetic experiments. Similar to RNA reprogramming, transient delivery of mRNA encoding Cas9 in combination with guide RNA sequences to target specific points in the genome eliminates the risk of potential integration of Cas9 plasmid constructs. We present optimized RNA-based laboratory procedure for making and editing iPSCs. In the near-term these two powerful technologies are being harnessed to dissect mechanisms of human development and disease in vitro, supporting both basic, and translational research. J. Cell. Physiol. 232: 1262-1269, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25597DOI Listing
June 2017

Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients.

J Hematol Oncol 2016 07 29;9(1):63. Epub 2016 Jul 29.

Hematology Unit, Department of Medical Sciences, Bone Marrow Transplant Center, R. Binaghi Hospital, University of Cagliari, Ospedale "R. Binaghi", Via Is Guadazzonis, 3, 09126, Cagliari, Italy.

We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age-corrected RTL (acRTL) was also obtained. The 36-month probability of treatment-free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002). CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation.
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http://dx.doi.org/10.1186/s13045-016-0293-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966800PMC
July 2016

The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR) A haplotype in patients with advanced-stage classic Hodgkin lymphoma.

J Hematol Oncol 2016 Mar 16;9:26. Epub 2016 Mar 16.

Hematology Unit, Department of Medical Sciences "M. Aresu", University of Cagliari, Via Is Guadazzonis, 3, 09126, Cagliari, Italy.

Background: Interim positron emission tomography after 2 cycles of ABVD (iPET-2) is a good predictor of outcome in advanced-stage classic Hodgkin lymphoma. So far, there are no other prognostic biomarkers capable of identifying chemotherapy refractory patients with comparable accuracy. Despite the considerable amount of evidence suggesting that antitumor immune surveillance is downregulated in classic Hodgkin lymphoma (cHL), few data exist on the impairment of natural killer cell function and the role of their killer immunoglobulin-like receptors (KIRs).

Methods: We investigated KIR gene frequencies, KIR haplotypes, and KIR-ligand combinations in a cohort of 135 patients with advanced-stage classic Hodgkin lymphoma and 221 healthy controls. We furthermore evaluated the correlation of KIR genes and KIR haplotypes with the achievement of negative iPET-2.

Results: In the cohort of patients, the 5-year overall survival and progression-free survival were 93.6 and 79%, respectively. Homozygosity for KIR A haplotype and the HLA-C1 KIR ligand (KIR-AA/C1C1) was significantly higher in healthy controls (15.7 vs. 4.8%, p = 0.001). The KIR-AA genotype resulted to have a significant predictive power for achieving iPET-2 negativity (p = 0.039).

Conclusions: Homozygosity for KIR A haplotype offers protection against classic Hodgkin lymphoma. The association found for the KIR-AA genotype and achievement of negative iPET-2 suggests that KIR-AA could be used in clinical practice to enhance the chemosensitivity predictive power of iPET-2. Our results point to the possibility of adapting treatment strategies based on the combination of KIR biomarkers and PET scan.
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http://dx.doi.org/10.1186/s13045-016-0255-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793496PMC
March 2016

Killer immunoglobulin-like receptors can predict TKI treatment-free remission in chronic myeloid leukemia patients.

Exp Hematol 2015 Dec 22;43(12):1015-1018.e1. Epub 2015 Aug 22.

Hematology Unit, Department of Medical Sciences, Bone Marrow Transplant Center, R. Binaghi Hospital, University of Cagliari, Cagliari, Italy.

