Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Contamination of transplants with tumour cells may contribute to relapse after peripheral blood stem cell transplantation (PBSCT). We studied the feasibility of CD34+ cell selection from blood-derived autografts obtained following G-CSF-supported cytotoxic chemotherapy in a group of 25 patients with breast cancer (10 with high-risk stage II/III and 15 with stage IV without bone or bone marrow involvement). Using immunomagnetic beads (Isolex 300 SA. Baxter) CD34+ cells were enriched and released by chymopapain resulting in a median purity of 95% (range 82-99%) and a median recovery of 80% (range 27-132%). The enrichment procedure did not change the proportion of CD34+ subsets coexpressing HLA-DR, CD38 and Thy-1, while L-selectin was removed from the cell surface following selection. Using a sensitive immunocytological technique with a cocktail of epithelial-specific antibodies (anti-cytokeratin 8, 18 and 19; HEA125; BM7 and BM8), five leukaphereses products contained epithelial cells, whereas the selected CD34+ cell fraction was free of tumour cells. A neutrophil count of 0.5 x 10(9)/l and a platelet count of 20 x 10(9)/l was reached after a median time of 14 and 10d following 40 high-dose chemotherapy (HDC) cycles. Our results indicate that immunomagnetic selection of CD34+ cells yields highly purified autografts devoid of tumour cells whereas the engraftment ability of the progenitor and stem cells is fully retained.
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PMID:Immunomagnetic selection of CD34+ peripheral blood stem cells for autografting in patients with breast cancer. 921 92

The importance of dose-intensity has been suggested in breast cancer. The aim of this study was to evaluate the feasibility of a high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells. Twenty-five patients with non-metastatic breast cancer received four cycles of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2) at 3 week intervals. Apheresis was performed after the first cycle and if necessary after the second cycle. Stem cells were reinfused after the third and fourth cycles. G-CSF was started on day 3 of each cycle (5 microg/kg/day) and was stopped the day before the last apheresis or when absolute neutrophil count was above 0.5 x 10(9)/l. Median received dose-intensity was respectively 25 mg/m2/week (range 22-26) and 1000 mg/m2/week (range 904-1065) for doxorubicin and cyclophosphamide. Grade IV thrombocytopenia occurred in 8% of cycles. Two patients needed platelets and 12 red cell transfusion. Fifteen patients were readmitted for a median duration of 4 days (range 1-7). We have established a safe, outpatient, high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells which can be submitted for comparison with the current standards.
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PMID:High-dose sequential chemotherapy with stem cell support for non-metastatic breast cancer. 925 87

Seventy women with high-risk stage II (n = 10), IIIA (n = 12), IIIB (n = 11), or IV (n = 37) breast cancer received cyclophosphamide 6000 mg/m2, etoposide 2400 mg/m2, and carboplatin 1200 mg/m2 followed by infusion of autologous hematopoietic stem cells (AHSC). Women with high-risk stage II disease had eight or more involved axillary lymph nodes (n = 9) or axillary and breast relapse following lumpectomy, chemotherapy, and radiation therapy (n = 1). Women with measurable stage III or stage IV disease were required to demonstrate complete or partial response to conventional-dose chemotherapy prior to transplant. The overall (complete plus partial) response rate for the 31 patients not in complete remission at the time of transplant was 55%. With a median follow-up of 545 days, the 2-year actuarial progression-free survival rates for patients with stage II, IIIA, IIIB and IV are 86, 75, 42 and 13%, respectively. Factors independently predictive of longer progression-free survival by multivariate analysis included lower stage disease, status of disease at transplant (in CR vs not in CR), and positive estrogen receptor status. Factors predictive of more rapid neutrophil engraftment by multivariate analysis included post-transplant administration of hematopoietic growth factors, greater number of infused CFU-GM, mobilization with G-CSF or cyclophosphamide/G-CSF (vs mobilization with GM-CSF or no mobilization), and lower stage disease. Only one patient (1.4%) died prior to day 100 from any cause. High-dose cyclophosphamide, etoposide, and carboplatin followed by infusion of AHSC constitutes an active and well-tolerated regimen in the treatment of women with high-risk non-metastatic or metastatic breast cancer.
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PMID:Phase II study of high-dose cyclophosphamide, etoposide, and carboplatin (CEC) followed by autologous hematopoietic stem cell rescue in women with metastatic or high-risk non-metastatic breast cancer: multivariate analysis of factors affecting survival and engraftment. 928 41

