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Biomedical subjects

S Siena

Publications and source records attributed to S Siena.

At least 73 records · Page 4Linked to original sources
PubMed1993

Clinical application of growth factors for collection of circulating hematopoietic progenitors in breast cancer patients treated with high-dose cyclophosphamide.

Seventy-seven (68 operable breast cancer with > 9 metastatic axillary nodes and 9 inflammatory breast cancer) entered this study. During hematopoietic recovery after cancer therapy with high-dose cyclophosphamide (7 g/m2; HD-CTX) circulating hematopoietic progenitors were collected by leukapheresis (LK) in all patients and then cryopreserved for autologous transplantation. Following HD-CTX, 70 patients were treated with hematopoietic growth factor(s) for 14 days: 38 with rhGM-CSF (group a), 16 with rhIL-3 (group b), 11 with sequential rhIL-3 and rhGM-CSF (group c), 5 with sequential rhIL-3 and rhG-CSF (group d). Seven control patients (group e) did not receive any growth factor. Leukaphereses, carried out over 2-4 consecutive days per patient, were started earlier in group c and in group d patients (mean day: +12 after HD-CTX). The sequential administration of rhIL-3 and rhG-CSF (group d) resulted in clearly higher yield of CFU-GM and CD34+ cells per leukapheresis (65.9 x 10(4)/Kg versus 20.9 x 10(6)/Kg, respectively) if compared with other groups of treatment.

Adult↗
PubMed1993

Quantization of CD34+ peripheral blood hematopoietic progenitors for autografting in cancer patients.

After myeloablative regimens, combined reinfusion of peripheral blood hematopoietic circulating progenitor cells (CPC) and bone marrow, yields a very rapid hematopoietic recovery. Therefore, based on the knowledge that CPC express the CD34 and CD33 differentiation antigen, we have developed a direct immunofluorescence flow cytometry assay to detect the peak of CPC in the peripheral blood of patients treated with high dose chemotherapy and growth factors. This assay, compared to CFU-GM assay, has the following advantages: 1) easy to do 2) standardized method 3) real time information on CPC number. This work illustrates the practical aspects of this assay and substantiate the widespread use of the CD34/33 flow cytometry assay to guide harvesting of circulating hematopoietic progenitors for autologous transplantation.

Antigens, CD↗
PubMed1993

Role of chemotherapy and GM-CSF on hemopoietic progenitor cell mobilization in multiple myeloma.

Circulating hemopoietic progenitors were evaluated in 19 multiple myeloma patients at diagnosis. Eleven patients received either high-dose cyclophosphamide (7 g/m2, 8 patients) or etoposide (2 g/m2, 3 patients) followed by GM-CSF administration; the remaining 8 patients received intermediate-dose cyclophosphamide (1.2 g/m2 on days 1 and 3), 4 of them with GM-CSF support. The highest levels of circulating progenitor cells were observed among patients in the high-dose chemotherapy group (median CFU-GM peak value of 6432 per ml), while in patients receiving intermediate-dose, with or without GM-CSF, median peak values were 2588 and 462 per ml, respectively. In all groups a remarkable heterogeneity in the yield of circulating progenitors was observed; this was particularly pronounced in the high-dose group, where CFU-GM peak values ranged between 200 and 38,070 per ml. At variance with the effect observed in previously untreated patients with lymphoma or breast cancer, the degree of mobilization in myeloma patients was rather unpredictable. The only pre-treatment characteristic correlating to some extent with a poor expansion of the circulating progenitor pool was heavy BM infiltration with plasma cells. The mobilizing effect was not restricted to the myeloid lineage, as demonstrated by the rise of BFU-E; CD34+ cells were increased as well. Indeed, a simultaneous evaluation of CFU-GM and CD34+ cells was carried out and a highly significant correlation (r = 0.9) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors.