Several factors are predictive of treatment-free remission (TFR) in chronic myeloid leukemia (CML), but few data exist on the role of natural killer (NK) cells and their killer-cell immunoglobulin-like receptors (KIRs). KIR and human leukocyte antigen (HLA) genotypes were investigated in 36 CML patients who discontinued tyrosine kinase inhibitor (TKI) treatment after achieving deep molecular response (MR(4.5)). Cumulative TFR was significantly higher in patients homozygous for KIR A haplotype (85.7% vs. 45.5%; p = 0.029). Younger age, Bx haplotype, and the combination KIR3DS1/KIR3DL1 present/HLA-Bw4 present were significantly associated with relapse. KIR genotypes could prove useful in identifying patients that are likely to maintain MR(4.5) after discontinuing TKI treatment.
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http://dx.doi.org/10.1016/j.exphem.2015.08.004DOI Listing
December 2015

Safe discontinuation of nilotinib in a patient with chronic myeloid leukemia: a case report.

J Med Case Rep 2014 Sep 6;8:295. Epub 2014 Sep 6.

Bone Marrow Transplant Center, "R Binaghi" Hospital, Via Is Guadazzonis 3, 09126 Cagliari, Italy.

Introduction: Although there is a considerable amount of data in the literature on safe discontinuation of first-generation tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia, little is known about discontinuation of second-generation tyrosine kinase inhibitor therapy. Most previous studies have been focused on dasatinib, and the few cases of nilotinib withdrawal that have been reported had a median follow-up of 12 months. To the best of our knowledge, the present report is the first to describe nilotinib withdrawal with 30 months of follow-up.

Case Presentation: We report the case of a 64-year-old Caucasian man diagnosed with chronic-phase chronic myeloid leukemia in April 2005. After 4 years of treatment with imatinib, he became intolerant to the drug and was switched to nilotinib. Two years later, he decided to stop nilotinib. Undetectable molecular response persisted for 30 months after discontinuation of the drug.

Conclusion: Our present case suggests that nilotinib withdrawal is safe for patients with chronic myeloid leukemia who achieve a stable undetectable molecular response. Our patient was homozygous for killer immunoglobulin-like receptor haplotype A, previously reported to be a promising immunogenetic marker for undetectable molecular response. We recommend additional studies to investigate patient immunogenetic profiles and their potential role in complete response to therapy.
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http://dx.doi.org/10.1186/1752-1947-8-295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160914PMC
September 2014

Immunological deregulation in classic hodgkin lymphoma.

Mediterr J Hematol Infect Dis 2014 1;6(1):e2014039. Epub 2014 Jun 1.

Hematology Unit, Department of Medical Sciences "Mario Aresu," University of Cagliari, Italy.

Classic Hodgkin Lymphoma (cHL) has a unique histology since only a few neoplastic cells are surrounded by inflammatory accessory cells that in the last years have emerged as crucial players in sustaining the course of disease. In addition, recent studies suggest that the abnormal activity of these inflammatory cells (such as deregulation in regulatory T cells signaling, expansion of myeloid derived suppressor cells, HLA-G signaling and natural killer cells dysfunction) may have prognostic significance. This review is focused on summarizing recent advanced in immunological defects in cHL with translational implications.
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http://dx.doi.org/10.4084/MJHID.2014.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063611PMC
June 2014

Early Complete Molecular Response to First-Line Nilotinib in Two Patients with Chronic Myeloid Leukemia Carrying the p230 Transcript.

Case Rep Hematol 2013 11;2013:871476. Epub 2013 Jul 11.

Hematology Unit and Bone Marrow Transplantation Center, "R. Binaghi" Hospital, Via Is Guadazzonis 3, 09126 Cagliari, Italy.

Chronic myeloid leukemia (CML) with the rare fusion gene e19a2, encoding a p230 protein, has been described in patients with typical or rather aggressive clinical course. Although tyrosine kinase inhibitors (TKIs) induce a substantial cytogenetic and molecular response in all phases of CML, a minority of p230 positive patients have been treated with TKIs. We report two cases of CML patients carrying the p230 transcript, who achieved fast and deep complete molecular response (CMR) after frontline treatment with nilotinib. Our results suggest the use of nilotinib as frontline agent for the treatment of this CML variant.
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http://dx.doi.org/10.1155/2013/871476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728508PMC
August 2013

Early Death in Two Patients with Acute Promyelocytic Leukemia Presenting the bcr3 Isoform, FLT3-ITD Mutation, and Elevated WT1 Level.