Neoadjuvant chemotherapy is used to improve patients' survival in locally-advanced and inflammatory breast cancer and to increase conservative surgical procedures in bulky tumours. Pathological complete responses are unusual. The aim of this pilot study was to assess the clinical and pathological response rates and to evaluate toxicity with a new protocol of primary chemotherapy in 50 high-risk breast cancer patients. All tumours were > 3 cm and had at least one other adverse prognostic factor: lymph node involvement (32 N1, 6 N2), SBR grade III (20), aneuploidy (29), negative hormonal receptors (19). Patients were treated by 3-week cycles of THP-doxorubicin 20 mg/m2 D1 to 3, vinorelbine 25 mg/m2 D1 and 4, cyclophosphamide 300 mg/m2 and 5-fluorouracil 400 mg/m2 D1 to 4 (TNCF). 38 patients received G-CSF or GM-CSF support. After 4-6 cycles, all underwent surgery (39 conservative, 11 modified radical). Tumour response was assessed clinically, by mammography and echography and on pathological specimens. An objective clinical response was observed for 43 patients: 26 complete (51%) and 18 partial (37%). After pathological review, 11 patients (22%) were devoid of any tumour cells, 4 others (8%) had only in situ carcinoma. From 253 evaluated cycles, grade III-IV toxicity occurred, 81% with neutropenia, 25% with anaemia, and 20% with thrombocytopenia. All patients recovered. This regimen induced a severe but not life-threatening haematological toxicity and resulted in a high pathological response rate (30%).
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PMID:Clinical and pathological response to primary chemotherapy in operable breast cancer. 929 6

The purpose of our investigation was to evaluate the pharmacokinetic profile of doxorubicin administered by a new schedule. Nine non-pretreated young women with high risk breast cancer (mean age: 38, range: 29-45) entered this trial and received, cyclophosphamide (600 mg/m2) given as a 30-min infusion followed by doxorubicin (120 mg/m2) as a continuous infusion over 6 h. Chemotherapy was combined with hematopoietic factor support (G-CSF or GM-CSF). Blood was sampled over the 0-54 h period and 14 cycles were studied for pharmacokinetics. Doxorubicin as well as its major metabolite doxorubicinol were assayed in plasma specimen by high performance liquid chromatography. Mean doxorubicin plasma concentration peak was 42.6 ng/ml (standard deviation (SD): 13.3). The mean terminal half-lives were 32.6 h (SD: 22.0) and 39.2 h (SD: 21.6) for doxorubicin and doxorubicinol, respectively. Mean areas under the plasma concentration-time curve (AUC) were 413 ng/h-1 ml (SD: 103) and 1,707 ng/h-1 ml (SD: 815) for doxorubicin and doxorubicinol respectively. Consequently, the ratio of the AUC of doxorubicinol to that of doxorubicin was high (mean: 4.1 (SD: 1.6)) contrasting with previous studies reporting ratios less than 1 in patients with normal liver function. The systemic clearance of doxorubicin was 5.23 l/min/m2 (SD: 1.91). The inter- and intra-patient variability for AUC was low for both drugs. Hence the coefficients of variation were 24.6% for doxorubicin, 26.2% for doxorubicinol (inter-individual variation) and less than 10% for both compounds (intra-individual variation). In conclusion, the pharmacokinetic profile of doxorubicin (120 mg/m2) administered as a 6 h-continuous infusion is characterized by a greater exposure to doxorubicinol. This could be explained by a saturation in the biliary excretion process during the period following the end of the infusion.
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PMID:[Pharmacokinetic profile of high-dose doxorubicin administered during a 6 h intravenous infusion in breast cancer patients]. 929 63

