In JoVE (2)

Other Publications (201)

Articles by Mario Petrini in JoVE

 JoVE Bioengineering

Mesenchymal Stromal Cell Culture and Delivery in Autologous Conditions: A Smart Approach for Orthopedic Applications

1Dept. of Clinical and Experimental Medicine, University of Pisa, 2OtoLab, Azienda Ospedaliero-Universitaria Pisana (AOUP), 3Dept. of Civil and Industrial Engineering, University of Pisa, 4Immunohematology Operative Unit, Azienda Ospedaliero-Universitaria Pisana (AOUP), 5Dept. Of Surgical, Medical, Molecular Pathology and Emergency Medicine, University of Pisa, 6II Orthopedic and Traumatologic Clinic, Azienda Ospedaliero-Universitaria Pisana (AOUP)


JoVE 54845

Other articles by Mario Petrini on PubMed

Bone and Bone Marrow Interactions: Hematological Activity of Osteoblastic Growth Peptide (OGP)-derived Carboxy-terminal Pentapeptide. II. Action on Human Hematopoietic Stem Cells

Leukemia Research. Sep, 2002  |  Pubmed ID: 12127560

Osteogenic growth peptide (OGP) is a peptide exerting regulatory effects on the bone and on bone marrow. The carboxy-terminal pentapeptide (OGP10-14) is the biologically active portion of OGP. We evaluated OGP10-14 hematopoietic activity performing colony-forming tests on human stem cells derived by bone marrow, peripheral blood and cord blood. Granulocyte-macrophage colony-forming unit (CFU) were significantly increased in OGP10-14-treated samples, while granulocyte-erythrocyte-monocyte-megakaryocyte CFU and burst-forming unit (BFU) erythroid were increased only in the cord blood test.Moreover, OGP10-14 preserves stem cells self renewal potential in long-term culture (LTC) initiating cells and acts directly on CD34+ enriched cells or by increasing activity of stem cell factor (SCF) and granulocyte-megakaryocyte colony-stimulating factor.

Bone and Bone-marrow Interactions: Haematological Activity of Osteoblastic Growth Peptide (OGP)-derived Carboxy-terminal Pentapeptide. Mobilizing Properties on White Blood Cells and Peripheral Blood Stem Cells in Mice

Leukemia Research. Jan, 2002  |  Pubmed ID: 11734300

Osteogenic growth peptide (OGP) increases blood and bone marrow cellularity in mice, and enhances engraftment of bone marrow transplant. Carboxy-terminal pentapeptide (OGP10-14) holds several properties of full-length polypeptide. We evaluated whether synthetic OGP-derived pentapeptide (sOGP10-14) has some activity on peripheral blood cell recovery after cyclophosphamide-induced aplasia, and on stem cell mobilization. Peripheral blood stem cell (PBSC) mobilization was evaluated by administering granulocyte-colony stimulating factor (G-CSF) or sOGP10-14 after cyclophosphamide (CTX) injection. Haematological parameters and CD34/Sca-1 positive cells were sequentially evaluated. Colony-forming tests were performed in bone marrow cells from CTX-, G-CSF- and sOGP10-14-treated mice. sOGP10-14 was able to enhance band cells and monocyte recovery after cyclophosphamide administration. White blood cell (WBC) counts reached the maximum peak by day +10 but, on day +7, a significant recovery was already detected in sOGP10-14 treated mice. On day +10 the WBC increase in sOGP10-14-treated mice was comparable to that found in G-CSF treated ones. Moreover, CD34/Sca-1 positive early precursors were significantly mobilized by sOGP10-14 compared to the control group. In sOGP10-14-treated mice, the colony-forming unit-granulocyte-macrophage-megakaryocyte (GEMM-CFU) and burst-forming unit-erythroid (BFU-E) were significantly increased in bone marrow cells in comparison to mice treated with CTX only. These results suggest a central role of sOGP10-14 in bone and bone marrow interaction, and a possible role of sOGP10-14 as a mobilizing agent.

Lithium Effects on Neutrophil Motility in Shwachman-Diamond Syndrome: Evaluation by Computer-assisted Image Analysis

British Journal of Haematology. Oct, 2003  |  Pubmed ID: 14531925

FLT3 Mutations Do Not Influence MDR-1 Gene Expression in Acute Myeloid Leukemia

Anticancer Research. Jul-Aug, 2003  |  Pubmed ID: 12926083

A worse outcome for patients carrying FLT3 mutations or expressing MDR1 gene has been reported. This study was designed to verify the possible co-expression of mutated-FLT3 and MDR1 genes and to evaluate their independent prognostic role.

Efficacy and Toxicity of Liposomal Daunorubicin Included in PVABEC Regimen for Aggressive NHL of the Elderly

Leukemia & Lymphoma. Mar, 2003  |  Pubmed ID: 12688316

Liposomes used for delivering antineoplastic drugs to sites of disease are able to minimize side effects and enhance therapeutic efficacy. Liposomal Daunorubicin (Daunoxome; DNX) has a selective and higher accumulation in neoplastic tissues and seems to be able to escape Multi-Drug Resistance (MDR). We treated 35 elderly patients with aggressive non-Hodgkin's lymphoma (NHL) with PVBECDNX, a regimen analogue to P-VABEC in which doxorubicin is replaced with DNX at a dose of 50 mg (first 13 patients) and thereafter 50 mg/m2. Twenty-six out of 35 patients were evaluable for response; 15 obtained a CR, 5 a PR (overall response rate of 77%). After a median follow-up of 13 months the 2-years actuarial overall survival was 75% and the failure-free survival was 71%. Two patients out of six no responders died because of progression of disease, and one died in CR because of pre-existing cardiovascular disorders. Eight patients did not tolerate DNX infusion (back pain). Non-haematological toxicity was mild. This study confirms that PVABEC-like regimens are able to induce a high overall response rate in a percentage of patients affected by aggressive lymphoma and shows that DNX is as effective as Daunorubicin in these disorders, but its acute toxicity is reduced.

Carboxy-terminal Fragment of Osteogenic Growth Peptide in Vitro Increases Bone Marrow Cell Density in Idiopathic Myelofibrosis

British Journal of Haematology. Apr, 2003  |  Pubmed ID: 12670334

Idiopathic myelofibrosis (IMF) is a clonal stem cell disorder characterized by reactive fibrosis of bone marrow sustained by a complex cytokine network. At present, no efficacious therapy for this disease exists. Synthetic carboxy-terminal pentapeptide of osteogenic growth factor (sOGP10-14) can increase bone marrow cellularity and the number of haematopoietic colonies; this study evaluated the activity of sOGP10-14 in IMF. Fragments of bone marrow biopsies from patients affected by IMF were cultured with or without the addition of sOGP10-14. Cellular density was evaluated by image analysis, and transforming growth factor-beta1 (TGF-beta1) concentration was immunologically assayed in the supernatant of cultured bone marrow biopsies. The proliferation rate of the megakaryoblastic M07-e cell line, cultured in the presence of either granulocyte-macrophage colony stimulating factor or thrombopoietin (TPO), and with or without sOGP10-14, was evaluated. Megakaryocyte colony forming unit (CFU-Mk) assay was performed on bone marrow samples of IMF patients with or without sOGP10-14. After 14 d, bone marrow cellularity was significantly increased in samples cultured with the pentapeptide. Moreover, sOGP10-14 induced a significant increase of TGF-beta in culture supernatants. TPO-primed proliferation of M07-e was reduced by sOGP10-14, and the pentapeptide significantly reduced CFU-Mk on IMF bone-marrow-derived cells. sOGP10-14 increased ex vivo bone marrow cellularity in IMF. This action could be related to the megakaryocyte inhibition induced by the interference of this pentapeptide with growth factor activities. These findings suggest that a deficiency of osteoblast-related factors may play a role in bone marrow failure in IMF.

Peripheral Blood Stem Cell Contamination Evaluated by a Highly Sensitive Molecular Method Fails to Predict Outcome of Autotransplanted Multiple Myeloma Patients

British Journal of Haematology. Feb, 2003  |  Pubmed ID: 12580954

To evaluate the clinical impact of minimal residual disease in multiple myeloma, apheretic products from 51 autotransplanted patients were tested by fluorescent (GeneScan) polymerase chain reaction (PCR). Sixty-nine per cent of harvests were contaminated when evaluated for IgH rearrangement. Forty-six patients responded to transplant, with 52.9% achieving complete response (CR). The clinical response of patients was significantly influenced by the number of re-infused CD34+ cells. Positive PCR results of re-infused harvests were not significantly related to patient outcome. Median overall survival (OS) was 33 months, and a significant advantage for patients transplanted by 12 months from diagnosis was observed. Moreover, OS was longer for patients receiving PCR-negative stem cells, with 72% of patients surviving to 70 months in the group receiving PCR-negative harvests vs 48% in the group transplanted with contaminated precursors (not statistically significant). Ex vivo purging caused a reduction of contamination of up to 3 logs; nevertheless, 80% of purged harvests remained PCR-positive and the purging procedure did not alter response or survival rates. Thus, the failure of a predictive role for this highly sensitive molecular method could be explained by the assumption that in vivo persisting malignant cells are the true source of relapse in MM.

Rituximab As Treatment for Minimal Residual Disease in Hairy Cell Leukaemia

European Journal of Haematology. Dec, 2004  |  Pubmed ID: 15522063

Purine analogues have dramatically improved the outcome of patients affected by hairy cell leukemia (HCL), although complete eradication of disease was achieved in few cases. The purpose of this study was to evaluate the role of Rituximab in eradicating minimal residual disease (MRD) in HCL patients after a pre-treatment with 2-chloro-deoxy-adenosine (2-CdA). Ten patients received four cycles of Rituximab after administration of Cladribrine. Before starting anti-CD20 antibody, two patients were in complete remission, six in partial remission and two showed no significant response to Cladribrine. All cases resulted IgH-positive. Median time from the last 2-CdA infusion was 5.7 months. Eight of 10 patients [four in partial remission (PR), two in complete remission (CR) and two unresponsive after 2-CdA] were evaluable for response. Two months after the end of anti-CD20 therapy, all evaluated patients presented a complete haematological remission. Moreover, Rituximab increased percentage of molecular remission up to 100% 1 yr after the end of treatment. Interestingly, in all cases but one, including those persistently polymerase chain reaction (PCR)-positive, semi-quantitative molecular analyses showed MRD levels lower than those found before Rituximab administration. Toxicity was very mild. The present results not only confirm the therapeutic effect of Rituximab, but also show its relevance in eradicating MRD in HCL.

Carboxy-terminal Fragment of Osteogenic Growth Peptide Regulates Myeloid Differentiation Through RhoA

Journal of Cellular Biochemistry. Dec, 2004  |  Pubmed ID: 15486974

The carboxy-terminal fragment of osteogenic growth peptide, OGP(10-14), is a pentapeptide with bone anabolic effects and hematopoietic activity. The latter activity appears to be largely enhanced by specific growth factors. To study the direct activity of OGP(10-14) on myeloid cells, we tested the pentapeptide proliferating/differentiating effects in HL60 cell line. In this cell line, OGP(10-14) significantly inhibited cell proliferation, and enhanced myeloperoxidase (MPO) activity and nitroblue tetrazolium reducing ability. Moreover, it induced cytoskeleton remodeling and small GTP-binding protein RhoA activation. RhoA, which is known to be involved in HL60 differentiation, mediated these effects as shown by using its specific inhibitor, C3. Treatment with GM-CSF had a comparable OGP(10-14) activity on proliferation, MPO expression, and RhoA activation. Further studies on cell proliferation and RhoA activation proved enhanced activity by association of the two factors. These results strongly suggest that OGP(10-14) acts directly on HL60 cells by activating RhoA signaling although other possibilities cannot be ruled out.

Quantitative Molecular Evaluation of Minimal Residual Disease in Patients with Chronic Lymphocytic Leukemia: Efficacy of in Vivo Purging by Alemtuzumab (Campath-1H)

Journal of Immunotherapy (Hagerstown, Md. : 1997). Sep-Oct, 2004  |  Pubmed ID: 15314547

Although novel therapies for chronic lymphocytic leukemia have resulted in higher hematologic response rates, the complete eradication of disease rarely occurs. Alemtuzumab (Campath-1H) seems to be extremely effective in this role in pretreated patients. The authors used a molecular semiquantitative polymerase chain reaction (PCR) method to assess the ability of alemtuzumab to induce PCR negativity in eight patients pretreated with fludarabine. IgH rearrangement was coamplified with a housekeeping gene and fluorescent PCR products were analyzed on a DNA automatic sequencer. Each patient was evaluated at diagnosis, after fludarabine, and after Campath-1H. The median interval between the last therapy course with fludarabine and the start of Campath-1H was 14 weeks. Patients received subcutaneous doses up to 10 mg, three times a week, for 12 weeks, with a median dose of 190 mg. After six cycles with fludarabine, only one patient (12.5%) achieved molecular remission, and in three other patients IgH levels decreased by 0.5 to 1 log. At the beginning of Campath-1H administration, all patients were PCR positive, including the one previously found to be negative. At the end of treatment, five patients achieved molecular remission (62.5%), four of them within 1 month after the end of therapy. Seventy-two percent of responses, with 43% of complete responses, were documented on bone marrow smears. A significant reduction of lymph node and spleen diameters was noted in 50% and 33% of patients, respectively. Four patients showed grade 2 skin reaction at the site of the subcutaneous injection and grade 1 or 2 fever. Two patients developed neutropenia (grade 2 and 3) and two hemolytic episodes. Three patients showed cytomegalovirus and one herpes zoster and Epstein-Barr virus reactivation. These results show that Campath-1H represents an efficacious in vivo purging tool with a safe profile.

Bone and Bone Marrow Interactions: Hematological Activity of Osteoblastic Growth Peptide (OGP)-derived Carboxy-terminal Pentapeptide III. Action on Human Megakaryocytopoiesis: Focus on Essential Thrombocythemia

Leukemia Research. Oct, 2004  |  Pubmed ID: 15289024

The increase of megakaryocytes and platelets that characterizes essential thrombocythemia (ET) appears to be secondary to a deregulation of megakaryocytopoiesis. The carboxy-terminal fragment of osteogenic growth peptide (OGP10-14) promotes bone formation and hemopoiesis, while it inhibits megakaryocytopoiesis. In this paper we show that treatment with synthetic OGP10-14 (sOGP10-14) induces a significant reduction of mid and large colony-forming unit-megakaryocytes (CFU-Mk) in ET patients as well as in controls, and is associated with a significant inhibition of thrombopoietin (TPO)-primed MO-7e megakaryoblastic cells proliferation. These actions appear to be related to sOGP10-14 modulation of TGF-beta(1) synthesis and/or secretion, although a direct effect on TGF-beta receptor expression cannot be excluded.

Bilateral Primary Renal Lymphoma Treated by Surgery and Chemotherapy

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. Jun, 2004  |  Pubmed ID: 15150359

Evaluation of BCRP and MDR-1 Co-expression by Quantitative Molecular Assessment in AML Patients

Leukemia Research. Apr, 2004  |  Pubmed ID: 15109536

Expression of two MDR genes, BCRP and MDR1, was evaluated by real-time PCR technique in 51 AML patients. Fifty-six percent expressed the BCRP gene, with the 48.2% showing intermediate levels. Eighty-eight percent expressed the MDR1, with 23.8% of cases at high expression. A significant correlation between BCRP and MDR1 values was found by regression analysis. Either levels of BCRP or MDR1 did not correlate with clinical characteristics of patients at diagnosis.

Expansion of TcRalphabeta+CD3+CD4-CD8- (CD4/CD8 Double-negative) T Lymphocytes in a Case of Staphylococcal Toxic Shock Syndrome

Acta Haematologica. 2004  |  Pubmed ID: 15034239

A 55-year-old woman presented with staphylococcal toxic shock syndrome (TSS). During the course of the disease a significant lymphocytosis appeared, and a high number of TcRalphabeta+CD3+CD4-CD8- (double-negative, DN) lymphocytes was observed both in bone marrow and in peripheral blood samples. Correction of the altered lymphocyte immunophenotype was observed only 6 weeks after recovery from TSS. The immunophenotype of circulating and bone marrow lymphocytes was also studied during a phase of an aspecific febrile episode observed 2 months after recovery, but no subset of DN lymphocytes was found. A small subset of DN lymphocytes can be found in normal bone marrow, liver, thymus, and skin. These cells show peculiar immune regulatory properties and can increase in certain autoimmune diseases. Our findings may represent a specific effect of lymphocyte stimulation by the staphylococcal exotoxin, which is the effector agent of TSS.

Chimerism Does Not Influence Graft-versus-myeloma and Graft-versus-host Disease in Reduced Intensity Setting

Transplant Immunology. Dec, 2005  |  Pubmed ID: 16412962

In this study we serially evaluated the chimerism status in 20 multiple myeloma patients allotransplanted with a reduced intensity regimen. All patients engrafted, with total 75% overall responses and 35% of CRs. After a median follow-up of 35 months, seven patients (35%) died, three of them due to disease progression. Four patients died before day +100, with a TRM of 20%. Nine patients (45%) developed aGVHD and six (40%) had cGVHD. Twenty-five percent of patients achieved full donor chimerism (FDC) before day +100, 42% before day +200 and 75% 24 months after graft. In our series, level of chimerism did not correlate with either the quality of response or aGVHD. No significant differences were found between bone marrow and peripheral blood samples. Analogously, even if donor DNA percentage often resulted higher in the PMN fraction than in the mononuclear one, these differences were not significant after statistical analysis. On the other hand, cGVHD was associated with increased rates of FDC, with 6/6 cases showing a full donor pattern in concomitance of the cGVHD versus 5/9 cases presenting a FDC in the group of patients without cGVHD (p=0.057). The Kaplan-Meier estimates of OS and PFS at 2 years were 59% and 58%, respectively; chimerism pattern did not impact in the predicting clinical outcome. In summary, our study shows that a stable engraftment and high frequency of donor chimerism are achievable after a reduced intensity conditioning regimen. Moreover, even as result of a single center experience, we suggest that chimerism, graft-versus-myeloma and GVHD would represent distinct entities that require larger immunological studies for further clarification.

