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S Siena

Publications and source records attributed to S Siena.

At least 37 records · Page 2Linked to original sources
PubMed2000

The effect of anticonvulsant drugs on blood levels of methotrexate.

The reduced bioavailability of chemotherapeutic agents is one of the reasons that explains the limited efficacy of adjuvant chemotherapy in high grade glioma patients. We report how even the results of high dose sequential chemotherapy can be influenced by antiepileptic drugs.

Adult↗
PubMed2000

Transfusion of platelet concentrates cryopreserved with ThromboSol plus low-dose dimethylsulphoxide in patients with severe thrombocytopenia: a pilot study.

We have recently reported the possibility of supporting the phase of severe thrombocytopenia after high-dose chemotherapy (HDC) and stem cell transplantation using 5% dimethylsulphoxide (DMSO)-cryopreserved autologous platelet concentrates (PCs). The aim of the present study was to evaluate the therapeutic potential of ThromboSol (a recently developed platelet storage solution) plus PCs cryopreserved in 2% DMSO in patients undergoing myeloablative chemotherapy and autologous transplantation. PCs were collected from 14 women with breast cancer by a single plateletapheresis and cryopreserved in ThromboSol/2% DMSO by either direct insertion in a -80 degrees C freezer or in liquid nitrogen after computer-controlled rate (CR) freezing. When required, PCs were thawed, centrifuged to remove the cryoprotectants and transfused. In vitro studies on thawed platelets showed loss of epitopes of surface glycoproteins and a marked reduction of functional activity compared with fresh platelets. Transfusion of CR-frozen PCs was associated with a mean 1 h corrected count increment (CCI) of 9.2 +/- 5.4 x 109/l and only one allogeneic PC was required in this group. In contrast, six out of seven patients required additional allogeneic transfusions in the -80 degrees C group (CCI = 2.7 +/- 1.4 x 109/l). ThromboSol-treated PCs have the ability to overcome thrombocytopenia if processed by a CR freezing protocol, but appear ineffective when frozen by direct placing at -80 degrees C.

Blood Transfusion, Autologous↗
PubMed2000

Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy.

PURPOSE: To review recent advances in peripheral-blood progenitor-cell (PBPC) transplantation in order to define the optimal cell dose required for autologous and allogeneic transplantation. MATERIALS AND METHODS: A search of MEDLINE was conducted to identify relevant publications. Their bibliographies were also used to identify further articles and abstracts for critical review. RESULTS: The CD34(+) cell content of a graft is regarded as an accurate predictor of engraftment success. Postchemotherapy autologous PBPC transplantation with >/= 5 x 10(6) CD34(+) cells/kg body weight leads to more rapid engraftment than does transplantation of lower cell doses. Further increases in transplant cell dose further accelerate platelet but not neutrophil engraftment. Evidence that long-term hematopoietic recovery may be more accurately predicted by the subpopulation of primitive progenitors transplanted suggests that the content of CD34(+)CD33(-) and long-term culture-initiating cells in cell collection samples may be important for predicting successful engraftment, particularly in patients with poor mobilization. Allogeneic transplantation has been limited by concerns regarding graft-versus-host disease and the use of hematopoietic growth factors in donors. The risk of graft rejection and engraftment failure after HLA-mismatched allogeneic transplantation may be overcome by intensive chemoradiotherapy and the infusion of large numbers of T cell-depleted hematopoietic stem cells. CONCLUSION: An optimal cell dose of >/= 8 x 10(6) CD34(+) cells/kg seems to be recommended for autologous PBPC transplantation. This dose facilitates the administration of scheduled chemotherapy on time and reduces the demand for other supportive therapies. A combination of growth factors may enable patients with poor mobilization to achieve a collection sufficient to allow transplantation. The optimum PBPC dose for allogeneic transplantation remains to be defined.

Antigens, CD34↗
PubMed1999

Improved collection of mobilized CD34+ hematopoietic progenitor cells by a novel automated leukapheresis system.