Seven patients received cancer chemotherapy with high-dose cyclophosphamide (HD-CTX) associated with either recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh interleukin-3 (rhIL-3), rh granulocyte-macrophage CSF (rhGM-CSF) plus rh erythropoietin (rhEpo), rhIL-3 plus rhGM-CSF, or rhIL-3 plus rhG-CSF. In the steady-state blood samples (before HD-CTX), megakaryocyte burst-forming units (BFU-Meg) and megakaryocyte colony-forming units (CFU-Meg) were virtually undetectable (< or = 1/mL BFU-Meg and CFU-Meg, range 0 to 1) by assaying unfractionated leukocytes. In contrast, in the recovery-phase blood samples (after HD-CTX), BFU-Meg and CFU-Meg increased several hundred-fold over steady-state values. This occurred regardless of the in vivo growth factors used and in parallel with increases in mixed, erythroid, and myeloid progenitors. In vitro, recovery-phase BFU-Meg and CFU-Meg responded to the novel GM-CSF/IL-3 fusion protein PIXY321 similarly as to optimal concentrations of rhIL-3 and rhGM-CSF. However, these progenitors differed from those in the steady state because BFU-Meg had faster duplication time and CFU-Meg prevailed numerically (CFU-Meg to BFU-Meg ratio 3.4 [recovery] vs. 0.52 [steady state]). Furthermore, soluble c-kit ligand/rh stem cell factor (rhSCF), in vitro in combination with rhIL-3 and rhGM-CSF or PIXY321, increased the size but not the number of colonies derived from recovery-phase BFU-Meg and CFU-Meg. These quantitative and qualitative changes occurring in circulating megakaryocyte progenitors contribute to the understanding of the rapid platelet recovery that occurs when peripheral blood hematopoietic progenitors elicited by HD-CTX and growth factor(s) are transplanted into patients treated with myeloablative chemoradiotherapy.

Adult↗
PubMed1992

Human peripheral blood hematopoietic progenitors are optimal targets of retroviral-mediated gene transfer.

Hematopoietic progenitor cells circulate in the peripheral blood (PB) of cancer patients during the recovery phase that follows treatment with high-dose cyclophosphamide followed by hematopoietic growth factor infusion. We report that when PB progenitors were exposed in vitro to filtered supernatant from cell line PA317-N2, producing amphotropic helper-free N2 vector at conventional titers, successful retroviral-mediated transfer of neomycin resistance gene was documented by polymerase chain reaction in 93% of day 14 myelomonocytic colonies. Under the same conditions, gene transfer was achieved in 22% of steady-state bone marrow-derived myelomonocytic colonies. Neo-resistance gene transfer was documented also in a CD34+/cyclophosphamide-resistant precursor to granulocyte-macrophage colonies, an undifferentiated progenitor close to the hematopoietic stem cell. Neither cocultivation with vector-producing cells nor high vector titer were stringent requisites for efficient gene transfer. The large-scale availability of PB hematopoietic progenitors in cancer patients, together with the high gene transfer rate achieved under safe and clinically feasible conditions, support an optimal approach for gene transfer procedures into the human hematopoietic system.

Base Sequence↗
PubMed1992

Recombinant human interleukin-3 and recombinant human granulocyte-macrophage colony-stimulating factor administered in vivo after high-dose cyclophosphamide cancer chemotherapy: effect on hematopoiesis and microenvironment in human bone marrow.

The effects on bone marrow (BM) cell proliferation and differentiation of recombinant human interleukin-3 (rhIL-3) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) administered after high-dose (7 g/m2/d) cyclophosphamide (HD-CTX) chemotherapy were studied in nine patients with malignancies without BM involvement and in three control patients. rhIL-3 at a dose of 1 to 5 micrograms/kg/day was administered for 14 to 18 days by continuous intravenous (i.v.) infusion and rhGM-CSF was administered at a dose of 5.5 micrograms/kg/day for 14 days. Changes induced by cytokine treatment were assessed by morphoimmunohistochemical analysis of BM biopsies. Comparison was made in the cytokine-treated groups and with control patients who received HD-CTX alone. BM cellularity and the myeloid/erythroid (ME) ratio were lower in rhIL-3-treated than in rhGM-CSF-treated patients, but in both groups it was significantly higher than in the controls. The proportion of BM cells stained by PC10, a monoclonal antibody (MoAb) recognizing a proliferation-associated nuclear protein (PCNA), increased from 6.78% to 21.18% (P less than .02) after rhIL-3, and from 5% to 35.33% (P less than .001) after rhGM-CSF; no increase was observed in the control group. The frequency of CD34+ BM cells was unchanged after rhIL-3 (P = NS) and decreased after rhGM-CSF (P less than .001). In both groups, most of the PC10+ cells were represented by promyelocytes and myelocytes with no increase in blast cell numbers. rhIL-3-treated BM showed an increased number of megakaryocytes and increased proliferative activity of erythroid cells as compared with rhGM-CSF cases. BM stroma changes observed in both treated groups included endothelial cell proliferation, increased BM macrophage concentration, and increase in BM fibroblasts as detected with an anti-nerve growth factor receptor antibody. In most rhIL-3-treated cases, BM fibrosis developed after treatment. The same effect was not observed in rhGM-CSF patients.