Effect of Epirubicin-based Chemotherapy and Dexrazoxane Supplementation on QT Dispersion in Non-Hodgkin Lymphoma Patients

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie. Dec, 2005  |  Pubmed ID: 16325366

Aim of the present study was to assess the effect of epirubicin-based chemotherapy on QT interval dispersion in patients with aggressive non-Hodgkin lymphoma (NHL), and the effect of dexrazoxane supplementation. Prolongation of QT dispersion may not only represent a sensitive tool in identifying the first sign of anthracycline-induced cardiotoxicity, but it may serve also in identifying patients who are at risk of arrhythmic events.

Quantitative Molecular Monitoring of BCR-ABL and MDR1 Transcripts in Patients with Chronic Myeloid Leukemia During Imatinib Treatment

Cancer Genetics and Cytogenetics. Oct, 2005  |  Pubmed ID: 16157201

Different mechanisms could sustain Imatinib resistance, including overexpression of MDR1, a gene already known to be responsible for multidrug resistance in other hematologic malignancies. In search for a possible correlation, BCR-ABL and MDR1 expression were measured in 115 serial bone marrow samples from 33 CML patients during Imatinib treatment. All patients achieved complete hematologic responses, and 22 patients also achieved complete cytogenetic responses, with median BCR-ABL mRNA values significantly lower than those observed in the group of cases that were persistently Philadelphia positive. All three cases treated during the accelerated phase showed disease progression after an initial period of remission; all presented either increased levels of BCR-ABL or MDR1 3 months before clinical progression. In the subgroup of cases treated during the chronic phase, BCR-ABL and MDR1 levels were significantly correlated after 3 and 6 months (88 and 80%, respectively) but not after 12 months of treatment (32%). Reported data maintain that MDR1 expression would play an important role in Imatinib resistance when the disease is not fully controlled (e.g., progressive disease or during the first months of treatment).

[Bone Marrow Infiltration in B-cell Non-Hodgkin's Lymphomas: Comparison Between Flow Cytometry and Bone Marrow Biopsy]

Recenti Progressi in Medicina. Jun, 2005  |  Pubmed ID: 16078757

A comparison of flow cytometry (FC) and bone marrow biopsy (BMB) to evaluate bone marrow infiltration was made in 114 patients suffering from B-cell non-Hodgkin's lymphomas (NHLs; 51 at diagnosis, 63 during post-therapy follow-up). The following parameters were indicative of bone marrow infiltration: altered surface k/l ratio; specific immunophenotypic pattern in particular NHLs (CLL, mantle cell lymphoma, hairy cell leukemia). FC and BMB agreed in 89.5% of cases (i.e. both showed 48 positive and 54 negative cases). In discordant cases (7.9%) and in cases not evaluable by FC (2.6%) IgH rearrangement and bcl-1 gene expression, both evaluated by PCR methods, were used to detect bone marrow infiltration with higher precision. These results show that a more complex analysis of bone marrow is needed to diagnose bone marrow infiltration, particularly in samples with minimal residual disease.

Imatinib Therapy in Hypereosinophilic Syndrome: a Case of Molecular Remission

Leukemia Research. Sep, 2005  |  Pubmed ID: 16038739

Prognostic Role of Minimal Residual Disease in Multiple Myeloma Patients After Non-myeloablative Allogeneic Transplantation

Leukemia Research. Aug, 2005  |  Pubmed ID: 15978948

This study evaluates the prognostic value of molecular monitoring of minimal residual disease (MRD) in 20 patients with multiple myeloma (MM) following autologous (peripheral blood stem cell transplantation, PBSCT) and non-myeloablative allogeneic (NMT) transplant. All patients completed their program, with a treatment-related mortality (TRM) of 20% and a 2-year progression-free survival (PFS) of 51%. After PBSCT, only 3 patients (15%) achieved PCR-negativity, versus 12 (60%) after NMT. The eradication of MRD had a favorable impact on 2-year OS. In fact, 76% of patients with no detectable MRD was still alive versus 34% of persistently IgH-positive cases (p=0.03). PCR status did not correlate with chimerism percentage: Seventy-five percent of patients achieved full donor chimerism, which was more frequently observed in cases presenting cGHVD (p=0.01). These data sustain the relevant role of molecular monitoring in MM patients undergoing NMT. MRD monitoring would assist physicians in making additional therapeutic decisions to better control this hematological malignancy.

Glycosylated or Non-glycosylated G-CSF Differently Influence Human Granulocyte Functions Through RhoA

Leukemia Research. Nov, 2005  |  Pubmed ID: 15916805

Granulocyte function may be altered after in vivo G-CSF administration and this has been related to both an immaturity of mobilized cells and to a defect in F-actin polymerization. In this paper we show that in resting Filgrastim (non-glycosylated G-CSF)-pulsed cells, F-actin polymerization, membrane-linked RhoA and cell polarization are enhanced compared to those found in resting Lenograstim (glycosylated G-CSF)-cells. The basal hyper-activation of RhoA could be responsible for the morphological and functional modifications of Filgrastim-mobilized cells. Moreover, Filgrastim-mobilized cells, but not Lenograstim-mobilized cells, are unable to correctly respond to LPS stimulation, as demonstrated by minor further RhoA activation and cell elongation.

Simultaneous Appearance of Acute Myeloid Leukemia in a Patient with Bilateral Primary Uveal Melanoma

Melanoma Research. Oct, 2006  |  Pubmed ID: 17013099

We report a rare case of a patient with bilateral uveal melanoma (the first eye surgically treated 6 years before the occurrence of melanoma in the contralateral eye), who developed an acute myeloid leukaemia.

More on Donor-derived T-cell Leukemia After Bone Marrow Transplantation

The New England Journal of Medicine. Jul, 2006  |  Pubmed ID: 16837689

Actin Polymerization in Neutrophils from Donors of Peripheral Blood Stem Cells: Divergent Effects of Glycosylated and Nonglycosylated Recombinant Human Granulocyte Colony-stimulating Factor

American Journal of Hematology. May, 2006  |  Pubmed ID: 16628714

Neutrophil functions can be modified by Recombinant human G-CSF (rhG-CSF) treatment, with divergent effects on phagocytosis, motility, bactericidal activity, and surface molecule expression. Neutrophil morphology is modified by treatment with filgrastim (the nonglycosylated form of rhG-CSF), while it is not affected by lenograstim (the glycosylated type of rhG-CSF). Little information is available about actin polymerization in neutrophils from subjects treated with the two types of rhG-CSF. In the current paper we evaluated two groups of donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. Ten subjects were treated with filgrastim and 10 with lenograstim to mobilize PBSC; 15 blood donors were evaluated as a control group. Actin polymerization (both spontaneous and fMLP-stimulated) was studied by a flow cytometric assay. A microscopic fluorescent assay was also carried out to evaluate F-actin distribution in neutrophils. We found that filgrastim induced an increased F-actin content in resting neutrophils, along with morphologic evidence for increased actin polymerization distributed principally at the cell membrane and frequently polarized in focal areas; in addition, fMLP was not able to induce further actin polymerization. On the contrary, treatment with lenograstim was associated with F-actin content, distribution, and polymerization kinetics indistinguishable from those displayed by control neutrophils. Such experimental results show that filgrastim and lenograstim display divergent effects also on neutrophil actin polymerization and provide further explanation for previous experimental findings.

Cytoplasmic Nucleophosmin in Myeloid Sarcoma Occurring 20 Years After Diagnosis of Acute Myeloid Leukaemia

The Lancet. Oncology. Apr, 2006  |  Pubmed ID: 16574551

Primary Lymphoma of the Bladder: Case Report

American Journal of Hematology. Jan, 2006  |  Pubmed ID: 16369978

Different Gamma/delta T Clones Sustain GVM and GVH Effects in Multiple Myeloma Patients After Non-myeloablative Transplantation

Leukemia Research. May, 2006  |  Pubmed ID: 16249028

TCR gamma/delta profiles were analyzed in 13 multiple myeloma patients after allogeneic non-myeloablative transplantation. Results show that both aGVHD and minimal residual disease (MRD) eradication did significantly affect TCR gamma/delta profile. During follow-up, six patients developed an aGVHD episode; in five of them, this event fitted with a modification of the TCR profile. Eleven patients achieved PCR-negativity during follow-up. In the 90% of them, the appearance of a new predominant TCR peak was concomitant to the disappearance of the IgH clone. These results suggest that different T gamma/delta populations would sustain GVM and GVH effects after non-myeloablative allogeneic transplant.

Chronic Myeloid Leukaemia and Hairy Cell Leukaemia Coexisting in a Single Patient: Difficulties at Diagnosis and Rational of the Therapeutic Strategy

Leukemia Research. Mar, 2006  |  Pubmed ID: 16182365

Chronic myeloid leukemia (CML) and hairy cell leukemia (HCL) are two distinct haematological disorders. Only one single case of coexistence of the two pathologies at diagnoses has been previously reported. We present a second case of coexistence at diagnosis, indicating the diagnostic procedures involving morphological, immunophenotyping, and molecular testing. We decided to use Interferon as common first-line therapy and Imatinib and Rituximab (anti-CD20 monoclonal antibody), to improve the first-line therapy result, obtaining a complete molecular remission for CML and clinical remission with molecular minimal residual disease for HCL. After a critical analysis of the results, we speculate on the different clonal origin of the two pathologies.

Hairy Cell Leukemia

Current Treatment Options in Oncology. Apr, 2007  |  Pubmed ID: 17926010

Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease, characterized by splenomegaly and pancitopenia related to this. The lymphocytes present characteristic citoplasmatic projections and are positive for tartrate-resistant acid phosphatase (TRAP). Immunophenotyping is necessary to identify the co expression of CD103, CD25, CD11c associated with a typical B-cell clonally pattern and to make a differential diagnosis from other indolent malignancies. Despite the indolent clinical course, treatment is required to resolve symptoms related to splenomegaly and to reduce the incidence of severe infections that are the major complications and a common cause of death. In the past the treatment was only able to resolve the symptoms. In the revised literature, purine analog have been identified as the treatment of choice for this disease. Cladribrine (2-CdA) is able to induce more than 80% of complete remission and is also effective in relapsed patients. Rituximab after 2-CdA treatment can obtain a molecular response in most cases. The introduction of purine analog, and recently of Rituximab, in association with conventional chemotherapy can modify the clinical course of the disease with low toxicities.

Suspension of Bone Marrow-derived Undifferentiated Mesenchymal Stromal Cells for Repair of Superficial Digital Flexor Tendon in Race Horses

Tissue Engineering. Dec, 2007  |  Pubmed ID: 17919069

It has been proven that mesenchymal stromal cells (MSCs) can differentiate into tenocytes. Attempts to repair tendon lesions have been performed, mainly using scaffold carriers in experimental settings. In this article, we describe the clinical use of undifferentiated MSCs in racehorses. Significant clinical recovery was achieved in 9 of 11 horses evaluated using ultrasound analysis and their ability to return to racing. Our results show that the suspension of a small number of undifferentiated MSCs may be sufficient to repair damaged tendons without the use of scaffold support. Ultrasound scanning showed that fibers were correctly oriented. By using undifferentiated cells, no ectopic bone deposition occurred. A sufficient number of cells was recovered for therapeutic purposes in all but 1 case. We suggest that the use of autologous MSCs is a safe therapeutic method for treating incompletely (i.e., not full-thickness) damaged tendons.

Concomitant Appearance of Trisomy 8 and Isochromosome 17q in a Philadelphia-positive Clone in a Patient with Chronic Myeloid Leukemia in Chronic Phase: an Alarm for Changing Therapeutic Strategy

Cancer Genetics and Cytogenetics. Sep, 2007  |  Pubmed ID: 17854678

Acute Myeloid Leukemia and Follicular Lymphoma After Very Low Dose Radioiodine Therapy for Thyroid Diseases

Haematologica. Sep, 2007  |  Pubmed ID: 17768141

Evaluation of the MDR1, ABCG2, Topoisomerases IIalpha and GSTpi Gene Expression in Patients Affected by Aggressive Mantle Cell Lymphoma Treated by the R-Hyper-CVAD Regimen

Leukemia & Lymphoma. Aug, 2007  |  Pubmed ID: 17701580

The genomic profile of mantle cell lymphoma (MCL) has been reported to be significantly different from that of other indolent lymphoproliferative disorders, Topoisomerase IIalpha, glutathione-s-transferasepi (GSTpi) and ABCG2 (BCRP) chemoresistance genes being over-expressed in MCL. In our study, expression levels of the above mentioned genes plus MDR1 were tested on bone marrow samples from 20 patients treated with Rituximab plus hyper-CVAD regimen, in order to evaluate a possible impact of the chemoresistance phenomenon on this promising treatment regimen. All patients expressed ABCG2 and MDR1 genes; 85% of cases expressed GSTpi and topoisomerase IIalpha. Only ABCG2 were over-expressed in comparison both with marrow from healthy donors and tonsilar CD5+/CD20+ lymphocytes (adopted as normal counterpart of the neoplastic population). The overall response rate of the entire series was 87.5%, with 44% of complete responses. Fifty-seven percent of patients achieved the clearance of minimal residual disease. Levels of tested genes did not condition either quality of clinical response or PFS (76% at 24 months). Nevertheless, an ABCG2 higher expression appeared associated with a worse PFS and levels of this gene paralleled the status of minimal residual disease. A further evaluation of ABCG2 expression in larger series of MCL patients would be suitable.

Effects of Aspergillus Fumigatus Gliotoxin and Methylprednisolone on Human Neutrophils: Implications for the Pathogenesis of Invasive Aspergillosis

Journal of Leukocyte Biology. Oct, 2007  |  Pubmed ID: 17626149

Aspergillus fumigatus (AF) is a ubiquitous mold and the most common cause of invasive aspergillosis (IA) in immunocompromised patients. In stem cell transplant recipients, IA now occurs most frequently in the setting of therapy with corticosteroids, including methylprednisolone (MP). We showed previously that gliotoxin (GT), an AF-derived mycotoxin, induces apoptosis in monocytes and dendritic cells, resulting in the suppression of AF-specific T cell responses. We examined the ability of GT to induce apoptosis in polymorphonuclear leukocytes (PMN) and assessed GT effects on important neutrophil functions, including phagocytic function, degranulation, myeloperoxidase activity, and the production of reactive oxygen species (ROS). In contrast to its effects on monocytes, PMN remained resistant to GT-mediated apoptosis. Although many essential neutrophil functions were unaffected, GT inhibited phagocytosis and also induced a decrease in ROS generation by PMN. In contrast, MP therapy potentiated ROS production, suggesting a mechanism that may facilitate tissue injury in IA. Distinct from its effects on untreated PMN, GT augmented ROS production in MP-treated PMN. Our results suggest that although GT may suppress the adaptive immune response, GT may also serve to increase PMN-mediated inflammation, which is likely to play an important role in tissue destruction in the setting of IA.

Comment on "Germinal Center Helper T Cells Are Dual Functional Regulatory Cells with Suppressive Activity to Conventional CD4+ T Cells"

Journal of Immunology (Baltimore, Md. : 1950). Jul, 2007  |  Pubmed ID: 17617558

RAF-1 Over-expression Does Condition Survival of Patients Affected by Aggressive Mantle Cell Lymphoma

Leukemia Research. Nov, 2007  |  Pubmed ID: 17572489

Unexpected Cardiotoxicity in Haematological Bortezomib Treated Patients

British Journal of Haematology. Aug, 2007  |  Pubmed ID: 17561972

Association of PIM Gene Translocation and TEL/AML1 Rearrangement

Leukemia Research. Dec, 2007  |  Pubmed ID: 17560648

Stable Low IgG Levels in Relapsed Non-Hodgkin's Lymphomas

Annals of Hematology. Nov, 2007  |  Pubmed ID: 17541588

Hypothesis: Central Nervous System Delivery of Cyclosporine A for Therapy of Progressive Multifocal Leukoencephalopathy

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Jun, 2007  |  Pubmed ID: 17499020

MDR1 Polymorphism Influences the Outcome of Multiple Myeloma Patients

British Journal of Haematology. Jun, 2007  |  Pubmed ID: 17488488

The multidrug resistance gene (MDR1) has been reported to be an additional prognostic factor in acute myeloid leukaemia patients. This study evaluated the prognostic role of MDR1 in the outcome of 115 multiple myeloma patients treated with DAV (dexamethasone, doxorubicin [adryamicin] and vincristine) regimen followed by autologous transplantation. In particular, when investigating the C3435T polymorphism, a prognostic value of MDR1 genotypes for overall survival (OS) was observed. Our data suggested a longer OS for patients with C/T and T/T genotypes (log-rank test, P = 0.02) compared with patients with C/C genotype.