BACKGROUND: For simplification of blood cell transplantation, an automated apheresis system that exploits a dual-stage channel device for mononuclear cell (MNC) collection (AutoPBSC, designed for the COBE Spectra) was studied. STUDY DESIGN AND METHODS: The automated default software (AutoPBSC-Default) and three software modifications of the harvest frequency during leukapheresis, referred to as AutoPBSC-1.25, AutoPBSC-1.75, and AutoPBSC-2.75, were evaluated in comparison with the semiautomated Version 4.7 (V4.7) apheresis system in 119 leukapheresis procedures performed in 90 cancer patients treated with chemotherapy plus granulocyte-colony-stimulating factor. CD34+ cell and platelet collection efficiency (CE); volume and cell composition of the leukapheresis components; and patient platelet and red cell (RBC) loss during leukapheresis were measured. RESULTS: The majority of collection measures evaluated with the AutoPBSC compared favorably to those obtained with the V4.7. CD34+ cell CE increased from 55 percent with V4.7 to 68 percent with the AutoPBSC-Default (p = 0.05). The AutoPBSC provided lower platelet contamination in the collected component (1.18 x 10(11) vs. 2.26 x 10(11) with the V4.7; p<0.001). The volume of the AutoPBSC-Default component was significantly lower (67 vs. 180 mL with the V4.7; p<0.001). The MNC purity of the AutoPBSC component was greater (52 vs. 28% with the V4.7; p<0.001), and the RBC contamination lower (AutoPBSC, 0.53 x 10(11) vs. 1.04 x 10(11) with the V4.7; p<0.001). Modifications of the AutoPBSC to increase the harvest frequency by 1.25-, 1.75-, and 2.75-fold resulted in increased CD34+ cell CE (77%, 75%, and 83%, respectively; p<0.001 in all cases), but also in reduced numbers of circulating platelets, higher platelet contamination of the component, and lower MNC purity than were seen with the AutoPBSC-Default. CONCLUSION: The AutoPBSC offers the following advantages over the V4.7 system: a) better CE of CD34+ cells; b) reduced collection of platelets; c) reduced contamination of the leukapheresis component with granulocytes, platelets, and RBCs; d) reduced component volume; and e) automation.

Adolescent↗
PubMed1999

New reciprocal translocation t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia.

We report a new chromosomal reciprocal translocation t(5;10)(q33;q22) in a 49-year-old man with atypical chronic myeloid leukemia (a-CML) and history of occupational exposure to petroleum products including benzene and other hydrocarbons. The t(5;10) (q33;q22) was found in 94% and 84% of metaphases in peripheral blood and bone marrow cells, respectively. Cytogenetic analysis of single colonies derived from granulocyte-macrophage (CFU-GM), and erythroid (BFU-E) hematopoietic progenitors showed that 88% and 40% of CFU-GM and BFU-E, respectively, had the t(5;10)(q33;q22). In contrast, peripheral blood T-lymphocytes, and cutaneous fibroblasts had normal 46,XY karyotype. Molecular analysis of the t(5;10)(q33;q22) translocation breakpoint is currently underway in order to identify genes located in this region which might provide insights into the pathogenesis of atypical myeloproliferative disorders.

Chromosomes, Human, Pair 10↗
PubMed1999

Ex vivo manipulation of hematopoietic stem cells for transplantation: the potential role of amifostine.