Case Rep Hematol 2013 7;2013:896394. Epub 2013 Jul 7.

Hematology Unit and Bone Marrow Transplantation Center, "R. Binaghi" Hospital, Via Is Guadazzonis 3, 09126 Cagliari, Italy.

Despite major advances in the treatment of acute promyelocytic leukemia (APL), the problem of early death (ED) remains unsolved. Alongside the currently known clinical and hematological risk factors, prognostic significance has been attributed to internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD), hypogranular variant morphology, and the bcr-3 isoform of PML-RAR α . We describe premature death of two patients with the hypogranular variant of APL who presented remarkably high expression levels of Wilms' tumor gene (WT1). Our results point to WT1 as an important prognostic factor of ED that needs to be promptly evaluated in all newly diagnosed cases of APL.
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http://dx.doi.org/10.1155/2013/896394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722971PMC
August 2013

Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients.

Exp Hematol 2013 May 1;41(5):424-31. Epub 2013 Feb 1.

Bone Marrow Transplant Center, R. Binaghi Hospital - ASL 8, Cagliari, Italy.

Several recent reports suggest a possible role for killer immunoglobulin-like receptors (KIR) in the onset of chronic myeloid leukemia (CML) and response to therapy with tyrosine kinase inhibitors (TKIs). To explore this hypothesis, we studied KIRs and their human leukocyte antigen class I ligands in 59 consecutive patients with chronic-phase CML (mean age, 53 years; range, 23-81 years) and a group of 121 healthy control participants belonging to the same ethnic group as the patients. The 2-year cumulative incidence of complete molecular response, obtained after a median of 27 months (range, 4-52 months), was 51.2%. An increased frequency of the activating receptor KIR2DS1 (pm = 0.05) and a reduced frequency of the KIR-ligand combination KIR2DS2/2DL2 absent/C1 present (pm = 0.001) were significantly associated with CML. Moreover, KIR repertoires in patients appeared to influence response to TKI therapy. Homozygosity for KIR haplotype A (pm = 0.01), a decreased frequency of the inhibitory KIR gene KIR2DL2 (pm = 0.02), and low numbers of inhibitory KIR genes (pm = 0.05) were all significantly associated with achievement of complete molecular remission. These data suggest that a decrease in properly stimulated and activated NK cells might contribute to the occurrence of CML and indicate homozygosity for KIR haplotype A as a promising immunogenetic marker of complete molecular response that could help clinicians decide whether to withdraw treatment in patients with CML.
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http://dx.doi.org/10.1016/j.exphem.2013.01.008DOI Listing
May 2013

Liver repopulation by transplanted hepatocytes and risk of hepatocellular carcinoma.

Transplantation 2006 Nov;82(10):1319-23

Dipartimento di Scienze e Tecnologie Biomediche, Università di Cagliari, Cagliari, Italy.

Background: Transplantation of isolated hepatocytes in rats treated with retrorsine (RS) results in massive repopulation of the host liver. In this study, the long-term fate of hepatocytes transplanted into RS-treated recipients was followed for up to two years.

Methods: Dipeptidyl-peptidase type IV-deficient (DPPIV) Fischer 344 rats were given two injections of RS (30 mg/kg), followed by transplantation of 2 million hepatocytes, isolated from a syngenic, DPPIV donor.

Results: Extensive (91+/-7%) liver replacement by transplanted hepatocytes was observed in animals sacrificed 18 months posttransplantation. Similar levels of repopulation persisted at two years (87+/-5%). No evidence of preneoplastic and/or neoplastic evolution of the transplanted cell population was present in the RS-treated and repopulated livers at any time point considered. Furthermore, serum parameters related to hepatocyte function and integrity were in the normal range. In control groups given cell transplantation in the absence of prior treatment with RS, only small clusters of donor-derived, DPPIV hepatocytes were discerned.

