1,721,288 research outputs found
Efficacy and toxicicty of sequential high-dose therapy with peripheral blood stem cell support in patients with high-risk breast cancer
No full textPatients with high-risk breast cancer may benefit from dose-escalated chemotherapy. We studied toxicity and therapeutic efficacy of sequential high-dose therapy consisting of two cycles of ifosfamide 12,000 mg/m2, carboplatin 900 mg/m2, and epirubicin 180 mg/m2 (ICE) with peripheral blood stem cell support. Ninety-one patients with advanced breast cancer were included. Fifty-one patients with stage II/III disease and 10 or more tumor-positive axillary lymph nodes received high-dose therapy as adjuvant treatment; the remaining 40 patients were treated for metastatic disease. Peripheral blood stem cells were collected following granulocyte colony-stimulating factor-supported induction chemotherapy. In 68 patients, induction chemotherapy included two cycles of ifosfamide 7,500 mg/m2 and epirubicin 120 mg/m2, while 23 patients received one cycle of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 135 mg/m2, ifosfamide 6,000 mg/m2, and epirubicin 90 mg/m2. One hundred ninety-two cycles of ICE were supported with a median of 3.5 x 10(6) CD34+ cells/kg body weight (range, 1.7 to 38 x 10(6) CD34+ cells/kg body weight), which resulted in rapid hematologic reconstitution with recovery times, for a median neutrophil count of 0.5 x 10(9)/L of 13 days (range, 6 to 20 days) and for a median platelet count greater than 20 x 10(9)L of 9 days (range, 5 to 24 days). Seven patients received only one cycle of ICE because of progressive disease (in two patients with metastatic disease), central nervous system toxicity (one patient), cardiac toxicity (one patient), severe enterocolitis (one patient), development of human leukocyte antigen antibodies (one patient), and wish to withdraw from the study (one patient). Seventeen patients with metastatic disease received an additional high-dose cycle consisting of the non-cross-resistant agents thiotepa 600 mg/m2, etoposide 1,500 mg/m2, and paclitaxel 165 mg/m2. In patients treated adjuvantly, the probability of disease-free survival was 64% at 47 months, which compares favorably with results of conventional treatment protocols, with a 47% event-free probability at the same time period. The probability of progression-free survival in patients with metastatic disease was 18% at 44 months. In conclusion, sequential high-dose therapy with peripheral blood stem cell support in patients with high-risk breast cancer can be administered safely and offers a potential benefit in the adjuvant setting
Myelodysplastic disorders carrying both isolated del(5q) and JAK2(V617F) mutation: concise review, with focus on lenalidomide therapy
Get PDFThe concomitant presence of del(5q) and JAK2(V617F) mutation is an infrequent event which occurs in rare patients with peculiar cytogenetic, molecular, morphological and clinical features, resembling those of both myelodysplastic syndromes and myeloproliferative neoplasms. Lenalidomide may induce rapid, profound, and long-lasting responses in a subset of these patients. However, the mechanism(s) by which the drug acts in these conditions remain not completely elucidated. A new case report and a review of all cases published so far in this setting are provided. Furthermore, the possibility of categorizing - from a clinical, pathological, and biological point of view - for at least some of these patients as a potential distinct entity is discussed
Therapy-related leukemias and myelodysplasia : susceptibility and incidence.
No full textTherapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is an increasingly recognized treatment complication in patients treated with radiotherapy or chemotherapy for previous hematologic malignancies or solid tumors. Distinct clinical entities have been described according to the primary treatment, corresponding to defined genetic lesions. Chromosome 7 and/or 5 losses or deletions are typical of alkylating agent-induced AML, while development of t-AML with balanced translocations involving chromosome bands 11q23 and 21q22 has been related to previous therapy with drugs targeting DNA-topoisomerase II. In addition, antimetabolites, and in particular the immunosuppressant azathioprine, have been shown to induce defective DNA-mismatch repair. This could promote survival of misrepaired cells giving rise to the leukemic clone. Individual predisposing factors, including polymorphisms in detoxification and DNA repair enzymes have been identified. Their combination may significantly increase the risk of t-MDS/AML. Among patients with hematologic malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased risk of t-MDS/AML, particularly when receiving MOPP-based, and escalated BEACOPP regimens, and when alkylators are combined with radiotherapy. Patients with Hodgkin's and non-Hodgkin's lymphoma are at highest risk when total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation therapy. The addition of granulocyte-colony-stimulating factor and radiotherapy plays a significant role in t-AML following treatment of children with acute lymphoblastic leukemia. In non-hematologic malignancies, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of both lymphoid as well as myeloid leukemia. In all cases the risk of t-MDS/AML drops sharply by 10 years after treatment
Gene expression profiling of myelodysplastic CD34+ hematopoietic stem cells treated in vitro with decitabine.