High-dose chemotherapy with autologous stem cell transplantation is an increasingly used procedure in oncohematologic diseases and represents a promising strategy in selected patients with solid tumors. In autologous stem cell transplantation, the risk of reinfusion of clonogenic tumor cells is a remarkable biologic obstacle that can be at least partly overcome by ex vivo graft purging to reduce residual tumor. Mafosfamide and 4-hydroxyperoxycyclophosphamide, active metabolites of cyclophosphamide, are the most widely used pharmacologic agents for ex vivo bone marrow purging. However, in addition to killing tumor cells, they are toxic to normal bone marrow as measured by reduced colony-forming unit granulocyte-macrophage (CFU-GM). Thus, the therapeutic index of these alkylating agents is narrow, and parameters for dose selection must include toxicity to normal bone marrow progenitor cells that can delay bone marrow engraftment and increase risk of infections, bleeding complications, hospitalization, and the need for a costly transplantation procedure. Amifostine (WR-2771, Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) selectively protects human CFU-GM progenitor cells from the cytotoxicities of active metabolites of cyclophosphamide without altering its cytotoxic effect on malignant cells. This has been demonstrated both in preclinical and clinical studies in patients with breast cancer, malignant lymphomas, and acute leukemia. Amifostine use during the ex vivo procedure significantly shortened the time to bone marrow engraftment with decreased incidence of infections and need for red blood cell transfusions.

Amifostine↗
PubMed1998

Adenovirus vectors for gene transduction into mobilized blood CD34+ cells.

Mobilized blood CD34+ cells from cancer patients were ex vivo infected by a recombinant adenovirus vector carrying an alkaline phosphatase gene, whose expression is evaluable by flow cytometry. A mean of 40% CD34+ cells were infected by the vector, with high levels of expression of the transgene. Among attempts to improve infection efficiency by manipulating culture conditions, only reinfection by the same vector achieved a 10% increase of transgene expression. Transduced CD34+ cells were induced to differentiate along the myeloid and the dendritic lineage, and in either case AP+ cells were detectable among the differentiated cell population. We conclude that adenovirus vectors may be useful tools for gene transduction into mobilized blood CD34+ cells, particularly for those applications in which high transgene expression for limited periods of time is required.

Adenoviridae↗
PubMed1998

Mobilized peripheral blood CD34+ cells express more amphotropic retrovirus receptor than bone marrow CD34+ cells.

BACKGROUND AND OBJECTIVE: The increased susceptibility to gene transfer by amphotropic retroviral vectors of mobilized peripheral blood (PB) CD34+ cells compared to their bone marrow (BM) counterparts may depend, among other factors, on the level of expression of the amphotropic receptor on the progenitor cell. Using a previously described flow cytometry strategy, we have studied retrovirus binding to mobilized CD+ cells, derived from cancer patients treated with high-dose chemotherapy and growth factor(s), that are efficiently transduced by N2 retrovirus vector. DESIGN AND METHODS: We measured the binding of the retrovirus to the cells using a rat monoclonal antibody reactive with the gp70 envelope glycoprotein, common to all replication-defective amphotropic retroviruses. Antibody-virus-cell complexes were indirectly labeled and analyzed by flow cytometry. We compared the binding of PA317-N2 vector to CD34+ cells derived from steady-state BM, steady-state PB and mobilized PB from cancer patients treated with high-dose chemotherapy and cytokine. RESULTS: The fluorescence intensity of mobilized CD34+ cells was approximately one log higher than that of steady-state BM or PB CD34+ cells, indicating that the expression of the amphotropic receptor was increased. Moreover, the virus binding was proportional to the gene transfer rate, as assessed by G418 resistance into mobilized PB-derived CFU-GM. The increase in fluorescence intensity appeared to be restricted to CD34+ cell subset, neither CD2+ nor CD14+ cells bound the virus in an appreciable amount. INTERPRETATION AND CONCLUSIONS: Virus binding, as assessed by indirect immunofluorescence assay, is increased in mobilized CD34+ cells. The increased binding may contribute to their high susceptibility to retrovirus vector infection.

Antigens, CD34↗
PubMed1998

Ex vivo expansion of hematopoietic cells and their clinical use.