The use of primed peripheral blood progenitor cells (PBPC) has improved platelet engraftment following autologous bone marrow/PBPC transplantation (ABMT). The thrombocytopenia associated with ABMT generally lasts 14-18 days, and is associated with variable platelet transfusion requirements. Little, if any, data exist examining prognostic parameters for platelet transfusion requirements during autologous transplantation. We retrospectively examined 286 consecutive patients undergoing autologous transplantation from 1 January 1994 to 1 June 1996 with respect to platelet engraftment and platelet transfusion requirements. One hundred and fifty four patients were transplanted for breast cancer (54%), 72 for non-Hodgkin's lymphoma (25%), 35 for Hodgkin's disease (12%), 13 for acute leukemia (5%), eight for myeloma (3%), and four for other malignancy (1%). The median age was 44. All patients received cytokine priming, usually with G-CSF, for the procurement of PBPC. The median number of CD34+ cells collected was 4.3 x 10(6)/kg. All patients received a chemotherapeutic preparative regimen and all received an autologous transplant using PBPC alone. The median time to a platelet count of 20 x 10(9)/l was 13 days. Patients beginning the transplant with a less than normal platelet count (less than 150 x 10(9)/l) engrafted in 17 days, and received a median number of seven platelet transfusions, as compared with platelet engraftment of 12 days, and four platelet transfusions, for patients beginning the transplant with a normal platelet count (P = 0.001). Both groups of patients received an equivalent dose of CD34+ cells. We conclude that thrombocytopenia at the initiation of autologous transplantation is associated with increased platelet transfusion requirements, independent of the dose of CD34+ cells infused.
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PMID:Platelet transfusion requirements during autologous peripheral blood progenitor cell transplantation correlate with the pretransplant platelet count. 931 78

Prolonged thrombocytopenia resulting from inadequate megakaryocyte (MK) progenitor cell reconstitution is a serious complication of hematopoietic cell-supported high-dose chemotherapy (HDC). In this situation, the infusion of MK progenitors that are expanded ex vivo could be clinically beneficial. In this study we investigated the ability of various growth factor combinations to generate MK progenitors. CD34+ cells derived from bone marrow (BM) and granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) from 17 patients with breast cancer, lymphoma, or myeloma were cultured unpertubed for 10 days in a serum-free liquid culture system that contained recombinant growth factors. Five different growth factors combinations were evaluated: Stem cell factor (SCF), interleukin (IL)-3, IL-6 + G-CSF (combination 1); SCF, megakaryocyte growth and development factor (MGDF) + G-CSF (combination 2); SCF + MGDF (combination 3); MGDF alone (combination 4); and SCF, IL-3, IL-6, G-CSF + MGDF (combination 5). PB CD34+ cells yielded significantly higher numbers of CD41+ MK progenitors than BM CD34+ cells with any of the growth factor regimens assayed. PB CD34+ cells (2x10[5]) at day 0 generated 1.2 to 1.3x10(6) CD41+ cells by day 10 when cultured in the presence of growth factor combinations 1, 2, or 3. In contrast, 2x10(5) BM CD34+ cells produced 5x10(5) CD41+ cells after 9 days in the presence of combination 1, whereas lower numbers of CD41+ cells were generated in cultures with combinations 2 and 3 (2.3x10[5] and 4.2x10[4], respectively). The addition of MGDF to cultures that were grown with combination 1 for 5 days increased the number of CD41+ cells (1.7-fold increase in PB-derived cultures, 1.6-fold increase in BM-derived cultures). Treatment with MGDF alone resulted in higher frequencies of MK progenitors than those obtained in cultures with combined growth factors (79% in PB-derived cultures, 25% in BM-derived cultures), but because total cell growth was attenuated, absolute numbers of MK progenitors were lower (7x10(5) in PB-derived cultures, 7x10(4) in BM). Morphological analysis of immunocytochemically identified megakaryocytic cells revealed mononuclear cells as the predominant cell type in all of the cultures. During the 10-day culture period, PB-derived MK progenitors did not show notable maturation, even under the influence of MGDF, whereas in BM-derived cultures MGDF induced a significant shift to binuclear cells and stage I MK after day 5. Phenotypic analysis of cell surface markers showed that the majority of cultured megakaryocytic cells coexpressed CD34 and platelet glycoproteins (GPs), also indicating an immature stage of development. The ex vivo proliferative activity of CD34+ cells and their potential to develop into the megakaryocytic lineage demonstrated considerably high interpatient variations. There was no correlation between platelet recovery following HDC with hematopoietic cell support and the magnitude of GP+ cell expansion ex vivo, suggesting the feasibilty of MK expansion ex vivo in patients with prolonged thrombocytopenia posttransplantation. In summary, these data indicate that GCSF-mobilized CD34+ PBPCs are more effectively expanded ex vivo into the megakaryocytic lineage than are CD34+ BMPCs. CD34+/GP+ MK progenitors may be an appropiate cell population for transplantion as prophylaxis or treatment of prolonged thrombocytopenia. The efficacy of this procedure will be tested prospectively in a clinical trial.
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PMID:Ex vivo expansion of megakaryocyte progenitors: effect of various growth factor combinations on CD34+ progenitor cells from bone marrow and G-CSF-mobilized peripheral blood. 932 49