No full textAbnormal gene promoter methylation contributes to deregulate gene expression of hematopoietic progenitors in myelodysplastic syndromes (MDS). We analyzed the gene expression profile of myelodysplastic and normal CD34+ hematopoietic stem cells (HSCs) treated in vitro with decitabine. We identified a list of candidate tumor suppressor genes, expressed at low levels in MDS HSCs and induced by hypomethylating treatment only in MDS, but not in normal HSCs. Real-time RT-PCR confirmed reduced CD9 expression in MDS CD34+ and bone marrow mononuclear cells, compared to normal controls. CD9 was specifically up-regulated by decitabine treatment in myelodysplastic CD34+ cell
A practical algorithm for acute myeloid leukaemia diagnosis following the updated 2022 classifications
No full textDisease classification of complex and heterogenous diseases, such as acute myeloid leukaemia (AML), is continuously updated to define diagnoses, appropriate treatments, and assist research and education. Recent availability of molecular profiling techniques further benefits the classification of AML. The World Health Organization (WHO) classification of haematolymphoid tumours and the International Consensus Classification of myeloid neoplasms and acute leukaemia from 2022 are two updated versions of the WHO 2016 classification. As a consequence, the European LeukemiaNet 2022 recommendations on the diagnosis and management of AML in adults have been also updated. The current review provides a practical interpretation of these guidelines to facilitate the diagnosis of AML and discusses genetic testing, disease genetic heterogeneity, and FLT3 mutations. We propose a practical algorithm for the speedy diagnosis of AML. Future classifications may need to incorporate gene mutation combinations to enable personalised treatment regimens in the management of patients with AML
DEREGULATION OF PI3K/AKT SIGNALING IN BONE MARROW MESENCHIMAL STROMAL CELLS FROM PATIENTS WITH DE NOVO AND THERAPY-RELATED ACUTE MYELOID LEUKEMIA
No full textBackground: In addition to neoplastic transformation of hematopoietic progenitors,
a damage of bone marrow microenvironment can contribute to leukemia
development and maintenance. Several functional and morphological abnormalities
of bone marrow mesenchimal stromal cells (BM-MSCs) have been
described in myeloid neoplasms. Nevertheless molecular bases of differences
between MSCs from normal and leukemic bone marrows are still unknown.
PI3K/AKT signaling pathway is involved in several MSC functions and deregulation
of genes belonging to these pathways have been described in MSCs
from different type of cancers.
Aims: To study the expression profile of genes belonging to PI3K/AKT signaling
pathway in MSCs from patients with de novo and therapy related Acute
Myeloid Leukemia (t-AML), using as normal counterpart BM-MSCs isolated
from patients with limited stage lymphoma without bone marrow involvement.
Methods: Study population included 5 patients with limited stage diffuse large
B cell lymphoma (DLBCL) without bone marrow involvement, as normal control,
and 10 patients with AML, including 5 de novo and 5 therapy-related cases.
Bone marrow mononuclear cells were obtained by Ficoll-gradient centrifugation
of bone marrow samples and cultured in Complete Human MesenCultR
Medium (Stem Cell Technologies) in 25 cm2 flask at 37°C. After 24 hours nonadherent
cells were removed and adherent cells were cultured up to 70% confluence,
then trypsinized and passed to a new flask. Cells at 2nd passage were
collected by trypsinization, RNA was extracted using RNase mini kit (Qiagen)
and cDNA was synthesized by QuantiTect Reverse Transcription kit (Qiagen).
The Human PI3K-AKT PCR array (RT2ProfilerTM PCR Array; SABioscience)
was used to analyze mRNA levels of 84 key genes involved in PI3K-AKT Signaling
Pathway, in a 96-well plate in the CFX96 thermocycler (Bio-Rad). Relative
changes in gene expression were calculated using the ΔΔCt method. An
average Ct value of five housekeeping genes (GAPDH, βactin, β2-microglobulin,
HPRT1 and RPLPO) was used to normalize the gene expression between
sample groups. Fold change (FC) variations ≥1.5 in association to statistically
significant T-test (P-value≤0.05) were used for the statistical analysis.
Results: Comparison of MSCs from AML samples versus normal controls
identified three genes significantly down-regulated in leukemic samples, including
GSK3B (P=0.0002, FC=-1.56), MTCP1 (P=0.019, FC=-1.62) and RASA1
(P=0.013, FC=-1.58). Stratifying the analysis according to AML subtypes, three
genes were significantly down-regulated in t-AML versus normal bone marrow,
including GSK3B (P=0.0009 and FC=-1.63), PTEN (P=0.004 and FC=-1.50)
and SOS1 (P=0.004 and FC=-1.50). Similarly when comparing MSC from de
novo AML versus normal bone marrow, GSK3B, MTCP1 and RASA1 resulted
still down-regulated in MSC from leukemic samples (P=0.005 and FC=-1.51;
P=0.018 and FC=-1.96; P=0.007 and FC=-1.81, respectively). No differences
were found in the expression levels of studied genes between de novo and therapy-
related AML.