Two Cases of Plasma Cell Leukemia with Atypical Immunophenotype

Acta Haematologica. 2007  |  Pubmed ID: 17429194

Risperidone-induced Reduction in JC Viruria As a Surrogate Marker for Efficacy Against Progressive Multifocal Leukoencephalopathy and Hemorrhagic Cystitis

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. May, 2007  |  Pubmed ID: 17409019

CD57 Expression on Lymphoma Microenvironment As a New Prognostic Marker Related to Immune Dysfunction

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Apr, 2007  |  Pubmed ID: 17401023

NQO1*2 Polymorphism and Response to Treatment in Patients with Multiple Myeloma

Leukemia Research. Aug, 2007  |  Pubmed ID: 17337051

Poor Prognosis Chronic Myeloid Leukemia with a Complex Variant Philadelphia Translocation, T(9;10;22)(q34;q24;q11)

Leukemia Research. Dec, 2007  |  Pubmed ID: 17320954

Gliptins

Lancet (London, England). Jan, 2007  |  Pubmed ID: 17258656

Posaconazole Vs. Fluconazole or Itraconazole Prophylaxis in Patients with Neutropenia

The New England Journal of Medicine. Jan, 2007  |  Pubmed ID: 17251531

Patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome are at high risk for difficult-to-treat and often fatal invasive fungal infections.

Folate Levels in Cancer: a Vitamin for a New Challenge

Annals of Hematology. May, 2007  |  Pubmed ID: 17211521

A Therapy Resistant Myelodysplastic Syndrome Characterized by the Presence of the Rare Reciprocal Translocation T(3;12)(q26.2;p13)

Leukemia Research. Nov, 2007  |  Pubmed ID: 17210176

PEG-Filgrastim Activity on Granulocyte Functions

Leukemia Research. Oct, 2007  |  Pubmed ID: 17197023

CD19/CD8 Coexpression in B-chronic Lymphocytic Leukemia

Acta Haematologica. 2007  |  Pubmed ID: 17164580

Progressive Multifocal Leukoencephalopathy in a Haploidentical Stem Cell Transplant Recipient: a Clinical, Neuroradiological and Virological Response After Treatment with Risperidone

Antiviral Research. May, 2007  |  Pubmed ID: 17140673

JC virus (JCV) is a double-stranded DNA virus belonging to family Polyomaviridae. It causes progressive multifocal leukoencephalopathy (PML), mainly in immunosuppressed people. JCV had been shown to require the serotonin 2A receptor for host cell entry. We report a case of clinical, neuroradiological and virological response of biopsy-proven PML in a 33-year-old comatose woman after treatment with the anti-psychotic drug risperidone. Since risperidone is the tightest binding of current drugs to this receptor we think this may have blocked JCV entry in our patient, allowing her immune recovery and viral clearance.

Folate Levels and Methylation of CDKI Proteins

Leukemia Research. Apr, 2007  |  Pubmed ID: 17118446

Match Unrelated Bone Marrow Transplantation in a Case of High Risk Myelodysplastic Syndrome Treated with Azacitidine and Concomitant 1alpha-25-dihydroxyvitamin D3, As Differentiating Agent

Leukemia Research. Sep, 2007  |  Pubmed ID: 17113639

Bortezomib Inhibits T-cell Function Versus Infective Antigenic Stimuli in a Dose-dependent Manner in Vitro

Leukemia Research. Jul, 2007  |  Pubmed ID: 17045335

Phase III Trial of Consolidation Therapy with Yttrium-90-ibritumomab Tiuxetan Compared with No Additional Therapy After First Remission in Advanced Follicular Lymphoma

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Nov, 2008  |  Pubmed ID: 18854568

We conducted an international, randomized, phase III trial to evaluate the efficacy and safety of consolidation with yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with advanced-stage follicular lymphoma in first remission.

Rituximab As Treatment for Minimal Residual Disease in Hairy Cell Leukaemia: Extended Follow-up

British Journal of Haematology. Oct, 2008  |  Pubmed ID: 18710384

Good Manufacturing Practice-grade Fibrin Gel is Useful As a Scaffold for Human Mesenchymal Stromal Cells and Supports in Vitro Osteogenic Differentiation

Transfusion. Oct, 2008  |  Pubmed ID: 18657082

Recently, there has been an increased interest in using mesenchymal stromal cells (MSCs) in bone tissue engineering coupled with a suitable scaffold of both biological and synthetic origin. The cells and these constructs can be combined in vitro or directly in vivo to enhance tissue repair. MSCs are spindle-shaped cells capable of self-renewal and can be induced to differentiate mainly into osteo-, chondro-, and adipogenic-progeny types. Several biomaterials are currently available and, among them, fibrin-based constructs seem to be suitable for guiding the cells during tissue repair or regeneration due to their biocompatibility and biodegradability.

MDR1 Modulates Apoptosis in CD34+ Leukemic Cells

Annals of Hematology. Dec, 2008  |  Pubmed ID: 18629500

Changes In CD8+57+ T Lymphocyte Expansions After Autologous Hematopoietic Stem Cell Transplantation Correlate with Changes in Torquetenovirus Viremia

Transplantation. Jun, 2008  |  Pubmed ID: 18580484

Sialic Acid Moieties and 5-HT2a: Two Faces of the Same Receptor for JC Virus?

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Sep, 2008  |  Pubmed ID: 18534904

Conditioning Response to Granulocyte Colony-stimulating Factor Via the Dipeptidyl Peptidase IV-adenosine Deaminase Complex

Journal of Leukocyte Biology. Aug, 2008  |  Pubmed ID: 18511574

G-CSF is routinely used to mobilize hematopoietic stem cells (HSCs) from bone marrow (BM) into peripheral blood before aphaeresis, but HSC harvesting can be suboptimal. On the other hand, transplanted HSCs sometimes fail to engraft a recipient BM microenvironment when G-CSF is used after transplantation, as pushing-CSF will push HSCs away from marrow. So, G-CSF action needs to be potentiated by other drugs. Marrow stromal cells establish a local CXCL12 concentration gradient that is the primary homing signal for HSCs. Pharmacological interventions that modify this gradient, therefore, have potential to help HSC mobilization (by decreasing CXCL12) and engraftment (by increasing CXCL12). CXCL12 inactivation is primarily mediated by dipeptidyl peptidase-IV. We review here the currently available drugs affecting this enzyme that could be used in the clinic to achieve phase-specific help for G-CSF.

The Small Peptide OGP(10-14) Acts Through Src Kinases and RhoA Pathways in Mo-7e Cells: Morphologic and Immunologic Evaluation

Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. Jun, 2008  |  Pubmed ID: 18509267

Osteogenic growth peptide (OGP) is an endogenous tetradecapeptide present in micromolar concentrations in mammalian serum; its carboxy-terminal pentapeptide, OGP(10-14), represents its physiologically active fragment. OGP(10-14) induces proliferation and differentiation in fibroblast and osteoblast cell lines, and it enhances hematopoiesis in vitro and in vivo. The signaling pathways triggered by OGP(10-14) are not yet fully known. In the present report, we evaluated the effect of OGP(10-14) on differentiation of a cancer megakaryoblast cell line and its involvement on RhoA and Src family kinases signaling pathway.

Gelatin/PLLA Sponge-like Scaffolds Allow Proliferation and Osteogenic Differentiation of Human Mesenchymal Stromal Cells

Macromolecular Bioscience. Sep, 2008  |  Pubmed ID: 18504804

Tissue engineering has the potential to supply constructs capable of restoring the normal function of native tissue following injury. Poly(L-lactic acid) (PLLA) scaffolds are amongst the most commonly used biodegradable polymers in tissue engineering and previous studies performed on ovine fibroblasts have showed that addition of gelatin creates a favorable hydrophilic microenvironment for the growth of these cells. The attractiveness of using mesenchymal stromal cells (MSCs) in tissue regeneration is that they are able to differentiate into several lines including osteoblasts. In this study, we investigated the ability of gelatin/PLLA sponges to support the adhesion, proliferation, and osteogenic differentiation of human MSCs isolated from the bone marrow of four donors. [Figure: see text].

JAK-2V617F Mutation in RARS-t: a Target for Imatinib Therapy?

Leukemia Research. Oct, 2008  |  Pubmed ID: 18433865

Folic Acid Fortification and Cancer Risk

Lancet (London, England). Apr, 2008  |  Pubmed ID: 18424322

MDR1 Diplotypes As Prognostic Markers in Multiple Myeloma

Pharmacogenetics and Genomics. May, 2008  |  Pubmed ID: 18408561

The aim of this study was to evaluate the effect of diplotypes of MDR1 polymorphisms at positions 2677 and 3435 on the clinical outcome of multiple myeloma, in terms of response to the therapy and overall survival (OS).

Acute Myeloid Leukaemia After Treatment with (90)Y-ibritumomab Tiuxetan for Follicular Lymphoma

Hematological Oncology. Sep, 2008  |  Pubmed ID: 18383187

We report here a patient with relapsed follicular lymphoma who developed secondary acute myeloid leukaemia 15 months after radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan, the fifth described case to date. We review the literature for the potential causal relationship between RIT and secondary myelodysplastic syndromes/acute myeloid leukaemia.

CD8 Expression in B-cell Non-Hodgkin's Lymphomas

Annals of Hematology. Jul, 2008  |  Pubmed ID: 18327585

JC Viremia and Multiple Sclerosis

Journal of Neurovirology. Jan, 2008  |  Pubmed ID: 18300079

Phenobarbital-associated Bone Marrow Aplasia: a Case Report and Review of the Literature

Acta Haematologica. 2008  |  Pubmed ID: 18230962

We report on a 22-year-old female who developed aplastic anemia after administration of phenobarbital for 6 years. Being refractory to steroid and anti-lymphocyte serum, the patient received allogeneic stem cell transplantation, achieving complete remission. We discuss here the potential mechanisms by which phenobarbital and other anti-epileptic drugs can cause aplastic anemia and review the literature for previous case reports and epidemiological studies.

Other Mechanisms to Explain the Role of Reduced Folate Carrier in Cancer

European Journal of Haematology. Apr, 2008  |  Pubmed ID: 18194482

5-HT2a Inhibitors for Progressive Multifocal Leukoencephalopathy: Old Drugs for an Old Disease

The Journal of Infectious Diseases. Jan, 2008  |  Pubmed ID: 18194091

Bortezomib is Able to Reduce Angiogenesis in Half of Patients Affected by Idiopathic Myelofibrosis: an Ex Vivo Study

Leukemia Research. Aug, 2008  |  Pubmed ID: 18192008

False Positive PET Scanning Caused by Inactivated Influenza Virus Vaccination During Complete Remission from Anaplastic T-cell Lymphoma

Annals of Hematology. Apr, 2008  |  Pubmed ID: 18092164

Progressive Multifocal Leukoencephalopathy: Report of Three Cases in HIV-negative Hematological Patients and Review of Literature

Annals of Hematology. May, 2008  |  Pubmed ID: 18064459

Progressive multifocal leukoencephalopathy (PML) is a central nervous system (CNS) disease usually observed in immunodeficient patients, especially human immunodeficiency virus (HIV)-positive, caused by John Cunningham virus. This infectious complication has been described in many HIV-negative hematological patients, especially affected by lymphoproliferative diseases. PML has been observed after both chemotherapy and bone marrow transplantation and, recently, in association with rituximab. Diagnosis can be complicated, and often a CNS biopsy is required. Current treatment approaches are not effective in both HIV-positive and HIV-negative patients, and the outcome remain very poor in the majority of cases, even after combination therapies. We report three cases of PML in hematological patients, treated respectively with conventional chemotherapy and autologous and haploidentical transplantation, and review the literature on PML. All of them received rituximab, which has recently been in the focus of a Food and Drug Administration warning.

Lack of Association of NQO1 and GSTP1 Polymorphisms with Multiple Myeloma Risk

Leukemia Research. Jun, 2008  |  Pubmed ID: 18061666

Individual differences in xenobiotica metabolising capacity can influence susceptibility to multiple myeloma. NQO1 and GSTT1 polymorphisms were recently reported as risk factors for multiple myeloma and GSTP1 genotype was found to be a prognostic marker for therapy outcome in multiple myeloma. The aim of this study was to determine whether specific defective alleles of NQO1 (P187S) and GSTP1 (I105V) genes are associated with increased risk of multiple myeloma. Individual genotypes of 128 patients affected by multiple myeloma and 245 healthy controls were determined and our results do not support any major role of NQO1 or GSTP1 polymorphisms in multiple myeloma pathogenesis.

Unusual Association of Endometrial Cancer and Multiple Myeloma

Gynecologic Oncology. Aug, 2008  |  Pubmed ID: 17961643

Human Autologous Plasma-derived Clot As a Biological Scaffold for Mesenchymal Stem Cells in Treatment of Orthopedic Healing

Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society. Feb, 2008  |  Pubmed ID: 17868116

Recent advances in the isolation, expansion, and characterization of human mesenchymal stem cells (hMSCs) have raised the possibility of using them in cell therapies and tissue engineering for bone reconstruction. hMSCs, isolated from the bone marrow of eight normal adult patients, were minimally expanded ex vivo and pulsed twice toward osteogenic lineage. The cells were then included into autologous plasma-derived clots. Cytofluorimetric analysis, immunocytochemistry (osteopontin), histochemistry (alkaline phosphatase, Alcian blue, Von Kossa, and alizarin red staining), and viable/proliferation tests were performed to study both stem and differentiating cells. Although two short inductions increased osteogenic markers in hMSCs, inside the clot the cells were able to terminally differentiate into osteoblasts. Moreover, we show that the clot is able to sustain cell proliferation under appropriate cell culture conditions. Our results suggested that clot could be useful for hMSC delivery into the site of the lesion to promote bone formation. Moreover, the plasticity of this material allowed good in vitro hMSC spreading and proliferation. The advantages of using this autologous biological material are its biocompatibility and reabsorption; furthermore, using a gel as scaffold, it is possible to mold it to the shape of a bone cavity.

Long-term Propylthiouracil Use and Acute Myeloid Leukemia: a Case Report and Review of the Literature

Annals of Hematology. Mar, 2008  |  Pubmed ID: 17846771

MDR1 Pump: More Than a Drug Transporter Comment on "Regulatory Polymorphisms of Multidrug Resistance 1 (MDR1) Gene Are Associated with the Development of Childhood Acute Lymphoblastic Leukaemia" by Hattori Et Al. [Leuk. Res. (in Press)]

Leukemia Research. Feb, 2008  |  Pubmed ID: 17727946

CD45 Expression in Low-grade B-cell Non-Hodgkin's Lymphomas

Leukemia Research. Feb, 2008  |  Pubmed ID: 17692374

CD45 is a glycoprotein expressed in all lymphohemopoietic cells. Its expression increases during B-lymphocyte ontogeny. Few data are available about CD45 expression in the various types of low-grade B-cell non-Hodgkin's lymphomas (NHL). Low levels of CD45 have been reported in pathologic lymphocytes from typical chronic lymphocytic leukemia (CLL) and higher levels of this antigen have been observed in some cases of atypical CLL and in some cases of other types of NHL. One hundred and seven bone marrow samples of NHL with bone marrow infiltration were investigated: 45 typical CLL, 15 atypical CLL, 9 mantle cell lymphomas (MCL), 1 MCL with CD23 expression, 18 marginal zone lymphomas (MZL), 6 lymphoplasmacytic lymphomas (LPL), 6 follicular lymphomas (FL), and 7 hairy cell leukemias (HCL). CD45 expression was evaluated by flow cytometry: pathologic lymphocytes were identified on the basis of specific immunophenotypic profile, CD19/K or CD19/lambda co-expression. Results were expressed as median fluorescence intensity (MFI) along a 1024 linear scale. CD45 expression was measured also on autologous T-lymphocytes and a "CD45 index" was calculated as the ratio MFI of pathologic B-lymphocytes/MFI of T-lymphocytes, to normalize the results obtained. We found four CD45 expression patterns: very low in typical CLL; relatively low in MCL; intermediate intensity in MZL, LPL, and FL; very high expression in HCL. Among the atypical cases, very high CD45 expression was found in one case of CD23-negative CLL, in CD23-positive MCL, and CLL with atypical morphology. The results indicate different levels of maturation in low-grade NHL and may help to characterize such neoplasias.

Response to Chemotherapy and Tandem Autologous Transplantation of Multiple Myeloma Patients and GSTP1 and TYMS Polymorphisms

Leukemia Research. Jan, 2008  |  Pubmed ID: 17512053

This study examines the response to dexamethasone-doxorubicin-vincristine (DAV) therapy, followed by conditioning regimen and autologous stem cells transplantation (ASCT) in patients with multiple myeloma in relation with the presence of polymorphisms in genes involved in drug metabolism (GSTP1) and DNA synthesis (TYMS). GSTP1 G313G genotype (OR=5.49; 95% CI, 1.3-22.5, p=0.02) and TYMS A227A genotype (OR=3.41; 95% CI, 1.3-8.9, p=0.01) resulted significantly associated with a poor response following chemotherapy and the risk increased for the combined genotype (OR=13.54; 95% CI, 2.0-91.3, p=0.01). TYMS T157T genotype was significantly associated with a poor response after ASCT (OR=4.60; 95% CI, 1.2-16.9, p=0.02). Pre-therapeutic individual determination of the GSTP1 and TYMS polymorphisms could help in choosing the most appropriate protocol.