Adult↗
PubMed1992

Granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor infusion makes high-dose etoposide a safe outpatient regimen that is effective in lymphoma and myeloma patients.

PURPOSE: This study assessed the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or recombinant human granulocyte colony-stimulating factor (rhG-CSF) in ameliorating the extent and duration of hematologic toxicity after high-dose etoposide cancer therapy. PATIENTS AND METHODS: Thirty-two non-Hodgkin's lymphoma and myeloma patients were treated with 2 to 2.4 g/m2 etoposide infused intravenously (IV) during a 10- to 12-hour period, followed 72 hours later by subcutaneous administration of rhGM-CSF or rhG-CSF. Hematologic toxicity was compared with that observed in 29 patients who were treated with high-dose etoposide without growth factors. RESULTS: The median duration of grade 4 neutropenia in growth factor-treated patients was 3 days, and granulocyte counts never decreased to less than 100/microL in approximately half of the patients. The corresponding figures in the control patients were 8 and 3 days, respectively (P < .0001). No effect was observed in platelet and RBC recovery. Growth factor-treated patients became eligible to receive additional myelotoxic chemotherapy a median of 5 days earlier than controls. Nonhematologic toxicity was minimal. Grade 1 mucositis was observed in two of 61 patients (3%). Antitumor activity assessed within 1 month after etoposide administration was documented in 58% of 38 assessable patients. Finally, high-dose etoposide expanded and mobilized the pool of peripheral-blood hematopoietic progenitors. CONCLUSION: The use of rhGM-CSF or rhG-CSF makes high-dose etoposide a safe outpatient regimen and should encourage the inclusion of this highly effective and well-tolerated drug in novel treatment strategies that use high-dose therapy early in the clinical course of chemosensitive tumors.

Adult↗
PubMed1991

Flow cytometry for clinical estimation of circulating hematopoietic progenitors for autologous transplantation in cancer patients.

Optimum methods of harvesting circulating hematopoietic progenitors for autologous transplantation to support myeloablative cancer therapy are still uncertain, mostly because of the lack of an assay for marrow-repopulating stem cells. The CFU-GM assay, the commonly used indirect indicator of the quality of the graft, is poorly standardized and provides results evaluable only retrospectively. Based on the knowledge that hematopoietic progenitors express CD34 and CD33 differentiation antigens, we developed a dual-color direct immunofluorescence flow cytometry assay with the aim of replacing the CFU-GM assay advantageously. For this purpose, we applied both assays to 157 blood samples obtained daily throughout 20 different recoveries from pancytopenia induced by high-dose cyclophosphamide or etoposide cancer therapy with or without recombinant human GM colony-stimulating factor (rhGM-CSF). The appearance of CD34+ cells in the circulation indicated that hematopoietic progenitors had increased to more than 500 CFU-GM/mL, a level clinically adequate for large-scale harvest by leukapheresis. Total CD34+ cells correlated well with CFU-GM (r = .89), and data could be fitted by a linear regression line described by the equation y = 388.3 + 64.0x, where y = CFU-GM/mL and x = CD34+ cells per microliter. Moreover, in a series of six patients treated with myeloablative chemoradiotherapy, early hematopoietic recovery of marrow functions was predicted more accurately by the number of transplanted CD34+/CD33+ cells than by either total nucleated cells, CFU-GM, CD34+/CD33- cells, or CD34-/CD33+ cells. Data presented in this article favor clinical use of the CD34/CD33 flow cytometry assay to guide harvesting of circulating hematopoietic progenitors for autologous transplantation and contribute to better understanding of the role played by circulating hematopoietic progenitor cell subsets in marrow recovery after myeloablative cancer therapy.

Antigens, CD↗
PubMed1991

Peripheral blood expansion of early progenitor cells after high-dose cyclophosphamide and rhGM-CSF.