BACKGROUND AND OBJECTIVE: Hematopoietic stem cells are being increasingly used for treatment of malignant and nonmalignant disorders. Various attempts have been made in recent years to expand and manipulate these cells in order to increase their therapeutic potential. A Working Group on Hematopoietic Cells has analyzed the most recent advances in this field. EVIDENCE AND INFORMATION SOURCES: The method used for preparing this review was an informal consensus development. Members of the Working Group met three times, and the participants at these meetings examined a list of problems previously prepared by the chairman. They discussed the single points in order to achieve an agreement on different judgments, and eventually approved the final manuscript. Some authors of the present review have been working in the field of stem cell biology, processing and transplantation, and have contributed original papers in peer-reviewed Journals. In addition, the material examined in the present review includes articles and abstracts published in Journals covered by the Science Citation Index and Medline. STATE OF ART: Over the last decade, recombinant DNA technology has allowed the large scale production of cytokines controlling the proliferation and differentiation of hemo-lymphopoietic cells. Thus, in principle, ex vivo manipulation of hemopoiesis has become feasible. The present review covers three major area of interest in experimental and clinical hematology: manipulation of hematopoietic stem/progenitor cells, cytotoxic effector cells and antigen presenting dendritic cells. Preliminary data demonstrate the possibility of using, in a clinical setting, ex vivo expanded hematopoietic cells with the aim of reducting, and perhaps abrogating, the myelosuppression after high-dose chemotherapy. Concurrently, other important potential applications for ex vivo manipulation of hematopoietic cells have recently been investigated such as the generation and expansion of cytotoxic cells for cancer immunotherapy, and the large scale production of professional antigen presenting cells capable of initiating the process of immune response. CONCLUSIONS AND PERSPECTIVES: Present and future challenges in this field are represented by the expansion of true human stem cells without maturation, to extend this strategy to allogeneic stem cell transplantation as well as the manipulation of cycling of primitive progenitors for gene therapy programs. The selective outgrowth of normal progenitor cells over neoplastic cells to achieve tumor-free autografts may ameliorate the results of autologous transplantation. The selective production of cellular subsets to manipulate the graft versus-host and graft versus-tumor effects and anti-tumor vaccination strategies may be important to improve cellular adoptive immunotherapy.

Animals↗
PubMed1997

Autologous dendritic cells derived from CD34+ progenitors and from monocytes are not functionally equivalent antigen-presenting cells in the induction of melan-A/Mart-1(27-35)-specific CTLs from peripheral blood lymphocytes of melanoma patients with low frequency of CTL precursors.

Peptide presentation by autologous dendritic cells (DCs) is a new tool to activate tumor antigen-specific T cells in melanoma patients. However, it is not known whether autologous DCs, differentiated by two of the most efficient protocols (from CD34+ progenitors or from monocytes), are equally effective as professional antigen-presenting cells (APCs) when the patients have a low frequency of peptide-specific precursors. To this end, a limiting dilution assay was applied to evaluate the frequency of antigen-specific CTL precursors (CTLps) in peripheral blood of HLA-A*0201+ melanoma patients. Then, from two melanoma patients showing low frequency of CTLps to melanoma antigen-A/melanoma antigen recognized by T cell (Melan-A/Mart-1)(27-35) peptide, autologous DCs were differentiated from granulocyte colony-stimulating factor-mobilized CD34+ progenitors or from monocytes. CD34+- and monocyte-derived DCs were characterized by a similar proportion of CD1a+ cells expressing HLA class II antigens and CD54, CD80, and CD86 molecules. Both types of DC presented Melan-A/Mart-1(27-35) and tyrosinase(369-377) peptides to melanoma-specific CTL clones and were equally effective as peptide-pulsed APCs in the activation of influenza A matrix(58-66)-specific CTLs from high-frequency precursors (1294/10(6) and 1789/10(6) lymphocytes in the two patients). However, efficient activation of Melan-A/Mart-1(27-35)-specific CTLs from low-frequency precursors (158/10(6) and 77/10(6) lymphocytes) of the two patients was markedly dependent on the use of peptide-loaded CD34+-derived DCs. These results suggest that CD34+- and monocyte-derived DCs are not functionally equivalent APCs for the activation of low-frequency peptide-specific CTLps.