Summary and Conclusions: Deregulation of genes belonging to PI3K/AKT
signaling pathway may contribute to MSC dysfunction described in leukemic
bone marrows and can affect their ability to interact with leukemic blasts and
normal hematopoietic cells, eventually contributing to bone marrow failure and
leukemia development. GSK3B was the most significantly and commonly
down-regulated gene in MSCs from leukemic samples and codifies for the serine/
threonine protein kinase Gsk3β which is also involved in additional signaling
pathways, such as Raf/Mek/Erk and Wnt/β-catenin
Efficacy of combined surgery and antifungal therapies for the management of invasive zygomycoses in patients with haematological malignancies
No full textGSK3β down-regulation in Mesenchymal Stem Cells from patients with Myelodysplastic Syndrome.
No full textIn addition to neoplastic transformation of hematopoietic progenitors,bone marrow microenvironment damages can contribute to myeloid neoplasms development and maintenance. Several functional and morphological abnormalities of bone marrow mesenchymal stromal cells (BM-MSC) have been described in myeloid neoplasms. Nevertheless, molecular bases of differences between MSCs from normal and leukemic/myelodysplastic bone marrows are still unknown. Deregulation of genes belonging to PI3K/AKT signaling pathway has been
described in MSC from different type of cancers. We studied the expression
profile of genes belonging to PI3K/AKT signaling pathway in MSCs from 40 patients including 10 de novo AML, 10 de novo MDS, 10 t-MN (therapy-related myeloid neoplasms) and 10 patients with limited stage lymphoma without bone marrow involvement (used as normal control). BM-MSCs were obtained by Ficoll-gradient centrifugation
of bone marrow samples and cultured up to 70% confluence in MesenCult Medium. Cells at 2nd passage were used for all experiments. The Human PI3K-AKT PCR array (SABioscience) was used to analyze mRNA levels of 84 key genes involved in PI3K-AKT signaling pathway, comparing 5 de novo AML, 5 de novo MDS and 5 t-MN vs 5 normal
bone marrows. Relative changes in gene expression were calculated using the DDCt method. Fold change variations ≥1.5 in association to statistically significant T-test (p-value≤ 0.05) were used for the statistical analysis. Genes resulted significantly deregulated were validated by
quantitative real time RT-PCR, in 10 de novo AML samples, 10 de novo
MDS, 10 t-MN and 10 normal controls. Total GSK3b protein level and
its Ser-9 phosphorylated isoform were measured by Western blot in a
subgroup of MDS patients and controls. PI3K-AKT PCR arrays revealed
a significantly down-regulation of GSK3b, MTCP1, RASA1 and SOS1
genes in MSC from all leukemic and myelodysplastic bone marrows
compared to control group. After validation, all genes were confirmed
as significantly down-regulated in de novo MDS samples respect to normal
controls: GSK3b (p=0.0056, FC=-1.94), RASA1 (p =0.0044, FC=-2.19), SOS1 (p=0.0047, FC=-1.9) and MTCP1 (p=0.0026, FC=-1.93). No significant differences were found in the expression levels of studied
genes in the validation group among de novo AML, t-MN and controls.
Western blot analysis confirmed the down-regulation of both GSK3b
total protein and of its Ser-9 phosphorylated isoform in MDS MSC
respect to controls. Deregulation of genes belonging to PI3K/AKT signaling
pathway may contribute to MSC dysfunction described in MDS
bone marrows and can affect their ability to interact with normal
hematopoietic cells, participating to bone marrow failure and
myelodysplastic development. GSK3b, a crucial regulatory kinase interacting
with multiple signaling pathways, is one of the most significantly
down-regulated genes in MSC from myelodysplastic bone marrows
and its functional significance is under investigation
Therapy-related myeloid neoplasms: Clinical perspectives
No full textTherapy-related myeloid neoplasms (t-MNs) are a complication of cytotoxic treatment for primary tumors and autoimmune diseases. t-MNs result from a complex interaction between individual predisposition and exposition to toxic agents. Some different biological and clinical characteristics can be recognized according to the type of anticancer drug. Compared to de novo myeloid neoplasms, prognosis of t-MN is dismal. Age and karyotype are the most important prognostic factors for t-MN, which should be treated with frontline chemotherapy treatments that are appropriate for patients with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) with similar disease characteristics. Allogeneic stem cell transplantation should be considered particularly for unfavorable karyotypes and younger patients with aggressive disease
Chronic myelomonocytic leukemia treatment with azacitidine: What have we learned so far?
No full textNO ABSTRAC
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