In 20 patients with non-Hodgkin lymphoma or breast cancer, high-dose cyclophosphamide induced, during the post-nadir period of rapid leucocyte recovery, on median day 19 about a 30-fold increase in the peak concentration of granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) colony-forming cells, and an even higher increase in the more immature pluripotent progenitors (CFU-Mix, 72-fold). After infusion of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), peak concentration was reached earlier (median day 15) and with further enhancements (159, 116 and 283-fold respectively, in the number of CFU-GM, BFU-E and CFU-Mix). Most CFU-GM were immature, lacking the differentiation antigen CD15, and gave rise to large myeloid colonies, reflecting a high proliferative capacity of the founder cells. Very immature maphosphamide-resistant progenitors were detectable. The marked expansion in the circulating pool was predictable and reliable, allowing harvesting, after two or three leukaphereses, of sufficient haematopoietic progenitors for autologous bone-marrow reconstitution.

Adult↗
PubMed1991

Tropisetron plus haloperidol to ameliorate nausea and vomiting associated with high-dose alkylating agent cancer chemotherapy.

Tropisetron is a novel antiserotoninergic drug with potent and specific activity against cancer chemotherapy-induced emesis. High-dose cyclophosphamide or high-dose melphalan are chemotherapeutic regimens associated with severe nausea and vomiting refractory to current antiemetic medications. We compared in a randomised open label study the antiemetic efficacy of tropisetron and alizapride in a first group of 32 consecutive patients treated with high-dose alkylating agent chemotherapy with or without autologous bone marrow transplantation. Tropisetron was more effective than alizapride in reducing vomiting episodes. In the first 24 h of treatment the median number of episodes in patients treated with tropisetron was 5 compared with 9 episodes in the alizapride group (P = 0.005). In the 72 h study period the median number of emetic episodes was 6 in the tropisetron group and 12 in the alizapride group (P = 0.004). In a second group of 26 consecutive patients, a combination of tropisetron plus haloperidol, a dopamine antagonist, was employed for prevention of emesis. This combination was more effective than tropisetron as single agent in preventing emetic episodes, as the median number of emetic episodes in the 72 h of observation was only 3, while they were 6 in the tropisetron group. The side-effects of tropisetron were mild and reversible upon discontinuation of the drug. We conclude that tropisetron is an effective antiemetic drug when employed in high-dose alkylating agent chemotherapy, and that its activity is potentiated by the association with haloperidol.

Adult↗
PubMed1991

Primary and salvage chemotherapy in advanced Hodgkin's disease: the Milan Cancer Institute experience.

This paper reviews the most relevant therapeutic results achieved by the Milan Cancer Institute through successive randomized studies in advanced Hodgkin's disease. The experience achieved confirms the therapeutic importance of an anthracycline-containing regimen such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) as salvage treatment and as primary chemotherapy, either when combined with irradiation or cyclically alternated with MOPP (mechlorethamine/vincristine/procarbazine/prednisone). Anthracycline-based combinations can be further refined to decrease toxicity. The biologic aspects of drug-sensitive v drug-resistant tumor cells and the accurate definition of prognostic categories at the time of first treatment failure are also discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Prolonged disease-free survival after high-dose sequential chemo-radiotherapy and haemopoietic autologous transplantation in poor prognosis Hodgkin's disease.

Although effective in achieving durable remission in selected tumors incurable by conventional-dose chemotherapy, high-dose regimens requiring bone marrow transplantation remain too toxic for widespread use. With the aim to improve the therapeutic index of high-dose therapy, we have developed a novel program whereby several non-cross-resistant agents (including total body irradiation at myeloablative dose) were delivered sequentially rather than concurrently. The regimen has been tested in 25 patients with Hodgkin's disease refractory to primary chemotherapy (MOPP and ABVD) or relapsed within 12 months after first complete remission. The efficacy of the sequential regimen (72% complete response rate, 49% event-free survival and freedom from progression at four years, with a median observation of 3.5 years for patients remaining alive) compares favorably with the activity so far reported for the most effective high-dose regimens. Toxicity was low; no toxic deaths occurred and only three life-threatening adverse events were documented after autografting. The excellent tolerability of the final myeloablative course most likely reflects the speed and completeness of haematologic recovery that followed the use of peripheral blood progenitors as the sole or additional source of myeloid stem cells. The reduction of haematologic toxicity was further emphasized when rhG-CSF was employed to both shorten post-chemotherapy neutropenic intervals and to collect large amounts of peripheral blood stem cells. We expect that the use of growth factors will have a major impact on the therapeutic index of high-dose regimens. This, in turn, will confirm their safety as primary treatment in selected high-risk subsets.