Antigen-Presenting Cells↗
PubMed1997

High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma.

BACKGROUND: We compared a regimen of six chemotherapeutic agents administered sequentially at high doses, followed by myeloablative treatment and bone marrow transplantation, with a regimen of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as initial or salvage treatment for adults with diffuse large-cell lymphoma. METHODS: Ninety-eight eligible patients with diffuse large-cell lymphoma of the B-cell type were randomly assigned to receive either MACOP-B (50 patients) or high-dose sequential therapy (48 patients). The study design allowed for patients in whom the assigned treatment failed to cross over to the other treatment group. RESULTS: After a median follow-up of 55 months, the patients given high-dose sequential therapy, as compared with those treated with MACOP-B, had significantly higher rates of complete response (96 percent vs. 70 percent, P=0.001), freedom from disease progression (84 percent vs. 49 percent, P<0.001), freedom from relapse (88 percent vs. 70 percent, P=0.055), and event-free survival (76 percent vs. 49 percent, P=0.004). The difference in overall survival at seven years, which also favored the group assigned to high-dose sequential therapy, was marginally significant (81 percent vs. 55 percent, P=0.09). CONCLUSIONS: High-dose sequential therapy is superior to standard-dose MACOP-B for patients with diffuse large-cell lymphoma of the B-cell type.

Adolescent↗
PubMed1997

Efficacy, toxicity, and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: five-year results.

PURPOSE: To assess the efficacy, toxicity, and applicability of high-dose therapy administered as adjuvant initial treatment to women with breast cancer with extensive nodal involvement. PATIENTS AND METHODS: Sixty-seven patients with stage II to III breast cancer involving > or = 10 axillary nodes received a novel high-dose sequential (HDS) regimen, including the high-dose administration of three non-cross-resistant drugs (cyclophosphamide, methotrexate, and melphalan) given within the shortest interval of time as possible with hematologic and nonhematologic toxicity. RESULTS: Sixty-three patients completed the program as planned, one patient died of acute toxicity, and three patients were switched to standard-dose adjuvant therapy. After a median follow-up duration of 48.5 months and a lead follow-up of 78 months, actuarial relapse-free survival for all 67 registered patients is 57% and overall survival is 70%, respectively. Comparison with a historical control group of 58 consecutive patients showed a significantly superior rate of freedom from relapse for the HDS-treated group (57% v 41%, respectively), in particular when two subgroups of patients, more homogeneous for their number of involved nodes, were compared (65% v 42%). Overall, treatment was of short duration (median, 70 days), required a median of 32 days of hospital stay, and was associated with only a few severe side effects (the most distressing being oral mucositis after melphalan therapy). CONCLUSION: HDS therapy emerges as an effective and applicable regimen, whose major toxicity was occasional. Final assessment of its value in a randomized, multicenter trial is presently underway.

Adult↗
PubMed1997

Expansion of Immunostimulatory Dendritic Cells from Peripheral Blood of Patients with Cancer.

Clinical investigators are keenly interested in the role of antigen-presenting cells (APCs) in the initiation of immune responses because of potential use of APCs in immune cell therapy. Pioneer studies in mammals by Steinman and coworkers have demonstrated that the specialized system of APCs is constituted by bone marrow-derived dendritic cells. Dendritic cells are distinguished by their unique ability to capture, process, and present antigens into peptide-HLA complexes to naive T lymphocytes and to deliver the costimulatory signal necessary for T-lymphocyte activation. In this article, we summarize the main experimental evidence supporting the hypothesis that individuals vaccinated with manipulated dendritic cells can mount tumor-specific humoral and cellular responses. This can lead to tumor regression as well as protective immunity to tumor growth in vivo.

Journal Article↗