Transitory Marrow Aplasia During Imatinib Therapy in a Patient with Chronic Myeloid Leukemia

Leukemia Research. Jan, 2008  |  Pubmed ID: 17459473

Complex Translocation T(6;9;22)(p21.1;q34;q11) at Diagnosis is a Therapy Resistance Index in Chronic Myeloid Leukaemia

Leukemia Research. Jan, 2008  |  Pubmed ID: 17418404

Reduction of Immunoglobulin Levels During Imatinib Therapy of Chronic Myeloid Leukemia

Leukemia Research. Jan, 2008  |  Pubmed ID: 17397920

Complex Translocation T(3;9;22)(q21;q34;q11) at Diagnosis is a Negative Prognostic Index in Chronic Myeloid Leukemia

Leukemia Research. Jan, 2008  |  Pubmed ID: 17391755

Concomitant Translocation T(14;22)(q32;q11) in a Case of Chronic Myeloid Leukemia

Leukemia Research. Jan, 2008  |  Pubmed ID: 17346791

Platelet-derived Growth Factor Beta Receptor (PDGFRB) Gene is Rearranged in a Significant Percentage of Myelodysplastic Syndromes with Normal Karyotype

British Journal of Haematology. Dec, 2009  |  Pubmed ID: 19758395

MDR1 C3435T Polymorphism Indicates a Different Outcome in Advanced Multiple Myeloma

Acta Haematologica. 2009  |  Pubmed ID: 19729888

Bortezomib and Liposomal Doxorubicin Are Highly Effective in Obtaining the Best Possible Response Before Autologous Transplant for Multiple Myeloma

Acta Haematologica. 2009  |  Pubmed ID: 19729887

Re: Rituximab Maintenance for the Treatment of Patients with Follicular Lymphoma: Systematic Review and Meta-analysis of Randomized Trials

Journal of the National Cancer Institute. Sep, 2009  |  Pubmed ID: 19687414

Monoclonal Antibody-associated Progressive Multifocal Leucoencephalopathy in Patients Treated with Rituximab, Natalizumab, and Efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project

The Lancet Oncology. Aug, 2009  |  Pubmed ID: 19647202

Progressive multifocal leucoencephalopathy (PML) is a serious and usually fatal CNS infection caused by JC polyoma virus. CD4+ and CD8+ T lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are the primary risk factors. The immune modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory approval in the USA and Europe for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, and chronic lymphocytic leukaemia (Europe only); multiple sclerosis and Crohn's disease; and psoriasis, respectively. Efalizumab and natalizumab administration is associated with CD4+ T lymphopenia and altered trafficking of T lymphocytes into the CNS, and rituximab leads to prolonged B-lymphocyte depletion. Unexpected cases of PML developing in people who receive these drugs have been reported, with many of the affected individuals dying from this disease. Herein, we review clinical findings, pathology, epidemiology, basic science, and risk-management issues associated with PML infection developing after treatment with these monoclonal antibodies.

Aberrant Expression of CD8 in B-cell Non-Hodgkin Lymphoma: a Multicenter Study of 951 Bone Marrow Samples with Lymphomatous Infiltration

American Journal of Clinical Pathology. Aug, 2009  |  Pubmed ID: 19605812

T-cell antigen expression can be observed in B-cell non-Hodgkin lymphoma (B-NHL). Although CD5 is expressed in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma, the presence of other T-cell antigens is less common. This article reports a retrospective multicenter analysis in which flow cytometry was used to evaluate aberrant CD8 expression on the pathologic B cells of 951 bone marrow samples from patients with various types of B-NHL. In a total of 18 patients, CD8 was coexpressed: 10 had B-CLL; 1, small lymphocytic lymphoma (SLL); 1, marginal zone lymphoma; 1, lymphoplasmacytic lymphoma; 2, diffuse large B-cell lymphoma; and 3, follicular lymphoma. There was a 1.89% overall frequency of CD8 coexpression in which B-CLL/SLL had a higher frequency (3.03%) than did the other B-cell neoplasms (1.18%). Most cases were characterized by a favorable outcome.

Hypercytokinemia-induced Metabolic Encephalopathy in a Multiple Myeloma Patient on Hemodialysis Undergoing Autologous Stem Cell Transplantation: Clinical Response After Plasma Exchange

Transplant Immunology. Sep, 2009  |  Pubmed ID: 19539028

We report here a 50-years old female with multiple myeloma-associated chronic renal failure who underwent high-dose chemotherapy supported by autologous hematopoietic stem cell transplantation. She developed progressive encephalopathy on day 5 progressing to coma despite hemodialysis and no obvious organ failure. She finally recovered after a single 1-liter plasma exchange. The final diagnosis was metabolic encephalopathy due to hypercytokinemia, particularly high serum TNF levels. We discuss here the pathogenesis and raise an alert for monitoring cytokine levels in patients with renal failure undergoing high-dose chemotherapy.

The Role of Bone Marrow Cells for JCV Pathogenicity

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Jul, 2009  |  Pubmed ID: 19505842

Polyomaviruses Other Than JCV Are Not Detected in Progressive Multifocal Leukoencephalopathy

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Jun, 2009  |  Pubmed ID: 19447072

Response-guided ABVD Chemotherapy Plus Involved-field Radiation Therapy for Intermediate-stage Hodgkin Lymphoma in the Pre-positron Emission Tomography Era: a Gruppo Italiano Studio Linfomi (GISL) Prospective Trial

Clinical Lymphoma & Myeloma. Apr, 2009  |  Pubmed ID: 19406724

In the pre-positron emission tomography era, the Gruppo Italiano Studio Linfomi (GISL) investigated the feasibility and efficacy of a treatment based on a response-tailored number of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) courses in 218 intermediate-stage Hodgkin lymphoma patients.

Selective Culture of Mesodermal Progenitor Cells

Stem Cells and Development. Oct, 2009  |  Pubmed ID: 19331526

We have recently identified mesodermal progenitor cells (MPCs) isolated from adult human bone marrow. These cells show unusual phenotypes, having putative embryonic markers and aldehyde dehydrogenase (ALDH) activity. Interestingly, these resting cells, which have been selected by culturing them in the presence of adult human serum, can easily be induced to differentiate into mature mesenchymal stromal cells (MSCs) after substituting the adult human serum for fetal bovine serum (FBS) or human cord serum. MPC-derived MSCs are, in turn, able to differentiate toward osteoblasts, chondrocytes, and adipocytes. Furthermore, MPCs are able to differentiate into endothelial cells. MPCs have been proven to be strongly adherent to plastic culture bottles and to be trypsin-resistant. In the present article, we show a simple and inexpensive method to isolate highly selected mesodermal progenitors from bone marrow or cord blood. The optimization of standard culture conditions (using commercial human AB sera and appropriate concentrations for cell seeding in plastics) allows a pure population of MPCs to be obtained even after a short culture period. We believe that this simple, repeatable, and standardized method will facilitate studies on MPCs.

Fatal Ongoing Human Cytomegalovirus Reactivation During High-dose Melphalan and Autologous Stem Cell Transplantation

Journal of Medical Virology. May, 2009  |  Pubmed ID: 19319946

Human cytomegalovirus (HCMV) reactivation can cause a wide range of complications in hematopoietic stem cell transplant recipients, ranging from pneumonia to graft failure. Although reactivations are usually seen in the early post-transplant period, ongoing and untreated HCMV reactivation at the time of high-dose chemotherapy and autologous stem cell support is an exceedingly rare circumstance whose consequences remain largely unknown. This case report describes a patient who underwent high-dose melphalan and autologous transplantation with unknown active HCMV replication.

Novel Biological/biohybrid Prostheses for the Ossicular Chain: Fabrication Feasibility and Preliminary Functional Characterization

Biomedical Microdevices. Aug, 2009  |  Pubmed ID: 19294514

Alternatives for ossicular replacements were fabricated in order to overcome persisting rejections in middle ear prosthetization. Unlike the synthetic prostheses in fashion, we propose biological and biohybrid replacements containing extra cellular matrix (ECM) molecules to improve biointegration. In this study, ECM-containing devices shaped as Partial Ossicular Replacement Prostheses (PORPs) were fabricated reproducing the current synthetic models. Biological PORPs were obtained from human decellularized cortical bone allografts by computer numerically controlled ultraprecision micromilling. Moreover, porous PORP-like scaffolds were produced and cultured with osteoinduced human mesenchymal stromal cells to generate in vitro bone ECM within the scaffold porosity (biohybrid PORPs). The acoustic responses of such devices were investigated and compared to those of commercial prostheses. Results showed that biological PORPs transmit mechanical signals with appropriate frequencies, amplitudes, and with early extinction time. Although signal transmission in biohybrid PORPs showed insufficient amplitude, we believe that tissue engineered constructs represent the new challenge in ossiculoplasty.

JC Virus DNA in Healthy Brain Tissue: a Challenge for Progressive Multifocal Leukoencephalopathy Diagnosis

Annals of Neurology. Feb, 2009  |  Pubmed ID: 19259969

Meningeal Relapse in a Case of B Acute Lymphoblastic Leukemia: the Role of CD56 Expression

Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. Feb, 2009  |  Pubmed ID: 19179973

Blasts from B acute lymphoblastic leukemia (B-ALL) may express CD56 in about 10% of cases. The presence of this marker at diagnosis is associated with an increased risk of meningeal relapse. A case is described of B-ALL which was CD56 negative at diagnosis, and expressed this marker when isolated meningeal relapse was diagnosed.

Expression of the Oncofetal ED-B-containing Fibronectin Isoform in Hematologic Tumors Enables ED-B-targeted 131I-L19SIP Radioimmunotherapy in Hodgkin Lymphoma Patients

Blood. Mar, 2009  |  Pubmed ID: 19131554

Current treatment of hematologic malignancies involves rather unspecific chemotherapy, frequently resulting in severe adverse events. Thus, modern clinical research focuses on compounds able to discriminate malignant from normal tissues. Being expressed in newly formed blood vessels of solid cancers but not in normal mature tissues, the extradomain B of fibronectin (ED-B FN) is a promising target for selective cancer therapies. Using immunohistology with a new epitope retrieval technique for paraffin-embedded tissues, ED-B FN expression was found in biopsies from more than 200 Hodgkin and non-Hodgkin lymphoma patients of nearly all entities, and in patients with myeloproliferative diseases. ED-B FN expression was nearly absent in normal lymph nodes (n = 10) and bone marrow biopsies (n = 9). The extent of vascular ED-B FN expression in lymphoma tissues was positively correlated with grade of malignancy. ED-B FN expression was enhanced in lymph nodes with severe lymphadenopathy and in some hyperplastic tonsils. The in vivo accessibility of ED-B FN was confirmed in 3 lymphoma patients, in whom the lymphoma lesions were visualized on scintigraphy with (131)I-labeled L19 small immunoprotein ((131)I-L19SIP). In 2 relapsed Hodgkin lymphoma patients(131)I-L19SIP radioimmunotherapy induced a sustained partial response, qualifying ED-B FN as a promising target for antibody-based lymphoma therapies.

Lymphotropic Polyomavirus and Progressive Multifocal Leukoencephalopathy

Journal of Clinical Microbiology. Jan, 2009  |  Pubmed ID: 19122182

Considerations in the Treatment of Multiple Myeloma: a Consensus Statement from Italian Experts

European Journal of Haematology. Feb, 2009  |  Pubmed ID: 19018865

PURPOSE AND BASIC PROCEDURE OF THE STUDY: The availability of new targeted therapies has revolutionised the treatment of multiple myeloma (MM), for both the newly diagnosed and the relapsed and refractory settings. A panel of Italian experts provided guidelines for optimal clinical practice in the treatment of MM.

Identification and Purification of Mesodermal Progenitor Cells from Human Adult Bone Marrow

Stem Cells and Development. Jul-Aug, 2009  |  Pubmed ID: 18991503

Bone marrow-derived mesodermal stem cells may differentiate toward several lines and are easily cultured in vitro. Some putative progenitors of these cells have been described in both humans and mice. Here, we describe a new mesodermal progenitor population [mesodermal progenitors cells (MPCs)] able to differentiate into mesenchymal cells upon appropriate culture conditions. When cultured in presence of autologous serum, these cells are strongly adherent to plastic, resistant to trypsin detachment, and resting. Mesodermal progenitor cells may be pulsed to proliferate and differentiate by substituting autologous serum for human cord blood serum or fetal calf serum. By these methods cells proliferate and differentiate toward mesenchymal cells and thus may further differentiate into osteoblats, chondrocytes, or adipocytes. Moreover MPCs are capable to differentiate in endothelial cells (ECs) showing characteristics similar to microvessel endothelium cells. Mesodermal progenitors cells have a defined phenotype and carry embryonic markers not present in mesenchymal cells. Moreover MPCs strongly express aldehyde dehydrogenase activity, usually present in hematopoietic precursors but absent in mesenchymal cells. When these progenitors are pulsed to differentiate, they lose these markers and acquire the mesenchymal ones. Interestingly, mesenchymal cells may not be induced to back differentiate into MPCs. Our results demonstrate the adult serum role in maintaining pluripotent mesodermal precursors and allow isolation of these cells. After purification, MPCs may be pulsed to proliferate in a very large scale and then induced to differentiate, thus possibly allowing their use in regenerative medicine.

Lithium and Hematology: Established and Proposed Uses

Journal of Leukocyte Biology. Jan, 2009  |  Pubmed ID: 18809733

Lithium (as lithium carbonate) is an inexpensive drug, widely used in psychiatry for over 50 years in treatment of mood instability (bipolar disorder) and as an adjunct to antidepressants. Hematological effects of neutrophilia and increased circulating CD34+ cells of marrow origin have long been known. Lithium was at the center of hematological investigations in the 1980s, but no definitive use in hematology has yet emerged. We review evidence that lithium increases G-CSF and augments G-CSF effects. We suggest possible therapeutic uses of lithium in neutropenia. In bone marrow transplantation, preharvest lithium-assisted hematopoietic stem cell mobilization may be useful as well.

Hyperbaric Oxygen Therapy in BKV-associated Hemorrhagic Cystitis Refractory to Intravenous and Intravesical Cidofovir: Case Report and Review of Literature

Leukemia Research. Apr, 2009  |  Pubmed ID: 18656258

Hemorrhagic cystitis is a common complication in hematopoietic stem cell transplant recipients. We report here a case of severe BKV-associated hemorrhagic cystitis who did not respond to intravenous cidofovir. Overt hematuria successfully resolved after a few days on hyperbaric oxygen and intravesical instillations of cidofovir, while BK viruria dropped after a few weeks and remained low. We review the literature for therapeutic options in hemorrhagic cystitis and try to explain how hyperbaric oxygen stimulates mucosal repair in the urinary bladder.

Enhancement of Hematopoietic Stem Cell Engraftment by Inhibition of CXCL12 Proteolysis with Sitagliptin, an Oral Dipeptidyl-peptidase IV Inhibitor: a Report in a Case of Delayed Graft Failure

Leukemia Research. Jan, 2009  |  Pubmed ID: 18513794

Morpho-functional Characterization of Human Mesenchymal Stem Cells from Umbilical Cord Blood for Potential Uses in Regenerative Medicine

Stem Cells and Development. Mar, 2009  |  Pubmed ID: 18444788

Mesenchymal stem cells (MSCs) represent a promising source of progenitor cells having the potential to repair and to regenerate diseased or damaged skeletal tissues. Bone marrow (BM) has been the first source reported to contain MSCs. However, BM-derived cells are not always acceptable, due to the highly invasive drawing and the decline in MSC number and differentiative capability with increasing age. Human umbilical cord blood (UCB), obtainable by donation with a noninvasive method, has been introduced as an alternative source of MSCs. Here human UCB-derived MSCs isolation and morpho-functional characterization are reported. Human UCB-derived mononuclear cells, obtained by negative immunoselection, exhibited either an osteoclast-like or a mesenchymal-like phenotype. However, we were able to obtain homogeneous populations of MSCs that displayed a fibroblast-like morphology, expressed mesenchym-related antigens and showed differentiative capacities along osteoblastic and early chondroblastic lineages. Furthermore, this study is one among a few papers investigating human UCB-derived MSC growth and differentiation on three-dimensional scaffolds focusing on their potential applications in regenerative medicine and tissue engineering. UCB-derived MSCs were proved to grow on biodegradable microfiber meshes; additionally, they were able to differentiate toward mature osteoblasts when cultured inside human plasma clots, suggesting their potential application in orthopedic surgery.

ITF2357 Interferes with Apoptosis and Inflammatory Pathways in the HL-60 Model: a Gene Expression Study

Anticancer Research. Nov, 2010  |  Pubmed ID: 21115902

Cytotoxic and pro-apoptotic effects exerted by the histone deacetylase inhibitor ITF2357 have been reported in acute myeloid leukemia HL-60 cells. In the current study, its mechanism of action was investigated at the molecular level.

Inclusion of Rituximab in Treatment Protocols for Non-Hodgkin's Lymphomas and Risk for Progressive Multifocal Leukoencephalopathy

The Oncologist. 2010  |  Pubmed ID: 21041380

Objectives. Rituximab is an anti-CD20 monoclonal antibody that promotes better treatment outcomes in patients with non-Hodgkin's lymphoma (NHL). Case series of progressive multifocal leukoencephalopathy (PML) in patients receiving rituximab within polychemotherapy regimens have led to the introduction of a black box warning, but no risk estimation has ever been provided. Methods. We performed a retrospective, monocentric cohort study on 976 NHL patients diagnosed in 1994-2008, including 517 patients who received at least one dose of rituximab. Results. Inclusion of rituximab into standard chemotherapy regimens for NHL caused a significantly higher incidence of PML cases (rate difference, 2.2 every 1,000 patient-years; 95% confidence interval, 0.1-4.3). Interpretation. Based on this finding, clinical surveillance of PML-related symptoms is recommended in NHL patients exposed to rituximab.

Enhancement of Neurite Outgrowth in Neuronal-like Cells Following Boron Nitride Nanotube-mediated Stimulation

ACS Nano. Oct, 2010  |  Pubmed ID: 20925390

In this paper, we propose an absolutely innovative technique for the electrical stimulation of cells, based on piezoelectric nanoparticles. Ultrasounds are used to impart mechanical stress to boron nitride nanotubes incubated with neuronal-like PC12 cells. By virtue of their piezoelectric properties, these nanotubes can polarize and convey electrical stimuli to the cells. PC12 stimulated with the present method exhibit neurite sprout 30% greater than the control cultures after 9 days of treatment.