Adult↗
PubMed1991

Hematopoietic stem cell transplantation in the treatment of lymphoma.

In 1990, high-dose chemotherapy, with or without radiotherapy, requiring the support of hematopoietic stem cell transplantation has been confirmed as an effective treatment modality for a fraction of recurring or refractory lymphomas. Most relevant clinical studies published in 1990 are summarized and commented on in this review. Upcoming developments expected to improve the therapeutic index of high-dose therapies comprise the identification of patients at high risk of relapse so they can be treated earlier in the course of the disease, and the utilization of hematopoietic growth factors for ameliorating myelosuppression, as well as for harvesting peripheral blood hematopoietic stem cells utilizable for transplantation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Selective purging by human interleukin-2 activated lymphocytes of bone marrows contaminated with a lymphoma line or autologous leukaemic cells.

The ability of recombinant interleukin 2 (rIL2) activated lymphocytes (LAK) to purge BM samples contaminated by tumour cells was evaluated. Human BM mononuclear cells were contaminated with 10% of the lymphoma line CA46 and then cultured in liquid medium containing 1000 U/ml of rIL2 and/or LAK autologous to the used BM. At the end of coculture the growth of residual tumour cells and of CFU-GM were evaluated by clonogenic assay. No tumour cell growth was observed in 5/5 independent experiments after 18 h of coculture with LAK. No significant inhibition of CFU-GM growth was also noted. Subsequently, the effect of LAK on BM obtained from four leukaemic patients and contaminated with 20-50% of their own AML and ALL cells was studied using MAb as a tool for identifying leukaemic cells. LAK eliminated 24-78% of contaminating cryopreserved uncultured autologous leukaemic cells. In five cases the BM was contaminated by a low (2%) amount of ALL cells. In these patients the monoclonal heavy chain rearrangement typical of ALL was no longer visible after coculture with LAK. Evidence for selective tumour cytotoxicity by LAK was confirmed by using autologous BM cells as hot and cold targets in a 51Cr release assay. Finally, successful haematologic reconstitution of lethally irradiated BALB/c mice was obtained using syngeneic BM cocultured with LAK. These results support the investigational use of rIL2 and LAK in the treatment of human leukaemia.

Acute Disease↗
PubMed1991

Methodologies to estimate circulating hematopoietic progenitors for autologous transplantation in cancer patients.

Optimal criteria for harvesting circulating hematopoietic progenitors (CHP) for autologous transplantation to support myeloablative cancer therapy are still uncertain mostly because the CFU-GM assay, the commonly used indirect indicator of the hematopoietic recovery of the graft, is poorly standardized and provides information evaluable only retrospectively. Based on the knowledge that CHP express CD34 and CD33 differentiation antigens and facilitated by the availability of a very efficient fluorescein-conjugated CD34 antibody (8G12), we developed a direct immunofluorescence flow cytometry assay with the aim of replacing the CFU-GM assay advantageously. Recently, in a comparative study, both assays were applied to 157 blood samples obtained daily throughout 20 different recoveries from pancytopenia induced by high-dose cyclophosphamide (7 g/m2) cancer therapy w/ or w/o rhGM-CSF. Results showed that: a) detectability of CD34+ CHP indicated an increase to greater than 500 CFU-GM/mL, a level clinically adequate for harvesting CHP; b) CD34+ cells correlated well with CFU-GM (R=0.89) and data fitted a linear regression line (y=388.3 + 64.0x; y=CFU-GM/mL and x=CD34+/uL); c) in a series of 8 patients treated with myeloablative chemoradiotherapy, early recovery of marrow functions was predicted more accurately by the number of transplanted blood CD34+/CD33+ cells than by nucleated cells, CFU-GM, CD34+/CD33-cells, or CD34-/CD33+ cells. As a guideline, provided platelets are greater than 70,000/uL, harvest of CHP by leukapheresis during recovery from chemotherapy induced pancytopenia should be started as soon as CD34+ cells appear in the circulation and continued until the threshold dose of 7.8x10(6) CD34+ cells/kg, equivalent to 50 x 10(4) CFU-GM/kg, is achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