Administration of hematopoietic growth factors is being used increasingly to obtain populations of blood progenitor/stem cells (PBPC) for clinical transplantation. Here we examined the effect of combining stem cell factor (SCF ) and granulocyte colony-stimulating factor (G-CSF ) versus G-CSF alone in a randomized clinical study involving 62 women with early-stage breast cancer. In the first patient cohorts, escalating doses of SCF were administered for 7 days with concurrent G-CSF administration. At baseline, levels of progenitor cells in the bone marrow or blood were comparable in the different patient groups. As with administration of G-CSF alone, the combination of SCF plus G-CSF did not alter the wide variation in levels of PBPC observed between individuals and did not alter the selective nature of PBPC release, with preferential release of day-14 granulocyte-macrophage colony-stimulating factor (GM-CFC) versus day-7 GM-CFC. However, SCF acted to sustain the levels of PBPC after cessation of growth factor treatment; levels of PBPC were elevated 100-fold at later timepoints compared with G-CSF alone. In addition, the maximum levels of PBPC observed were increased approximately fivefold at day 5 of growth-factor administration. The increased levels of PBPC resulted in significantly increased levels of PBPC obtained by leukapheresis. In a subsequent patient cohort, 3-days pretreatment with SCF was introduced and followed by 7 days concurrent SCF plus G-CSF. The 3-days pretreatment with SCF resulted in an earlier wave of PBPC release in response to commencement of G-CSF. In addition, maximum PBPC levels in blood and PBPC yield in leukapheresis products were further increased. Unexpectedly however, SCF pretreatment resulted in progenitor cells with enhanced self-generation potential. Recloning assays documented the ability of approximately 30% of primary granulocyte-macrophage (GM) colonies from control cell populations to generate secondary GM colonies (n = 1,106 primary colonies examined). In contrast approximately 90% of GM colonies from PBPC after SCF pretreatment generated secondary clones and 65% generated secondary colonies. The action of SCF was not explicable in terms of altered SCF, GM-CSF, or G-CSF responsiveness, but SCF pretreatment was associated with maximum serum SCF levels at the time G-CSF was commenced. These results show that PBPC populations mobilized by different growth factor regimens can differ in their functional properties and caution against solely considering number of harvested progenitor cells without regard to their function.
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PMID:Enhanced levels and enhanced clonogenic capacity of blood progenitor cells following administration of stem cell factor plus granulocyte colony-stimulating factor to humans. 934 20