CD23 Expression in Plasma Cell Leukaemia

British Journal of Haematology. Sep, 2010  |  Pubmed ID: 20629658

Barium Titanate Nanoparticles: Highly Cytocompatible Dispersions in Glycol-chitosan and Doxorubicin Complexes for Cancer Therapy

Nanoscale Research Letters. 2010  |  Pubmed ID: 20596329

In the latest years, innovative nanomaterials have attracted a dramatic and exponentially increasing interest, in particular for their potential applications in the biomedical field. In this paper, we reported our findings on the cytocompatibility of barium titanate nanoparticles (BTNPs), an extremely interesting ceramic material. A rational and systematic study of BTNP cytocompatibility was performed, using a dispersion method based on a non-covalent binding to glycol-chitosan, which demonstrated the optimal cytocompatibility of this nanomaterial even at high concentration (100 μg/ml). Moreover, we showed that the efficiency of doxorubicin, a widely used chemotherapy drug, is highly enhanced following the complexation with BTNPs. Our results suggest that innovative ceramic nanomaterials such as BTNPs can be realistically exploited as alternative cellular nanovectors.

Progressive Multifocal Leukoencephalopathy: What's New?

The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. Jun, 2010  |  Pubmed ID: 20479473

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease that is caused by human JC polyomavirus, was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. The prognosis has remained dismal since then, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication. PML is caused by reactivation of latent JC virus, and serotonergic 5-HT(2a) receptors have been identified as being critical for viral infection of glial cells. In recent years, immunosuppressive therapeutic antibodies have been associated with an increased incidence rate of PML. Here, the authors review findings on the pathogenesis of PML and the encouraging case reports of novel treatments.

Synergistic Antiproliferative Effect of Arsenic Trioxide Combined with Bortezomib in HL60 Cell Line and Primary Blasts from Patients Affected by Myeloproliferative Disorders

Cancer Genetics and Cytogenetics. Jun, 2010  |  Pubmed ID: 20471514

Both arsenic trioxide (ATO) and bortezomib show separate antileukemic activity. With the purpose of evaluating whether the combination of ATO and bortezomib would be an option for patients with acute leukemia, we incubated HL60 leukemic cells with ATO alone and in combination with bortezomib. ATO and bortezomib cooperated to induce cell death and to inhibit proliferation and apoptosis in a synergistic way. The combined treatment resulted in a stronger activation of caspase 8 and 9, moderate activation of caspase 3, and increased expression of Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-DR5 receptors. When bortezomib was added, some proapoptotic genes (CARD9, TRAIL) were upregulated, and some antiapoptotic genes (BCL2, BCL3, FLICE) were downregulated. When coincubated, approximately 80% of cells showed altered mitochondrial membrane permeability. Moreover, ATO alone and in combination with bortezomib abrogated DNA-binding activity of nuclear factor kappa beta (NF-kappaB). Gene expression assays showed that more deregulated genes were related to proliferation of leukocytes, tumorigenesis, control of cell cycle, hypoxia and oxidative stress, cytokines, PI3K-AKT, ERK-MAPK, EGF pathways, and ubiquitination. Finally, in three cases of acute myeloid leukemia, the addition of bortezomib to ATO significantly increased cytotoxicity. We conclude that the combination of bortezomib and ATO may be efficacious in the treatment of myeloid disorders.

Role of Hematopoietic Cells in the Maintenance of Chronic Human Torquetenovirus Plasma Viremia

Journal of Virology. Jul, 2010  |  Pubmed ID: 20410268

Many aspects of the life cycle of torquetenoviruses (TTVs) are essentially unexplored. In particular, it is still a matter of speculation which cell type(s) replicates the viruses and maintains the generally high viral loads found in the blood of infected hosts. In this study, we sequentially measured the TTV loads in the plasma of four TTV-positive leukemia patients who were strongly myelosuppressed and then transplanted with haploidentical hematopoietic stem cells. The findings provide clear quantitative evidence for an extremely important role of hematopoietic cells in the maintenance of TTV viremia.

Constitutive Expression of Pluripotency-associated Genes in Mesodermal Progenitor Cells (MPCs)

PloS One. 2010  |  Pubmed ID: 20360837

We recently characterized a progenitor of mesodermal lineage (MPCs) from the human bone marrow of adults or umbilical cord blood. These cells are progenitors able to differentiate toward mesenchymal, endothelial and cardiomyogenic lineages. Here we present an extensive molecular characterization of MPCs, from bone marrow samples, including 39 genes involved in stem cell machinery, differentiation and cell cycle regulation.

WU and KI Polyomaviruses Remain Orphans in Adults

The Journal of Infectious Diseases. Apr, 2010  |  Pubmed ID: 20225965

Abnormal Phenotype of Bone Marrow Plasma Cells in Patients with Chronic Myeloid Leukemia Undergoing Therapy with Imatinib

Leukemia Research. Oct, 2010  |  Pubmed ID: 20149455

Imatinib induces several effects on the immune system, including hypogammaglobulinemia and has been associated with multiple myeloma in some patients. We studied the phenotype of plasma cells from patients with chronic myeloid leukemia (CML) undergoing therapy with Imatinib mesylate (Glivec). Bone marrow samples from 30 CML patients were evaluated and plasma cells were identified by multiparametric flow cytometry. In 21 patients an abnormal plasma cell phenotype, characterized by the absence of CD19, was registered, with 12 patients expressing also the CD56 molecule. A significant correlation between abnormal plasma cell phenotype and reduced gamma-globulin levels was found. Immunofixation was always negative. Therapy with Imatinib for CML seems to induce a plasma cell phenotype with the same characteristics as monoclonal gammapathies. These findings deserve further studies and suggest to monitor plasma protein electrophoresis and gamma-globulin levels in all patients treated with Imatinib.

Areas with High Soil Percolation by Herbicides Have Higher Incidence of Low-grade Non-Hodgkin Lymphomas

Annals of Hematology. Sep, 2010  |  Pubmed ID: 20111967

Consensus Conference on the Use of 90-yttrium-ibritumomab Tiuxetan Therapy in Clinical Practice. A Project of the Italian Society of Hematology

American Journal of Hematology. Feb, 2010  |  Pubmed ID: 20095035

WT1 Expression Levels at Diagnosis Could Predict Long-term Time-to-progression in Adult Patients Affected by Acute Myeloid Leukaemia and Myelodysplastic Syndromes

British Journal of Haematology. May, 2010  |  Pubmed ID: 20085581

Torquetenovirus Viremia Kinetics After Autologous Stem Cell Transplantation Are Predictable and May Serve As a Surrogate Marker of Functional Immune Reconstitution

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Feb, 2010  |  Pubmed ID: 20034850

It is common experience that retreating patients too early after a course of intensive chemotherapy predisposes to opportunistic infections despite apparently normal lymphocyte levels.

In Vitro and in Vivo Study on the Antioxidant Activity of Dexrazoxane

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie. Apr, 2010  |  Pubmed ID: 19932589

The iron chelator dexrazoxane has been shown to significantly reduce anthracycline-induced cardiac toxicity in several randomized controlled studies. Aim of the present study was to assess the in vitro and in vivo antioxidant effects of dexrazoxane.

Fludarabine, Bortezomib, Myocet and Rituximab Chemotherapy in Relapsed and Refractory Mantle Cell Lymphoma

British Journal of Haematology. Mar, 2010  |  Pubmed ID: 19919649

CD57+ T Lymphocytes and Functional Immune Deficiency

Journal of Leukocyte Biology. Jan, 2010  |  Pubmed ID: 19880576

CD57(+) expression in T lymphocytes has been recognized for decades as a marker of in vitro replicative senescence. In recent years, accumulating evidences have pointed on the utility of this marker to measure functional immune deficiency in patients with autoimmune disease, infectious diseases, and cancers. We review here the relevant literature and implications in clinical settings.

Consistent Bone Marrow-derived Cell Mobilization Following Repeated Short Courses of Granulocyte-colony-stimulating Factor in Patients with Amyotrophic Lateral Sclerosis: Results from a Multicenter Prospective Trial

Cytotherapy. 2010  |  Pubmed ID: 19878077

The aim of this study was to evaluate and characterize the feasibility and safety of bone marrow-derived cell (BMC) mobilization following repeated courses of granulocyte-colony stimulating factor (G-CSF) in patients with amyotrophic lateral sclerosis (ALS).

Progressive Multifocal Leukoencephalopathy: a Report of Three Cases in HIV-negative Patients with Non-Hodgkin's Lymphomas Treated with Rituximab

Annals of Hematology. May, 2010  |  Pubmed ID: 19727726

2CdA Chemotherapy and Rituximab in the Treatment of Marginal Zone Lymphoma

Leukemia Research. Feb, 2010  |  Pubmed ID: 19414190

Standard chemotherapic approach for MZL is missing. We are presenting our monocenter experience with 2CdA+/-rituximab. Patients received 2CdA, 5mg/m(2), weekly, for 6 weeks. Patients receiving rituximab underwent to antibody administration in association with 2CdA, or after the end of chemotherapy. Global ORR was 89.3%, with 53.6% CR, with 60 months of median of TTF. 2CdA and rituximab led to 96.5% ORR, with 60.3% CR, while 2CdA alone to 73.1% ORR, with 38.5% CR. TTF median was reached at 35 months with 2CdA alone; not reached yet in the combination arm. Considering subgroups of MZL, combination therapy has a more favorable outcome in SMZL and NMZL, while MALT does not differ. However, all subgroups present a delayed relapse. Considering minimal residual disease (MRD), adding of rituximab converted 65.0% to negativity versus 15.4% of 2CdA alone, with TTF in positive patients reached after 34 months; not reached yet in negatives. Concomitant use of rituximab with 2CdA allowed an ORR of 98.0%, with 68% CR and 56.3% of MRD conversion, while consequent use 100%, 54.6%, and 70.8%, respectively. TTF does not differ. 2CdA therapy is effective in the treatment of MZL. Adding rituximab allows increasing ORR and CR, prolonging TTF.

Development of Tissue-engineered Substitutes of the Ear Ossicles: PORP-shaped Poly(propylene Fumarate)-based Scaffolds Cultured with Human Mesenchymal Stromal Cells

Journal of Biomedical Materials Research. Part A. Mar, 2010  |  Pubmed ID: 19353559

This is a novel study aimed at exploring possible tissue engineering (TE) options for fabricating middle ear ossicle replacements. Alternatives to prosthetic replacements currently used in ossiculoplasty are desirable, considering that current devices are known to suffer from a persistent rejection phenomenon, known as extrusion. In this study a biocompatible and biodegradable polymer, poly(propylene fumarate)/poly(propylene fumarate)-diacrylate (PPF/PPF-DA), was chosen to assess the fabrication feasibility of highly porous devices shaped as partial ossicular replacement prostheses (PORPs). PORP-like scaffolds were produced, and their poral features (porosity and pore interconnectivity) were evaluated via micro-CT. In addition, their capability to support human mesenchymal stromal cell (hMSC) colonization and osteoblastic differentiation in vitro was investigated with both quantitative and qualitative analyses. This report summarizes and discusses all the fundamental issues associated with ossicle prosthetization as well as the challenging opportunities potentially offered to middle ear reconstruction by TE; moreover it demonstrates that PPF/PPF-DA PORP-like scaffolds can be appropriately fabricated to allow both the colonization of hMSCs and their osteoblastic maturation in vitro. Specifically, the expression patterns of the main osteogenic markers (alkaline phosphatase, calcium) and of various matrix biomolecules (glycoproteins, glycosaminoglycans, collagen I) were studied. These preliminarily obtained outcomes may launch a new trend in otology dedicated to TE ossicle development to improve on the performance of current prosthetic replacements.

Impaired Function of Gamma-delta Lymphocytes in Melanoma Patients

European Journal of Clinical Investigation. Nov, 2011  |  Pubmed ID: 22775565

Melanoma is an immunogenic tumour but, despite the wide range of immunotherapies tested, only few promising results have been reported to date. Both in vitro and in xenograft models, γδ lymphocyte-mediated cytotoxicity against melanoma cells has been reported. IL-2/zoledronate treatment can expand γδ cells in vitro and in animal models. This could represent an immunotherapeutic strategy against melanoma. To evaluate the feasibility of this approach, we studied γδ lymphocyte phenotype from patients with melanoma, their ability to be expanded by IL-2/zoledronate and their cytotoxic activity against SK-MEL-30 cell line.

Mesodermal Progenitor Cells (MPCs) Differentiate into Mesenchymal Stromal Cells (MSCs) by Activation of Wnt5/calmodulin Signalling Pathway

PloS One. 2011  |  Pubmed ID: 21980498

Mesenchymal Stromal Cells (MSCs) remain poorly characterized because of the absence of manifest physical, phenotypic, and functional properties in cultured cell populations. Despite considerable research on MSCs and their clinical application, the biology of these cells is not fully clarified and data on signalling activation during mesenchymal differentiation and proliferation are controversial. The role of Wnt pathways is still debated, partly due to culture heterogeneity and methodological inconsistencies. Recently, we described a new bone marrow cell population isolated from MSC cultures that we named Mesodermal Progenitor Cells (MPCs) for their mesenchymal and endothelial differentiation potential. An optimized culture method allowed the isolation from human adult bone marrow of a highly pure population of MPCs (more than 97%), that showed the distinctive SSEA-4+CD105+CD90(neg) phenotype and not expressing MSCA-1 antigen. Under these selective culture conditions the percentage of MSCs (SSEA-4(neg)CD105+CD90(bright) and MSCA-1+), in the primary cultures, resulted lower than 2%.

Discordant Lymphoma Consisting of Splenic Mantle Cell Lymphoma and Marginal Zone Lymphoma Involving the Bone Marrow and Peripheral Blood: a Case Report

Journal of Medical Case Reports. 2011  |  Pubmed ID: 21943040

Discordant lymphomas are rare entities characterized by the simultaneous presence of two distinct types of lymphomas in different anatomic sites. We describe a very rare case of simultaneous occurrence of splenic mantle cell lymphoma and marginal zone lymphoma involving the bone marrow and peripheral blood.

High-dose (40,000 IU Twice/week) Alpha Recombinant Human Erythropoietin As Single Agent in Low/intermediate Risk Myelodysplastic Syndromes: a Retrospective Investigation on 133 Patients Treated in a Single Institution

American Journal of Hematology. Sep, 2011  |  Pubmed ID: 21850658

We investigated the efficacy of alpha recombinant human erythropoietin (α-rHuEPO) administered as single agent to 133 patients affected by myelodysplastic syndromes referring to our Institution in the last 10 years. WPSS score was "very low" in 67%, "low" in 19%, "intermediate" in 14%. The starting schedule was: 40,000 IU bi-weekly, with reduction or suspension, when necessary, in responsive patients. According to new IWG criteria, response rate (RR) was 75%, 66%, 59% after 8, 16, 24 weeks, respectively. Comparing "very low" and "low/intermediate" risk, RR was 81% vs. 43% (P < 0.001); 70% vs. 45% (P = 0.040); 63% vs. 42% (P = NS) after 8, 16, 24 weeks. RR was significantly influenced by transfusion dependence (P = 0.039) and basal serum EPO level (P < 0.001). Mean Hb value was 94 ± 11 g/l before therapy; 114 ± 19 after 8 weeks (P < 0.001); 116 ± 18 after 16 weeks (P < 0.001); 114 ± 17 after 24 weeks (P < 0.001). Reduction or suspension of therapy significantly affected Hb level after 4 (P < 0.001) and 8 weeks (P < 0.01). Conversely, restart of full dosage significantly enhanced again Hb level after 4 (P < 0.01) and 8 weeks (P < 0.001). 65% patients are alive (mean survival: 74 weeks). Seventy percent are alive in the "very low risk" group and 38% in "low/intermediate risk" group (P < 0.001). Overall mean follow-up was 69 weeks (range, 8-376): it was 80 weeks in responsive patients (max 376) and 38 weeks in patients who progressively became unresponsive (max 168) (P < 0.01). Median response was 36 weeks, with 33% of patients still responding after one year. Treatment was well tolerated.

A Simple Prognostic Scoring System for Newly Diagnosed Cytogenetically Normal Acute Myeloid Leukemia: Retrospective Analysis of 530 Patients

Leukemia & Lymphoma. Dec, 2011  |  Pubmed ID: 21745171

We retrospectively analyzed the data of 337 patients with cytogenetically normal (CN) acute myeloid leukemia (AML), aged ≤ 65 years (training set). A prognostic index score (PIS) was calculated by totaling the score derived from the regression coefficients of each clinical variable, significantly associated with prognosis by multivariate analysis. The variables that were independent prognostic factors for event-free survival (EFS) and overall survival (OS) in the training set were: age ≥ 50 years, secondary AML and white blood cell count (WBC) ≥ 20 × 10(9)/L. The patients of the training set were stratified into three groups: low-, intermediate- and high-risk. The median EFS was 25, 12 and 7 months in the low-, intermediate- and high-risk groups (p < 0.0001), respectively. The median OS was not reached in the low-risk group and was 19 and 10 months in the intermediate- and high-risk groups (p < 0.0001). This PIS was validated in a series of 193 patients with CN-AML. The median EFS was 66, 16, and 3 months (p < 0.0001) and the median OS was 66, 16, and 5 months in the three risk groups, respectively (p < 0.0001). This PIS may be useful for clinical decision-making in CN-AML and may be prospectively integrated with the newest biological markers which at present are not routinely assessed and need prognostic validation.