Conclusions: These results indicate that liver repopulation in this model is largely stable, persisting for up to two years and allowing for a normal liver function. In addition, no increased risk of neoplastic transformation appears to be associated with the process of liver repopulation for as long as over two thirds of the life span of the recipient animal.
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http://dx.doi.org/10.1097/01.tp.0000228239.78290.13DOI Listing
November 2006

Aging is associated with increased clonogenic potential in rat liver in vivo.

Aging Cell 2006 Oct 15;5(5):373-7. Epub 2006 Aug 15.

Department of Biomedical Sciences and Biotechnology, Section of Experimental Pathology, University of Cagliari, Cagliari, Italy.

Cancer increases with age and often arises from the selective clonal growth of altered cells. Thus, any environment favoring clonal growth per se poses a higher risk for cancer development. Using a genetically tagged animal model, we investigated whether aging is associated with increased clonogenic potential. Groups of 4-, 12-, 18-, and 24-month-old Fischer 344 rats were infused (via the portal vein) with 2x10(6) hepatocytes isolated from a normal syngenic 2-month-old donor. Animals deficient in dipeptidyl-peptidase type IV (DPP-IV-) enzyme were used as recipients, allowing for the histochemical detection of injected DPP-IV+ cells. Groups of animals were sacrificed at various times thereafter. No growth of DPP-IV+ transplanted hepatocytes was present after either 2 or 6 months in the liver of rats transplanted at young age, as expected. In striking contrast, significant expansion of donor-derived cells was seen in animals transplanted at the age of 18 months: clusters comprising 7-10 DPP-IV+ hepatocytes/cross-section were present after 2 months and were markedly enlarged after 6 months (mean of 88+/-35 cells/cluster/cross-section). These results indicate that the microenvironment of the aged liver supports the clonal expansion of transplanted normal hepatocytes. Such clonogenic environments can foster the selective growth of pre-existing altered cells, thereby increasing the overall risk for cancer development associated with aging.
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http://dx.doi.org/10.1111/j.1474-9726.2006.00230.xDOI Listing
October 2006

Cyclin D1 is up-regulated in hepatocytes in vivo following cell-cycle block induced by retrorsine.

J Hepatol 2005 Sep;43(3):485-90

Section of Experimental Pathology, Department of Biomedical Sciences and Biotechnology, University of Cagliari, Via Porcell, 4, 09125 Cagliari, Italy.

Background/aims: We reported massive liver repopulation by transplanted hepatocytes in rats given retrorsine (RS), a pyrrolizidine alkaloid which blocks proliferation of resident cells. In these studies, molecular alterations induced by RS on hepatocyte cell cycle were investigated.

Methods: Animals were treated according to the protocol for liver repopulation, i.e. two injections of RS (30 mg/kg) followed by two-thirds partial hepatectomy (PH) and were sacrificed at various time points thereafter. Livers were analyzed for the expression of cell cycle-related genes.

Results: Prior to PH, increased cyclin D1 mRNA and protein levels were found in livers of RS-treated rats. Expression of PCNA was also increased; however, DNA synthesis was not significantly changed. Other cyclins, including cyclin B and cyclin E, were not induced. Cyclin D1 expression increased in controls post-PH and then declined by 48 h, as expected. By contrast, no such modulation of cyclin D1 levels was seen in RS group receiving PH and expression remained high at 48 h, without mitotic division.

Conclusions: Exposure to RS is able to block cell cycle progression after cyclin D1 and PCNA induction, but prior to S phase. Such persistent block outside the resting phase may contribute to the selective replacement of resident cells during liver repopulation.
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http://dx.doi.org/10.1016/j.jhep.2005.03.029DOI Listing
September 2005