There is an urgent need for more active and better tolerated chemotherapy regimens for the treatment of advanced breast and ovarian cancers. Current therapeutic strategies in these malignancies include the use of moderately effective initial regimens that are usually accepted by patients. Tolerability considerations are especially important in the development of palliative regimens: retreatment for persistent or hormone-resistant disease must include quality-of-life analyses. Pegylated liposomal doxorubicin (PLD) has demonstrated a better therapeutic index than free doxorubicin in murine solid tumours and human tumour xenografts in nude mice. In early clinical studies in patients with refractory ovarian cancer, PLD has produced high response rates (26%) and gratifyingly long response durations (8 to 21 + months after onset of therapy). Less mature data also suggest that PLD is active against breast cancer. Information from these same clinical studies confirms the marked reduction in several toxicities associated with free doxorubicin, including nausea and vomiting, myelosuppression and cardiotoxicity. Alopecia is also markedly diminished. On the other hand, mucosal and skin toxicities appear to be more common with PLD. PLD therefore offers the prospect of retaining activity, together with attenuated acute toxicity. In addition to facilitating the development of palliative regimens with better tolerability, the drug may lend itself to effective integration of chemotherapy with loco-regional therapies; utilisation in 'maintenance' regimens that are associated with an acceptable quality of life for the patient, and the avoidance of long term toxicities associated with treatment. Moreover, additional study of PLD in combination with other drugs and modalities may extend the use of the drug beyond palliation to the development of combination regimens with other drugs at conventional doses, and high doses with G-CSF support.
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PMID:Clinical efficacy and prospects for use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers. 936 58

Promising results from clinical trials with unconjugated antibodies stimulated renewed interest in immune effector mechanisms of monoclonal antibodies (MoAbs). We investigated the potential of IgA as antibody isotype for cell- or complement-mediated tumor cell lysis and assessed the potential of its myeloid Fc receptor, FcalphaRI (CD89), as trigger molecule for bispecific antibody (BsAb)-mediated immunotherapy. Comparing hapten-directed antibodies of human IgA2 with IgG1 or IgG3 isotypes, we found all three to mediate effective killing of sensitized tumor target cells in whole blood assays. Analysis of effector mechanisms showed IgG-mediated lysis to be predominantly complement-dependent, whereas IgA-dependent killing was primarily effector cell-mediated. A comparison of effector cell populations in antibody-dependent cell-mediated cytotoxicity (ADCC) showed neutrophils to be most important for IgA-dependent tumor cell killing, involving FcalphaRI as shown with Fc receptor blocking antibodies. Reverse ADCC experiments against target cells sensitized with Fc receptor antibodies, or assays with FcalphaRI-directed bispecific antibodies confirmed FcalphaRI as effective trigger molecule in polymorphonuclear neutrophil (PMN)-mediated lysis. During granulocyte colony-stimulating factor (G-CSF ) therapy, (FcalphaRI x HER-2/neu) bispecific antibodies induced enhanced killing of HER-2/neu positive SK-BR-3 breast cancer cells in whole blood assays. This enhanced cytotoxicity was paralleled by increased PMN counts, which lead to higher effector to target cell ratios in G-CSF-primed blood. Furthermore, bispecific antibodies, directed to FcalphaRI and Candida albicans, enhanced neutrophils' phagocytosis of fungi. In summary, these results identify IgA as an effective antibody isotype for immunotherapy, working primarily via FcalphaRI on neutrophils. They suggest FcalphaRI-directed bispecific antibodies and G-CSF to be an attractive combination for malignant or infectious diseases.
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PMID:FcalphaRI (CD89) as a novel trigger molecule for bispecific antibody therapy. 937 59


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