Repeated Courses of Granulocyte Colony-stimulating Factor in Amyotrophic Lateral Sclerosis: Clinical and Biological Results from a Prospective Multicenter Study

Muscle & Nerve. Feb, 2011  |  Pubmed ID: 21254083

Granulocyte colony-stimulating factor (G-CSF) induces a transient mobilization of hematopoietic progenitor cells from bone marrow to peripheral blood. Our aim was to evaluate safety of repeated courses of G-CSF in patients with amyotrophic lateral sclerosis (ALS), assessing disease progression and changes in chemokine and cytokine levels in serum and cerebrospinal fluid (CSF). Twenty-four ALS patients entered an open-label, multicenter trial in which four courses of G-CSF and mannitol were administered at 3-month intervals. Levels of G-CSF were increased after treatment in the serum and CSF. Few and transitory adverse events were observed. No significant reduction of the mean monthly decrease in ALSFRS-R score and forced vital capacity was observed. A significant reduction in CSF levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-17 (IL-17) was observed. G-CSF treatment was safe and feasible in a multicenter series of ALS patients. A decrease in the CSF levels of proinflammatory cytokines MCP-1 and IL-17 was found, indicating a G-CSF-induced central anti-inflammatory response.

Prethymic Cytoplasmic CD3 Negative Acute Lymphoblastic Leukemia or Acute Undifferentiated Leukemia: a Case Report

Case Reports in Hematology. 2011  |  Pubmed ID: 22937302

Acute undiffentiated leukemia (AUL) is an acute leukemia with no more than one membrane marker of any given lineage. Blasts often express HLA-DR, CD34, and/or CD38 and may be positive for terminal deoxynucleotidyl transferase (TdT). The expression of CD34, HLA-DR, and CD38 has been shown in pro-T-ALL, although in this case, blasts should also express CD7 and cyCD3. However, some cases of T-ALL without CD3 in the cytoplasm and all TCR chain genes in germ line configuration are reported, features that fit well with a very early hematopoietic cell. We report a case of acute leukemia CD34+/-HLADR+CD7+CD38+cyCD3- in which a diagnosis of AUL was considered. However the blasts were also positive for CD99 and TCR delta gene rearrangement which was found on molecular studies. Therefore a differential diagnosis between AUL and an early cyCD3 negative T-ALL was debated.

Pegylated Liposomal Doxorubicin in Combination with Dexamethasone and Bortezomib (VMD) or Lenalidomide (RMD) in Multiple Myeloma Pretreated Patients

Annals of Hematology. Sep, 2011  |  Pubmed ID: 21181162

The Small Peptide OGP(10-14) Reduces Proliferation and Induces Differentiation of TPO-primed M07-e Cells Through RhoA/TGFbeta1/SFK Pathway

Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. Jan, 2011  |  Pubmed ID: 21169922

Osteogenic growth peptide (OGP) is a 14-mer peptide found in relevant concentration in blood, and its carboxy-terminal fragment [OGP(10-14)] represents the active portion of the full-length peptide. In addition to stimulating bone formation, OGP(10-14) shows hematological activity. In fact, it highly enhances hematopoiesis-affecting stem progenitors. Moreover, OGP(10-14) reduces the growth and induces the differentiation of the hematological tumour cell line trombophoietin(TPO)-primed M07-e by interfering with RhoA and Src kinase pathways. In the present report, we went deeper into this mechanism and evaluated the possible interference of the OGP(10-14) signal pathway with TGFβ1 and TPO receptor Mpl.

Lenograstim Reduces the Incidence of Febrile Episodes, when Compared with Filgrastim, in Multiple Myeloma Patients Undergoing Stem Cell Mobilization

Leukemia Research. Jul, 2011  |  Pubmed ID: 21134693

The aim of this study was to show a lower incidence of febrile episodes in multiple myeloma patients receiving lenograstim vs. filgrastim after high-dose cyclophosphamide for stem cell mobilization. Patients treated with cyclophosphamide were randomly assigned to receive filgrastim or lenograstim. Primary endpoint was the incidence of febrile episodes. 5.1% patients developed a febrile episode, 9.1% with filgrastim and 1.1% with lenograstim. Lenograstim group presented a significantly higher absolute CD34+ cell number compared with the filgrastim group but no differences were detected for collection efficacy. The study demonstrated a lower incidence of febrile episodes with lenograstim compared to filgrastim.

Outcome of Patients with Mantle Cell Lymphoma is Not Influenced by Vascular Endothelial Growth Factor Polymorphisms

Leukemia & Lymphoma. Jan, 2011  |  Pubmed ID: 21067446

Human Dental Pulp Stem Cells Protect Mouse Dopaminergic Neurons Against MPP+ or Rotenone

Brain Research. Jan, 2011  |  Pubmed ID: 20854799

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive death of substantia nigra dopaminergic neurons that results in a regional loss of striatal dopamine (DA) levels. Dental pulp contains ex vivo-expandable cells called dental pulp stem cells (DPSCs), with the capacity to differentiate into multiple cell lineages. More interestingly, due to their embryonic origin, DPSCs express neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor and glial cell-derived neurotrophic factor. The aim of the present study was to investigate the neuroprotective effects of DPSCs against MPP+ (2.5, 5, and 10 μM) and rotenone (0.25, 0.5 and 1 μM) in an in vitro model of PD, using an indirect co-culture system with mesencephalic cell cultures. When mesencephalic cultures were challenged with MPP+ or rotenone, in the presence of DPSCs a statistically significant protective effect was observed at all the tested doses in terms of DA uptake. DPSCs protective effect on DA neurons was also confirmed by immunocytochemistry: an increased number of spared tyrosine hydroxylase (TH)+ cells was observed in co-culture conditions compared to controls, and neurons showed longer processes in comparison with mesencephalic cells grown without DPSCs. In conclusion, the co-culture with DPSCs significantly attenuated MPP+ or rotenone-induced toxicity in primary cultures of mesencephalic neurons. Considering that the direct contact between the two cell types was prevented, it can be speculated that neuroprotection could be due to soluble factors such as BDNF and NGF, released by DPSCs. Blocking BDNF and NGF with neutralizing antibodies, the neuroprotecting effect of DPSCs was completely abolished. Therefore DPSCs can be viewed as possible candidates for studies on cell-based therapy in neurodegenerative disorders.

Glycosylation Interference on RhoA Activation: Focus on G-CSF

Leukemia Research. Feb, 2011  |  Pubmed ID: 20573400

Glycosylation of cytokines appears to be responsible for several differences in their activity, and focusing on G-CSF, several divergences between the non-glycosylated G-CSF, Filgrastim, and the glycosylated G-CSF, Lenograstim, have been reported. To verify the role of G-CSF glycosylation in mediating these differences we tested in vitro the effects on the RhoA activation of the different G-CSFs, including deglycosylated Lenograstim. The results showed that Filgrastim induced sustained-RhoA activation while Lenograstim did not do so. Deglycosylated Lenograstim mimicked Filgrastim, resulting in RhoA hyper-activation. These in vitro findings demonstrate that the glycosylation of G-CSF plays a crucial role in RhoA activation.

B-cell Acute Lymphoblastic Leukemia with T(4;11)(q21;q23) in a Young Woman: Evolution into Mixed Phenotype Acute Leukemia with Additional Chromosomal Aberrations in the Course of Therapy

Hematology Reports. Jul, 2012  |  Pubmed ID: 23087804

About 5% of adult B-cell acute lymphoblastic leukemias (B-ALL) are characterized by t(4;11)(q21;q23), which confers peculiar features to this B-ALL subtype, including a very immature immunophenotype and poor prognosis. We describe the case of a 21-year-old female who presented with B-ALL carrying the t(4;11)(q21;q23) and blasts positive for CD19, TdT, CD79a, CD38, HLA-DR. Before completing the Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) therapy regimen, the B-cell leukemic clone still was detected, but an additional leukemic clone appeared, with morphology and immunophenotype (CD13, CD33, CD64, CD38, CD56, CD15, CD4(dim)) compatible with derivation from the myeloid/monocytic lineage. Karyotype showed the co-existence of three cell lines, with persistence of t(4;11)(q21;q23) and appearance of +8,+12,+13 and two der(4). The patient died because of disseminated intravascular coagulation. Our report describes a rare, possible evolution of such a subtype of B-ALL, with transformation into mixed phenotype acute leukemia in the course of therapy. This finding suggests a blast cell derivation from a common lymphoid/monocytic precursor leading to a final bilineal acute leukemia.

Arsenic Trioxide and Ascorbic Acid Interfere with the BCL2 Family Genes in Patients with Myelodysplastic Syndromes: an Ex-vivo Study

Journal of Hematology & Oncology. 2012  |  Pubmed ID: 22964015

Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); its mechanisms of action have already been evaluated in vitro, but the in vivo activity is still not fully understood. Since ATO induces apoptosis in in vitro models, we compared the expression of 93 apoptotic genes in patients' bone marrow before and after ATO treatment. For this analysis, we selected 12 patients affected by MDS who received ATO in combination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530, EudracT Number 2005-001321-28.

Impact of Polymorphic Variation at 7p15.3, 3p22.1 and 2p23.3 Loci on Risk of Multiple Myeloma

British Journal of Haematology. Sep, 2012  |  Pubmed ID: 22823248

Comprehensive Investigation of Genetic Variation in the 8q24 Region and Multiple Myeloma Risk in the IMMEnSE Consortium

British Journal of Haematology. May, 2012  |  Pubmed ID: 22590720

Genome-wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0·0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.

Radioimmunotherapy with Radretumab in Patients with Relapsed Hematologic Malignancies

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Jun, 2012  |  Pubmed ID: 22577235

We present here a systematic analysis of lymphoma and MM patients recruited into 2 clinical trials or treated with radretumab according to compassionate use, describing the biodistribution, dosimetry, safety, and clinical activity of radretumab.

Human Mesenchymal Stem Cells Reduce Mortality and Bacteremia in Gram-negative Sepsis in Mice in Part by Enhancing the Phagocytic Activity of Blood Monocytes

American Journal of Physiology. Lung Cellular and Molecular Physiology. May, 2012  |  Pubmed ID: 22427530

The potential therapeutic value of cell-based therapy with mesenchymal stem cells (MSC) has been reported in mouse models of polymicrobial peritoneal sepsis. However, the mechanisms responsible for the beneficial effects of MSC have not been well defined. Therefore, we tested the therapeutic effect of intravenous bone marrow-derived human MSC in peritoneal sepsis induced by gram-negative bacteria. At 48 h, survival was significantly increased in mice treated with intravenous MSC compared with control mice treated with intravenous fibroblasts (3T3) or intravenous PBS. There were no significant differences in the levels of TNF-α, macrophage inflammatory protein 2, or IL-10 in the plasma. However, there was a marked reduction in the number of bacterial colony-forming units of Pseudomonas aeruginosa in the blood of MSC-treated mice compared with the 3T3 and PBS control groups. In addition, phagocytic activity was increased in blood monocytes isolated from mice treated with MSC compared with the 3T3 and PBS groups. Furthermore, levels of C5a anaphylotoxin were elevated in the blood of mice treated with MSC, a finding that was associated with upregulation of the phagocytosis receptor CD11b on monocytes. The phagocytic activity of neutrophils was not different among the groups. There was also an increase in alternately activated monocytes/macrophages (CD163- and CD206-positive) in the spleen of the MSC-treated mice compared with the two controls. Thus intravenous MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis.

Could Age Modify the Effect of Genetic Variants in IL6 and TNF-α Genes in Multiple Myeloma?

Leukemia Research. May, 2012  |  Pubmed ID: 22387051

Cytokines play a central role in multiple myeloma (MM) pathogenesis thus genetic variations within cytokines coding genes could influence MM susceptibility and therapy outcome. We investigated the impact of 8 SNPs in these genes in 202 MM cases and 235 controls also evaluating their impact on therapy outcome in a subset of 91 patients. Despite the overall negative findings, we found a significant age-modified effect of IL6 and TNF-α SNPs, on MM risk and therapy outcome, respectively. Therefore, this observation suggests that genetic variation in inflammation-related genes could be an important mediator of the complex interplay between ageing and cancer.

The Role of CD19 and CD27 in the Diagnosis of Multiple Myeloma by Flow Cytometry: a New Statistical Model

American Journal of Clinical Pathology. Mar, 2012  |  Pubmed ID: 22338049

We have developed a new statistical diagnostic model that examines the correlation between immunophenotype and clonality as detected by flow cytometry (FC) and histology, defining the diagnostic role of FC in multiple myeloma (MM). The 192 bone marrow samples from patients and control subjects were studied for routine diagnostic analysis of MM; a minimum of 100 plasma cells (PCs) were analyzed for each patient sample. A direct 7- or 8-color method was applied to study the immunophenotype of PCs, utilizing a FACSCanto II (BD Biosciences, San Jose, CA). Samples were labeled with fluorochrome-conjugated monoclonal antibodies (AmCyan, Pac Blue, fluorescein isothiocyanate, phycoerythrin [PE], PECy7, peridinin-chlorophyll protein, allophycocyanin [APC], and APC-Cy7) to the following antigens: CD138, CD81, CD200, CD221, CD45, CD38, CD28, CD19, CD27, CD117, CD38, CD33, CD20, CD56, CD10, and immunoglobulin κ and λ light chains. Among all antigens tested, CD19 and CD27, when applied to our model, resulted in optimal concordance with histology. This model defines the effective diagnostic role FC could have in MM and in the detection of minimal residual disease.

Genetics and Molecular Epidemiology of Multiple Myeloma: the Rationale for the IMMEnSE Consortium (review)

International Journal of Oncology. Mar, 2012  |  Pubmed ID: 22159523

There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.

Rituximab Plus HyperCVAD Alternating with High Dose Cytarabine and Methotrexate for the Initial Treatment of Patients with Mantle Cell Lymphoma, a Multicentre Trial from Gruppo Italiano Studio Linfomi

British Journal of Haematology. Feb, 2012  |  Pubmed ID: 22145911

This study investigated the clinical activity and toxicity of R-HCVAD-AM [rituximab plus HyperCVAD (R-HCVAD) alternating with high-dose cytarabine and methotrexate (AM)] in patients with newly diagnosed Mantle Cell Lymphoma (MCL). Patients aged ≤70years with confirmed MCL received four alternating cycles each of R-HCVAD and AM. Patients who obtained a partial response proceeded to autologous stem cell transplant. Sixty-three patients were enrolled and 60 were fully eligible. Median age was 57years (22-66); 60%, 33% and 7% were classified at low (L)-, intermediate (I)- or high (H)-risk, respectively, according to the MCL International Prognostic Index (MIPI). Only 22 patients (37%) completed the four cycles and three patients died during therapy. Overall response and complete response rates were 83% and 72% respectively. After a median follow-up of 46months (range 1-72) the estimated 5-year overall survival (OS) and progression-free survival rates were 73% [95% confidence interval (CI) 59-83%], and 61% (95%CI 45-73%) respectively. MIPI maintained the prognostic value with an estimated 5-year OS of 89%, 80% and 24% for L, I, and H groups respectively (P<0·001). This multicentre study confirms that R-HCVAD-AM is an active regimen for the initial treatment of patients with MCL, but is associated with significant toxicity.

Lithium in the Treatment of Neutropenia

Current Opinion in Hematology. Jan, 2012  |  Pubmed ID: 22123660

The capacity of lithium to induce neutrophilia and increase circulating CD34(+) cells of marrow origin has long been known. Lithium has been the object of hematological investigations for many years, but no definitive use in hematology has yet emerged.

CD57 and γδ T-cell Receptor Expression in Nodal Metastatic Spread of Melanoma

European Journal of Clinical Investigation. May, 2012  |  Pubmed ID: 22050593

Boron Nitride Nanotubes and Primary Human Osteoblasts: in Vitro Compatibility and Biological Interactions Under Low Frequency Ultrasound Stimulation

Nanotechnology. Nov, 2013  |  Pubmed ID: 24150892

In this paper we investigated a novel and non-invasive approach for an endogenous osteoblast stimulation mediated by boron nitride nanotubes (BNNTs). Specifically, following the cellular uptake of the piezoelectric nanotubes, cultures of primary human osteoblasts (hOBs) were irradiated with low frequency ultrasound (US), as a simple method to apply a mechanical input to the cells loaded with BNNTs. This in vitro study was aimed at investigating the main interactions between hOBs and BNNTs and to study the effects of the 'BNNTs + US' stimulatory method on the osteoblastic function and maturation.A non-cytotoxic BNNT concentration to be used in vitro with hOB cultures was established. Moreover, investigation with transmission electron microscopy/electron energy loss spectroscopy (TEM/EELS) confirmed that BNNTs were internalized in membranal vesicles. The panel of investigated osteoblastic markers disclosed that BNNTs were capable of fostering the expression of late-stage bone proteins in vitro, without using any mineralizing culture supplements. In our samples, the maximal osteopontin expression, with the highest osteocalcin and Ca(2+) production, in the presence of mineral matrix with nodular morphology, was observed in the samples treated with BNNTs + US. In this group was also shown a significantly enhanced synthesis of TGF-β1, a molecule sensitive to electric stimulation in bone. Finally, gene deregulations of the analyzed osteoblastic genes leading to depletive cellular effects were not detected. Due to their piezoelectricity, BNNT-based therapies might disclose advancements in the treatment of bone diseases.

Use of Autologous Human Mesenchymal Stromal Cell/fibrin Clot Constructs in Upper Limb Non-unions: Long-term Assessment

PloS One. 2013  |  Pubmed ID: 24023694

Tissue engineering appears to be an attractive alternative to the traditional approach in the treatment of fracture non-unions. Mesenchymal stromal cells (MSCs) are considered an appealing cell source for clinical intervention. However, ex vivo cell expansion and differentiation towards the osteogenic lineage, together with the design of a suitable scaffold have yet to be optimized. Major concerns exist about the safety of MSC-based therapies, including possible abnormal overgrowth and potential cancer evolution.

A Case of Primary Non-Hodgkin's Lymphoma of the External Auditory Canal

Case Reports in Otolaryngology. 2013  |  Pubmed ID: 23984144

Lymphomas represent the second most frequent malignant tumor (incidence 2.5%) in the head and neck region. Non-Hodgkin lymphomas (NHLs) present with cervical lymph node involvement, but in 40% extranodal site could be primary involved: nasopharynx, the lacrimal sac, the temporal bone, or the others areas. NHLs of the ear are rarely reported. In this report, we described a patient with primary NHL of the external ear canal who was successfully treated with surgical excision and chemotherapy.

Treatment of Oral Mucositis in Hematologic Patients Undergoing Autologous or Allogeneic Transplantation of Peripheral Blood Stem Cells: a Prospective, Randomized Study with a Mouthwash Containing Camelia Sinensis Leaf Extract

Hematology Reports. Jan, 2013  |  Pubmed ID: 23888242

Oral mucositis is an important side effect of hematopoietic stem cell transplantation (HCST), mainly due to toxicity of conditioning regimens. It produces significant pain and morbidity. The present study reports a prospective, randomized, non-blinded study testing the efficacy of a new mouthwash, called Baxidil Onco(®) (Sanitas Farmaceutici Srl, Tortona, Italy) in 60 hematologic patients undergoing HCST (28 autologous, 32 allogeneic). Baxidil Onco(®), used three times a day from Day -1 to Day +30, in addition to standard prophylactic schedules, was administered to 14 patients undergoing autologous and 14 patients undergoing allogeneic HCST. The remaining 32 patients (14 autologous and 18 HCST) were treated only with standard prophylactic schedules and served as control. In our study, the overall incidence of oral mucositis, measured according to the World Health Organization 0-4 scale, was 50% in the Baxidl Onco(®) group versus 82% in the control group (P=0.022). In addition, a significant reduction in scale 2-4 oral mucositis was observed in the Baxidil Onco(®) group (25% vs 56.2%; P=0.0029). The results obtained indicate that incidence, severity and duration of oral mucositis induced by conditioning regimens for HCST can be significantly reduced by oral rinsing with Baxidil Onco(®), in addition to the standard prophylaxis scheme. Since Camelia Sinensin extract, which is used to produce green tea, is the main agent in this mouthwash, we hypothesize that the anti-oxidative properties of polyphenolic compounds of tea might exert protective effects on oral mucosa.

Simultaneous Presentation of Waldenström Macroglobulinemia and Multiple Myeloma: Multidisciplinary Diagnosis, Treatment and 30-month Follow-up

Journal of Clinical and Experimental Hematopathology : JCEH. 2013  |  Pubmed ID: 23801131

Waldenström macroglobulinemia and multiple myeloma are mature B-cell neoplasms deriving from post-germinal cells at different stages of differentiation. The simultaneous presentation of Waldenström macroglobulinemia and multiple myeloma in the same patient is a very rare phenomenon and, so far, only two cases have been described. We report the case of a 75-year Caucasian female patient, with a silent clinical history, who presented with anemia and two different monoclonal proteins (IgMκ and IgGκ). The trephine biopsy showed the presence of a dual population, represented by small lymphoplasmacytoid cells and by plasma cells, which infiltrated the bone marrow with a clearly different pattern. Both immunohistochemistry and flow cytometry demonstrated the biclonal origin such neoplastic cells, since lymphoplasmacytoid cells resulted IgMκ while plasma cells were IgGκ. This biclonal pattern was further confirmed by the demonstration of a different IgH gene rearrangement of the two neoplasms. The patient was treated with bortezomib, dexamethasone and rituximab, achieving partial remission of both Waldenström macroglobulinemia and multiple myeloma. After a 30-month follow-up, she is in stable disease. Multiple myeloma has been described in association with other indolent B-cell neoplasms, mostly chronic lymphocytic leukemia, while Waldenström macroglobulinemia can be followed by diffuse large B-cell lymphoma in some instances, after chemotherapy. The association of Waldenström macroglobulinemia and multiple myeloma seems to be very rare. Our study shows that an integrated diagnostic work-up is very useful in such cases, with an interesting role for flow cytometry. [J Clin Exp Hematop 53(1): 29-36, 2013].

Growing Bone Tissue-engineered Niches with Graded Osteogenicity: an in Vitro Method for Biomimetic Construct Assembly

Tissue Engineering. Part C, Methods. Dec, 2013  |  Pubmed ID: 23537352

The traditional bone tissue-engineering approach exploits mesenchymal stem cells (MSCs) to be seeded once only on three-dimensional (3D) scaffolds, hence, differentiated for a certain period of time and resulting in a homogeneous osteoblast population at the endpoint. However, after achieving terminal osteodifferentiation, cell viability is usually markedly compromised. On the other hand, naturally occurring osteogenesis results from the coexistence of MSC progenies at distinct differentiative stages in the same microenvironment. This diversification also enables long-term viability of the mature tissue. We report an easy and tunable in vitro method to engineer simple osteogenic cell niches in a biomimetic fashion. The niches were grown via periodic reseeding of undifferentiated MSCs on MSC/scaffold constructs, the latter undergoing osteogenic commitment. Time-fractioning of the seeded cell number during differentiation time of the constructs allowed graded osteogenic cell populations to be grown together on the same scaffolds (i.e., not only terminally differentiated osteoblasts). In such cell-dynamic systems, the overall differentiative stage of the constructs could also be tuned by varying the cell density seeded at each inoculation. In this way, we generated two different biomimetic niche models able to host good reservoirs of preosteoblasts and other osteoprogenitors after 21 culture days. At that time, the niche type resulting in 40.8% of immature osteogenic progenies and only 59.2% of mature osteoblasts showed a calcium content comparable to the constructs obtained with the traditional culture method (i.e., 100.03 ± 29.30 vs. 78.51 ± 28.50 pg/cell, respectively; p=not significant), the latter colonized only by fully differentiated osteoblasts showing exhausted viability. This assembly method for tissue-engineered constructs enabled a set of important parameters, such as viability, colonization, and osteogenic yield of the MSCs to be balanced on 3D scaffolds, thus achieving biomimetic in vitro models with graded osteogenicity, which are more complex and reliable than those currently used by tissue engineers.

Specific Integrin Expression is Associated with Podosome-like Structures on Mesodermal Progenitor Cells

Stem Cells and Development. Jun, 2013  |  Pubmed ID: 23379672

Mesenchymal stromal cells (MSCs) are a heterogeneous cell population capable of differentiating toward several cell lines in vitro and, possibly, in vivo. Within cultured MSCs, we identified and purified a precursor cell population [mesodermal progenitor cells (MPCs)] retaining robust proliferation potential and ability to differentiate into endothelial or mesenchymal cells. MPC-derived MSCs retain the ability to further differentiate into osteoblasts, cartilage, or fat cells. Here we further characterized MPCs and MSCs by evaluating expression of integrins and adhesion molecules showing their ability to assemble the molecular machinery involved in endothelium adhesion. MPCs were shown to interact with activated and nonactivated endothelium, whereas MSCs exhibited activation of focal adhesion complexes, higher cell motility, and reduced or absent adhesiveness onto endothelial cells, suggesting a matrix remodeling vocation. We also reported a consistent expression of CXCR4 on the MPC cell surface, suggesting that the different phenotypic behavior could be related to specific functions of the cell in each differentiation stage.

Polymorphisms in Regulators of Xenobiotic Transport and Metabolism Genes PXR and CAR Do Not Affect Multiple Myeloma Risk: a Case-control Study in the Context of the IMMEnSE Consortium

Journal of Human Genetics. Mar, 2013  |  Pubmed ID: 23303387

The exposure to pesticides and toxic compounds in xenobiotic transport and metabolism genes has been shown to affect risk of developing multiple myeloma (MM). Therefore, we hypothesized that genetic variations in xenobiotic transport and metabolism regulator genes PXR (NR1I2) and CAR (NR1I3) could determine a difference in MM susceptibility. Ten tagging single-nucleotide polymorphisms (SNPs) for PXR and seven for the CAR genes were selected and genotyped in 627 MM cases and 883 controls collected in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium. None of the 17 SNPs investigated showed significant association with MM risk either alone or when combined in haplotypes. Significant SNP-SNP interactions were not found, neither with 58 previously genotyped polymorphisms in ABC transporters. We can therefore exclude that common genetic variants in the xenobiotic transport and metabolism regulator genes PXR and CAR affect MM risk.

Bortezomib with Thalidomide Plus Dexamethasone Compared with Thalidomide Plus Doxorubicin and Dexamethasone As Induction Therapy in Previously Untreated Multiple Myeloma Patients

Acta Haematologica. 2013  |  Pubmed ID: 23107867

We conducted a retrospective study to compare thalidomide, bortezomib and dexamethasone (VTD) with thalidomide plus doxorubicin and dexamethasone (TAD). Until now, first-line treatment with these combinations has not been reported in any comparative study. The principal objective of this study was to determine whether VTD would improve the complete response (CR) and CR plus very good partial response rates compared with TAD. Second, using additional methods, such as flow cytometric assays and polymerase chain reaction technology, we evaluated the molecular residual disease in the subgroup of patients that obtained CR. Our study shows that VTD is a superior induction regimen compared with TAD, with a higher response rate after induction, translating into greater CR plus very good partial response.

HOX and TALE Signatures Specify Human Stromal Stem Cell Populations from Different Sources

Journal of Cellular Physiology. Apr, 2013  |  Pubmed ID: 23018864

Human stromal stem cell populations reside in different tissues and anatomical sites, however a critical question related to their efficient use in regenerative medicine is whether they exhibit equivalent biological properties. Here, we compared cellular and molecular characteristics of stromal stem cells derived from the bone marrow, at different body sites (iliac crest, sternum, and vertebrae) and other tissues (dental pulp and colon). In particular, we investigated whether homeobox genes of the HOX and TALE subfamilies might provide suitable markers to identify distinct stromal cell populations, as HOX proteins control cell positional identity and, together with their co-factors TALE, are involved in orchestrating differentiation of adult tissues. Our results show that stromal populations from different sources, although immunophenotypically similar, display distinct HOX and TALE signatures, as well as different growth and differentiation abilities. Stromal stem cells from different tissues are characterized by specific HOX profiles, differing in the number and type of active genes, as well as in their level of expression. Conversely, bone marrow-derived cell populations can be essentially distinguished for the expression levels of specific HOX members, strongly suggesting that quantitative differences in HOX activity may be crucial. Taken together, our data indicate that the HOX and TALE profiles provide positional, embryological and hierarchical identity of human stromal stem cells. Furthermore, our data suggest that cell populations derived from different body sites may not represent equivalent cell sources for cell-based therapeutical strategies for regeneration and repair of specific tissues.

Myelomatous Meningitis Evaluated by Multiparameter Flow Cytometry : Report of a Case and Review of the Literature

Journal of Clinical and Experimental Hematopathology : JCEH. 2014  |  Pubmed ID: 25318945

Central nervous system (CNS) involvement in multiple myeloma (MM) is uncommon. Among its possible presentations, leptomeningeal involvement of MM, also termed central nervous system myelomatosis (CNS-MM) is rare and is characterized by the presence of neoplastic plasma cells in the cerebrospinal fluid (CSF). So far, 187 cases of CNS-MM have been reported : the great majority of them were diagnosed by cytological assays and flow cytometry was used in only eight cases. We describe a case of CNS-MM in a 62-year-old woman, previously treated with chemotherapy (VTD) and autologous peripheral blood hematopoietic stem cell transplantation for stage IIIB IgG-λ MM. After achieving a very good partial response, the patient showed progression of disease, with an extramedullary localization. During administration of second-line therapy, the patient showed severe neurological symptoms. MRI resulted negative. Diagnosis of CNS-MM was made by multiparameter flow cytometry, which showed the presence of CD56(+) plasma cells in a CSF sample, in the absence of plasma cell leukemia. In this paper we also present a review of the eight previous cases of CNS-MM diagnosed by flow cytometry. We found that the application of flow cytometry in cases of MM with neurological symptoms allows a rapid diagnosis of CNS-MM and provides useful information about plasma cell phenotype (including CD56 expression). Some cases of CNS-MM are characterized by normal MRI. In addition, some evidences deriving from the review of literature suggest that CSF monitoring by flow cytometry in such cases might be used to evaluate the efficacy of drugs capable of crossing the blood-brain barrier.

Minimal Residual Disease After Conventional Treatment Significantly Impacts on Progression-free Survival of Patients with Follicular Lymphoma: the FIL FOLL05 Trial

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Dec, 2014  |  Pubmed ID: 25316810

The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients receiving R-CHOP, R-FM, or R-CVP.

Plasticity of Human Dental Pulp Stromal Cells with Bioengineering Platforms: a Versatile Tool for Regenerative Medicine

Micron (Oxford, England : 1993). Dec, 2014  |  Pubmed ID: 25180486

In recent years, human dental pulp stromal cells (DPSCs) have received growing attention due to their characteristics in common with other mesenchymal stem cells, in addition to the ease with which they can be harvested. In this study, we demonstrated that the isolation of DPSCs from third molar teeth of healthy individuals allowed the recovery of dental mesenchymal stem cells that showed self-renewal and multipotent differentiation capability. DPSCs resulted positive for CD73, CD90, CD105, STRO-1, negative for CD34, CD45, CD14 and were able to differentiate into osteogenic and chondrogenic cells. We also assayed the angiogenic potential of DPSCs, their capillary tube-like formation was assessed using an in vitro angiogenesis assay and the uptake of acetylated low-density lipoprotein was measured as a marker of endothelial function. Based on these results, DPSCs were capable of differentiating into cells with phenotypic and functional features of endothelial cells. Furthermore, this study investigated the growth and differentiation of human DPSCs under a variety of bioengineering platforms, such as low frequency ultrasounds, tissue engineering and nanomaterials. DPSCs showed an enhanced chondrogenic differentiation under ultrasound application. Moreover, DPSCs were tested on different scaffolds, poly(vinyl alcohol)/gelatin (PVA/G) sponges and human plasma clots. We showed that both PVA/G and human plasma clot are suitable scaffolds for adhesion, growth and differentiation of DPSCs toward osteoblastic lineages. Finally, we evaluated the interactions of DPSCs with a novel class of nanomaterials, namely boron nitride nanotubes (BNNTs). From our investigation, DPSCs have appeared as a highly versatile cellular tool to be employed in regenerative medicine.

Processing Large-diameter Poly(L-lactic Acid) Microfiber Mesh/mesenchymal Stromal Cell Constructs Via Resin Embedding: an Efficient Histologic Method

Biomedical Materials (Bristol, England). Aug, 2014  |  Pubmed ID: 25029413

In this study, we performed a complete histologic analysis of constructs based on large diameter ( >100 μm) poly-L-lactic acid (PLLA) microfibers obtained via dry-wet spinning and rat Mesenchymal Stromal Cells (rMSCs) differentiated towards the osteogenic lineage, using acrylic resin embedding. In many synthetic polymer-based microfiber meshes, ex post processability of fiber/cell constructs for histologic analysis may face deterring difficulties, leading to an incomplete investigation of the potential of these scaffolds. Indeed, while polymeric nanofiber (fiber diameter = tens of nanometers)/cell constructs can usually be embedded in common histologic media and easily sectioned, preserving the material structure and the antigenic reactivity, histologic analysis of large polymeric microfiber/cell constructs in the literature is really scant. This affects microfiber scaffolds based on FDA-approved and widely used polymers such as PLLA and its copolymers. Indeed, for such constructs, especially those with fiber diameter and fiber interspace much larger than cell size, standard histologic processing is usually inefficient due to inhomogeneous hardness and lack of cohesion between the synthetic and the biological phases under sectioning. In this study, the microfiber/MSC constructs were embedded in acrylic resin and the staining/reaction procedures were calibrated to demonstrate the possibility of successfully employing histologic methods in tissue engineering studies even in such difficult cases. We histologically investigated the main osteogenic markers and extracellular matrix molecules, such as alkaline phosphatase, osteopontin, osteocalcin, TGF-β1, Runx2, Collagen type I and the presence of amorphous, fibrillar and mineralized matrix. Biochemical tests were employed to confirm our findings. This protocol permitted efficient sectioning of the treated constructs and good penetration of the histologic reagents, thus allowing distribution and expression of almost all the tested molecules to be revealed. Our results demonstrated that it is possible to perform histologic analyses of large-diameter PLLA-based microfiber scaffold/MSC constructs that face the failure of standard histologic procedures.

Genetic Variants and Multiple Myeloma Risk: IMMEnSE Validation of the Best Reported Associations--an Extensive Replication of the Associations from the Candidate Gene Era

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Apr, 2014  |  Pubmed ID: 24521996

Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies.

Safety and Efficacy of (90) Yttrium-ibritumomab-tiuxetan for Untreated Follicular Lymphoma Patients. An Italian Cooperative Study

British Journal of Haematology. Mar, 2014  |  Pubmed ID: 24344981

(90) Yttrium ((90) Y)-Ibritumomab-Tiuxetan combines the targeting advantage of a monoclonal antibody with the radiosensitivity of Follicular Lymphoma (FL). Previous studies showed that 90Y-IT is safe and effective in relapsed/refractory indolent FL, irrespective of prior treatment with rituximab. This multicentre trial aimed to evaluate the safety and the efficacy of "upfront" single-agent ((90) Y)-Ibritumomab-Tiuxetan in advanced-stage FL. The primary objective was the incidence of responses in terms of complete (CR) and partial remission (PR). Fifty patients with stage II "bulky", III or IV FL received a single treatment course with ((90) Y)-Ibritumomab-Tiuxetan as initial therapy. The median age was 60 years. Bone marrow involvement (<25%) was observed in 24 patients (48%) and 7 (14%) had an elevated lactate dehydrogenase level. The overall response (ORR) and CR rates were 94% and 86%, respectively with a median follow-up of 38·8 months. The median progression-free survival (PFS) was not reached, whereas the 3-year estimated PFS and overall survival (OS) rate was 63·4% and 90%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 30% and 26% of patients respectively; none experienced grade 3/4 non-haematological toxicity. No cases of secondary haematological malignancies were observed. ((90) Y)-Ibritumomab-Tiuxetan was demonstrated to be highly effective and safe as first-line treatment for advanced-stage FL.

Sorafenib As Monotherapy or in Association with Cytarabine and Clofarabine for the Treatment of Relapsed/refractory FLT3 ITD-positive Advanced Acute Myeloid Leukemia

Clinical Lymphoma, Myeloma & Leukemia. Feb, 2014  |  Pubmed ID: 24144836

Modifications in B-Lymphocyte Number and Phenotype in the Course of Pregnancy in a Woman with Persistent Polyclonal B-Cell Lymphocytosis: A Flow Cytometric Study

Journal of Clinical and Experimental Hematopathology : JCEH. 2015  |  Pubmed ID: 26490519

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare clinical condition, characterized by a persistent, generally moderate lymphocytosis, generally due to stimulation of central memory B-lymphocytes, and by a moderate increase of polyclonal IgM. In some patients, slight or moderate splenomegaly is observed. A variable percentage of circulating, bone marrow and splenic lymphocytes display an abnormal nucleus (generally bilobated) or are binucleated. The clinical course is benign in most cases and transformation into splenic B-cell lymphoma occurs in few cases. In the current paper we report the first case of pregnancy in PPBL. Our patient became pregnant 18 months after diagnosis. In the course of pregnancy, a marked down-regulation of lymphocytosis (from 6 × 10(9)/L to 2.1 × 10(9)/L) and a decrease in B-lymphocyte number was observed (from 3.6 × 10(9)/L to 1 × 10(9)/L), mainly due to a marked reduction in the percentage and absolute number of central memory B-cells. Such modifications were similar to those described in normal pregnant women. One year after the delivery of a healthy female baby, the number of total lymphocytes and B-lymphocytes showed an inverse behavior, with a new expansion of central memory B-cells. Our case shows that a normal pregnancy can occur in patients with PPBL and that pregnancy can induce marked modifications in B-lymphocyte kinetics and phenotype.

Combination of CD157 and FLAER to Detect Peripheral Blood Eosinophils by Multiparameter Flow Cytometry

Journal of Clinical and Experimental Hematopathology : JCEH. 2015  |  Pubmed ID: 26490516

The identification of eosinophils by flow cytometry is difficult because most of the surface antigens expressed by eosinophils are shared with neutrophils. Some methods have been proposed, generally based on differential light scatter properties, enhanced autofluorescence, lack of CD16 or selective positivity of CD52. Such methods, however, show several limitations. In the present study we report a novel method based on the analysis of glycosylphosphatidylinositol (GPI)-linked molecules. The combination of CD157 and FLAER was used, since FLAER recognizes all GPI-linked molecules, while CD157 is absent on the membrane of eosinophils and expressed by neutrophils. Peripheral blood samples from normal subjects and patients with variable percentages of eosinophils (n = 31), and without any evidence for circulating immature myeloid cells, were stained with the combination of FLAER-Alexa Fluor and CD157-PE. A FascCanto II cytometer was used. Granulocytes were gated after CD33 staining and eosinophils were identified as CD157(-)/FLAER(+) events. Neutrophils were identified as CD157(+)/FLAER(+) events. The percentages of eosinophils detected by this method showed a very significant correlation both with automated counting and with manual counting (r = 0.981 and 0.989, respectively). Sorting assays were carried out by a S3 Cell Sorter: cytospins obtained from CD157(-)/FLAER(+) events consisted of 100% eosinophils, while samples from CD157(+)/FLAER(+) events were represented only by neutrophils. In conclusion, this method shows high sensitivity and specificity in order to distinguish eosinophils from neutrophils by flow cytometry. However, since CD157 is gradually up-regulated throughout bone marrow myeloid maturation, our method cannot be applied to cases characterized by immature myeloid cells.

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia

International Journal of Molecular Sciences. 2015  |  Pubmed ID: 26402671

Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed.

Ofatumumab Maintenance Versus Observation in Relapsed Chronic Lymphocytic Leukaemia (PROLONG): an Open-label, Multicentre, Randomised Phase 3 Study

The Lancet. Oncology. Oct, 2015  |  Pubmed ID: 26377300

Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia.

Polycomb Genes Are Associated with Response to Imatinib in Chronic Myeloid Leukemia

Epigenomics. Aug, 2015  |  Pubmed ID: 26343356

Imatinib is a tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia (CML). Despite its efficacy, about a third of patients discontinue the treatment due to therapy failure or intolerance. The rational identification of patients less likely to respond to imatinib would be of paramount clinical relevance. We have shown that transmembrane transporter hOCT1 genotyping predicts imatinib activity. In parallel, Polycomb group genes (PcGs) are epigenetic repressors implicated in CML progression and in therapy resistance.

Type 2 Diabetes-related Variants Influence the Risk of Developing Multiple Myeloma: Results from the IMMEnSE Consortium

Endocrine-related Cancer. Aug, 2015  |  Pubmed ID: 26099684

Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case-control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)=1.32-2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76-0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)=0.645 vs AUC=0.629; P=4.05×10(-) (06)). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (Pinteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.

Kinetics of Hematogones in Bone Marrow Samples from Patients with Non-Hodgkin Lymphomas Treated with Rituximab-containing Regimens: a Flow Cytometric Study

International Journal of Hematology. Jul, 2015  |  Pubmed ID: 25953308

Treatment with rituximab, either alone or in combination with antiblastic drugs, causes significant depletion of circulating B-lymphocytes and modifications of B cell maturation in the bone marrow. In the present study, we analyzed the kinetics of hematogones in bone marrow samples from 55 patients suffering from non-Hodgkin lymphomas and treated with rituximab-containing regimens. Maturation arrest at the level of stage 2 hematogones, along with complete depletion of naïve, mature B-lymphocytes, was observed as short-term effects (2 months after completion of chemo-immunotherapy). Further bone marrow samples, obtained 12 months after the last rituximab infusion in 21 patients undergoing long-term follow-up and treated with rituximab maintenance therapy, showed complete normalization of B-lymphocyte ontogeny. Hypogammaglobulinemia developed in 26 patients, and was still observed in nine of the 21 patients undergoing long-term follow-up. Our study provides novel data on hematogone kinetics in the setting of patients with non-Hodgkin lymphomas treated with chemo-immunotherapy containing rituximab and with rituximab maintenance. Our observations show that hypogammaglobulinemia can persist in a significant percentage of patients, despite complete recovery of B-lymphocyte ontogeny.

Bortezomib and Arsenic Trioxide Activity on a Myelodysplastic Cell Line (P39): A Gene Expression Study

Turkish Journal of Haematology : Official Journal of Turkish Society of Haematology. Sep, 2015  |  Pubmed ID: 25913414

We aimed to understand the molecular pathways affected by bortezomib and arsenic trioxide treatment on myelomonocytoid cell line P39.

Reduced Circulating B-lymphocytes and Altered B-cell Compartments in Patients Suffering from Chronic Myeloid Leukaemia Undergoing Therapy with Imatinib

Hematological Oncology. Dec, 2015  |  Pubmed ID: 25256816

Risk of Multiple Myeloma is Associated with Polymorphisms Within Telomerase Genes and Telomere Length

International Journal of Cancer. Mar, 2015  |  Pubmed ID: 25066524

Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72-0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy-free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63-2.24; p(trend)  = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.

Safety and Efficacy of Pomalidomide Plus Low-dose Dexamethasone in STRATUSTM (MM-010): a Phase 3b Study in Refractory Multiple Myeloma

Blood. May, 2016  |  Pubmed ID: 27226434

Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS(TM) study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for pts aged > 75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well-tolerated. www.Clinicaltrials.gov identifier NCT01712789.

A Systematic Literature Review and Network Meta-analysis of Treatments for Patients with Untreated Multiple Myeloma Not Eligible for Stem Cell Transplantation

Leukemia & Lymphoma. Apr, 2016  |  Pubmed ID: 27124703

In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting.

Grafting of Expanded Mesenchymal Stem Cells Without Associated Procedure in a Healed Case of Ulna Pseudarthrosis: A Case Report

Surgical Technology International. Apr, 2016  |  Pubmed ID: 27121410

The surgical management of pseudoarthrosis is often a challenge. The use of mesenchymal multipotent cells expanded and manipulated in the laboratory is an interesting treatment of pseudoarthrosis, because they can lead to differentiation into osteocytes and thus the formation of bone tissue.

Discrepancy Between FLC Assays: Only a Problem of Quantification?

Clinical Chemistry and Laboratory Medicine. Jun, 2016  |  Pubmed ID: 27107836

First Report of Wautersiella Falsenii Genomovar 2 Isolated from the Respiratory Tract of an Immunosuppressed Man

IDCases. 2016  |  Pubmed ID: 27051582

Wautersiella falsenii is a Gram-negative, non-motile rod, which grows aerobically on common isolation media and is the only acknowledged species among the genus Wautersiella. Two genomovars, namely 1 and 2, phenotypically indistinguishable but genotypically different, are described. To date, few case reports detailing the clinical disease associated with W. falsenii have been reported, all describing localized infection. To our knowledge, this study reports the first isolation of W. falsenii genomovar 2 from a respiratory sample of an immunosuppressed man. Our hypothesis is that the patient was harboring W. falsenii genomovar 2 and both the immunosuppression and the antimicrobial treatments provided a chance for this organism to emerge. The clinical significance of this result is yet to be evaluated. Although infection with W. falsenii remains rare, this bacterium should not be underestimated mainly because of its natural resistance to many available antimicrobials.

Mesangiogenic Progenitor Cells Derived from One Novel CD64(bright)CD31(bright)CD14(neg) Population in Human Adult Bone Marrow

Stem Cells and Development. May, 2016  |  Pubmed ID: 26975798

Mesenchymal stromal cells (MSCs) have been the object of extensive research for decades, due to their intrinsic clinical value. Nonetheless, the unambiguous identification of a unique in vivo MSC progenitor is still lacking, and the hypothesis that these multipotent cells could possibly arise from different in vivo precursors has been gaining consensus in the last years. We identified a novel multipotent cell population in human adult bone marrow that we first named Mesodermal Progenitor Cells (MPCs) for the ability to differentiate toward the mesenchymal lineage, while still retaining angiogenic potential. Despite extensive characterization, MPCs positioning within the differentiation pathway and whether they can be ascribed as possible distinctive progenitor of the MSC lineage is still unclear. In this study, we describe the ex vivo isolation of one novel bone marrow subpopulation (Pop#8) with the ability to generate MPCs. Multicolor flow cytometry in combination with either fluorescence-activated cell sorting or magnetic-activated cell sorting were applied to characterize Pop#8 as CD64(bright)CD31(bright)CD14(neg). We defined Pop#8 properties in culture, including the potential of Pop#8-derived MPCs to differentiate into MSCs. Gene expression data were suggestive of Pop#8 in vivo involvement in hematopoietic stem cell niche constitution/maintenance. Pop#8 resulted over three logs more frequent than other putative MSC progenitors, corroborating the idea that most of the controversies regarding culture-expanded MSCs could be the consequence of different culture conditions that select or promote particular subpopulations of precursors.

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease

The New England Journal of Medicine. Jan, 2016  |  Pubmed ID: 26735993

Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling.

Positron Emission Tomography Response and Minimal Residual Disease Impact on Progression-free Survival in Patients with Follicular Lymphoma. A Subset Analysis from the FOLL05 Trial of the Fondazione Italiana Linfomi

Haematologica. Feb, 2016  |  Pubmed ID: 26471485

CD229 Expression on Bone Marrow Plasma Cells from Patients with Multiple Myeloma and Monoclonal Gammopathies of Uncertain Significance

Acta Haematologica. 2016  |  Pubmed ID: 26303094

Identification of MiRSNPs Associated with the Risk of Multiple Myeloma

International Journal of Cancer. Oct, 2016  |  Pubmed ID: 27718532

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.

Genetic Predisposition and Induced Pro-inflammatory/pro-oxidative Status May Play a Role in Increased Atherothrombotic Events in Nilotinib Treated Chronic Myeloid Leukemia Patients

Oncotarget. Aug, 2016  |  Pubmed ID: 27527867

Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced "inflammatory/oxidative status", together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing.

LH and FSH Promote Migration and Invasion Properties of a Breast Cancer Cell Line Through Regulatory Actions on the Actin Cytoskeleton

Molecular and Cellular Endocrinology. Dec, 2016  |  Pubmed ID: 27502036

Reproductive hormones influence breast cancer development and progression. While the actions of sex steroids in this setting are established, tentative evidence suggests that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) may also play a role, yet this remains elusive. We here identify that T-47D breast cancer cells express functional receptors for FSH and LH, and that these hormones regulate breast cancer cell motility and invasion through the control of the actin cytoskeleton and the formation of cortical actin aggregates and focal adhesion complexes. Such actions are mediated by the cytoskeletal controllers Moesin and focal adhesion kinase (FAK). Moesin is recruited rapidly by FSH and LH through a signaling cascade requiring the G protein Gα13 and the Rho-associated kinase, ROCK-2. FSH and LH activate FAK via a Gαi/β and c-Src-dependent signaling cascade. Both cascades involve signaling to phosphatidylinositol-3 kinase and Akt. FSH and LH receptors and the related signaling intermediates are necessary for the actions of gonadotrophins on breast cancer cell cytoskeletal rearrangement, migration and invasion. These findings provide original information on the actions of gonadotrophins on breast cancer cells and may have clinical implications for the use of drugs that modulate gonadotrophins in breast cancer patients.

ATP-binding Cassette Transmembrane Transporters and Their Epigenetic Control in Cancer: an Overview

Expert Opinion on Drug Metabolism & Toxicology. Dec, 2016  |  Pubmed ID: 27459275

Members of the ATP-binding cassette (ABC) transmembrane transporters control the passage of several substrates across cell membranes, including drugs. This means that ABC transporters may exert a significant influence on the kinetics and dynamics of pharmacological agents, being responsible for the occurrence of multidrug-resistant (MDR) phenotype. Pharmacogenetic analyses have shed light on gene expression and polymorphisms as possible markers predictive of transporter activity. However, a non-negligible part of the variability in drug pharmacokinetics and pharmacodynamics still remains. Further research has demonstrated that different epigenetic mechanisms exert a coordinated control over ABC genes, and on the corresponding MDR phenotype. Areas covered: DNA methylation and histone modifications (namely acetylation, methylation, phosphorylation, etc.) significantly impact gene expression, as well as noncoding RNA molecules that are involved in the post-transcriptional control of the ABC transporters ABCB1, ABCC1 and ABCG2. We describe the epigenetic mechanisms of gene expression control for ABC transporters and their relevant association with the MDR phenotype in human cancer. Expert opinion: The clinical meaning of those observations is discussed in the review, highlighting the importance of the epigenetic control of the ABC transporters for the clinical therapeutic outcomes that despite their effects and applications, requires further investigation.

How to Treat Splenic Marginal Zone Lymphoma (SMZL) in Patients Unfit for Surgery or More Aggressive Therapies: Experience in 30 Cases

Journal of Chemotherapy (Florence, Italy). Jul, 2016  |  Pubmed ID: 27454143

Splenic marginal zone lymphoma (SMZL) is an indolent disease that typically affects elderly patients. Thanks to its outcome, most patients don't need any specific therapy and 'a watch and wait' policy is frequently employed. Treatment is required in symptomatic cases. Splenectomy remains one of the first line options in patients fit for surgery. The best pharmacological strategy has not yet been identified for poor surgical risk cases. Amongst different possible chemotherapeutic approaches, alkylating agents, alone or in association with Rituximab, could employ in 'frail' patients. In the present study, the role of oral cyclophosphamide (100 mg per day for 15 consecutive days, every 30 for a total of six cycles) associated with anti-CD20 monoclonal antibody has been evaluated in 30 newly diagnosed SMZL patients, not fit for splenectomy or more toxic chemotherapic regimens. Overall response rate was 87% (CR 70%; PR 17%). Median PFS was 20 months (range, 1-53), with better outcome for low-risk cases according to IIL score prognostic index. Toxicity profile resulted mild.

A Common Variant Within the HNF1B Gene is Associated with Overall Survival of Multiple Myeloma Patients: Results from the IMMEnSE Consortium and Meta-analysis

Oncotarget. Jul, 2016  |  Pubmed ID: 27437873

Diabetogenic single nucleotide polymorphisms (SNPs) have recently been associated with multiple myeloma (MM) risk but their impact on overall survival (OS) of MM patients has not been analysed yet. In order to investigate the impact of 58 GWAS-identified variants for type 2 diabetes (T2D) on OS of patients with MM, we analysed genotyping data of 936 MM patients collected by the International Multiple Myeloma rESEarch (IMMENSE) consortium and an independent set of 700 MM patients recruited by the University Clinic of Heidelberg. A meta-analysis of the cox regression results of the two sets showed that rs7501939 located in the HNF1B gene negatively impacted OS (HRRec= 1.44, 95% CI = 1.18-1.76, P = 0.0001). The meta-analysis also showed a noteworthy gender-specific association of the SLC30A8rs13266634 SNP with OS. The presence of each additional copy of the minor allele at rs13266634 was associated with poor OS in men whereas no association was seen in women (HRMen-Add = 1.32, 95% CI 1.13-1.54, P = 0.0003). In conclusion, these data suggest that the HNF1Brs7501939 SNP confers poor OS in patients with MM and that a SNP in SLC30A8 affect OS in men.

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