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H M Lazarus

Publications and source records attributed to H M Lazarus.

At least 55 records · Page 3Linked to original sources
PubMed2001

Effect of induction chemotherapy and tandem cycles of high-dose chemotherapy on outcomes in autologous stem cell transplant for metastatic breast cancer.

We assessed the effect standard-dose induction chemotherapy and tandem cycles of high-dose chemotherapy (HDC) have on outcomes in metastatic breast cancer. One hundred and one women with metastatic breast cancer were enrolled in two non-randomized phase II studies. The first group of 64 patients (induction group) received four cycles of docetaxel 75 mg/m2 and doxorubicin 50 mg/m2. The next 37 patients did not receive induction (no induction group). Both groups received two (tandem) cycles of HDC. Blood-derived stem cells were collected after the first HDC cycle, processed using CD34+ cell selection and then reinfused after the second HDC cycle. Outcomes were compared between the two groups and also to patients participating in the Philadelphia (inter-group) randomized metastatic breast cancer transplant trial (PBT-01). Intent-to-treat analysis revealed no significant differences in complete response rates (37.5% vs 27%; P = 0.20), overall response (75% vs 71%), median progression free survival (PFS) (11.9 vs 8 months; P = 0.24) and overall survival (OS) (>36 vs 25 months; P = 0.16), in the induction vs no induction groups, respectively. Adjusting for differences in known baseline characteristics, induction group patients were found to have significantly longer PFS (P = 0.002), OS (P = 0.01) and more frequent conversion from a partial to complete response (58% vs < or = 13%, P < or = 0.0002) when compared with PBT-01 patients. Induction chemotherapy administered prior to tandem cycles of HDC does not appear to adversely affect outcomes in metastatic breast cancer patients. Outcomes in our induction group also compare favorably with those observed in PBT-01 and warrant further clinical investigation.

Adult↗
PubMed2001

A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation.

Intravenous immunoglobulin is approved for use in allogeneic bone marrow transplant recipients for prevention of graft-versus-host disease (GVHD) and infections, but the minimally effective dose has not been established. In this multicenter, randomized, double-blind trial, patients undergoing allogeneic marrow transplantation were randomized to receive 100 mg/kg, 250 mg/kg, or 500 mg/kg doses of intravenous immunoglobulin. Each dose was given weekly for 90 days and then monthly until 1 year after transplant. Six hundred and eighteen patients were evaluated. Acute GVHD (grades 2-4) occurred in 39% of the patients (80 of 206) in the 100 mg/kg group, 42% of the patients (88 of 208) in the 250 mg/kg group, and in 35% of the patients (72 of 204) in the 500 mg/kg group (P = 0.344). Among patients with unrelated marrow donors, a higher dose of intravenous immunoglobulin (500 mg/kg) was associated with less acute GVHD (P = 0.07). The incidences of chronic GVHD, infection and interstitial pneumonia were similar for all three doses of intravenous immunoglobulin. The dose of intravenous immunoglobulin also had no effect on the types of infection, relapse of hematological malignancy or survival. Except for more frequent chills (P = 0.007) and headaches (P = 0.015) in patients given the 500 mg/kg or 250 mg/kg dose of immunoglobulin, adverse events were similar for all three doses. These results suggest that 100 mg/kg, 250 mg/kg, and 500 mg/kg doses of intravenous immunoglobulin are associated with similar incidences of GVHD and infections in most allogeneic marrow transplants. These results should be considered when designing cost-effective strategies for the use of intravenous immunoglobulin in allogeneic marrow transplants receiving other current regimens for prophylaxis of GVHD and infection.

Adolescent↗
PubMed2001

Chronic graft-versus-host disease: clinical manifestation and therapy.

Chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in long-term survivors of allogeneic stem cell transplantation. The immunopathogenesis of chronic GVHD is, in part, TH-2 mediated, resulting in a syndrome of immunodeficiency and an autoimmune disorder. The most important risk factor for chronic GVHD is prior history of acute GVHD and strategies that prevent acute GVHD also decrease the risk of chronic GVHD. Other important risk factors are the use of a non-T cell-depleted graft, and older age of donor and recipient. Whether recipients of peripheral blood stem cells are at increased risk of chronic GVHD remains unsettled. There are no known pharmacologic agents which can specifically prevent development of chronic GVHD. Agents which have efficacy in the treatment of autoimmune disorders have been utilized as therapy for established chronic GVHD and are associated with response rates of 20% to 80%. Most responses are confined to skin, soft tissue, oral mucosa and occasionally liver. Bronchiolitis obliterans responds infrequently to therapy and is associated with a dismal prognosis. Newer, promising therapeutic strategies under investigation include thalidomide, photopheresis therapy, anti-tumor necrosis factor and B cell depletion with anti-CD20 monoclonal antibody.

Animals↗
PubMed2001

Controversy in multiple myeloma transplants: tandem autotransplants and mini-allografts.

Autologous stem cell transplantation appears to enhance outcome in multiple myeloma patients. To improve upon these results, various groups have utilized tandem autografts, as well as used reduced-conditioning allogeneic stem cell transplantation. These two approaches, discussed herein, have been promising. Inherent patient selection, however, appears to play a role and much of the data have not yet been subjected to peer-review scrutiny. At present, these strategies remain investigational and cannot be considered the standard-of-care for multiple myeloma patients.

Adult↗
PubMed2001

Vaccination against infectious disease following hematopoietic stem cell transplantation.

Patients undergoing hematopoietic stem cell transplantation (HSCT) experience a prolonged period of dysfunctional immunity associated with an increased risk of bacterial and viral infections. Effective approaches toward vaccinating patients against common pathogens are being explored but are limited by poor levels of responsiveness. Relevant studies examining the nature of reconstitution of cellular and humoral immunity and its impact on vaccination strategies against infectious pathogens are reviewed. Following transplantation, deficiencies in cellular immunity are characterized by the inversion of CD4/CD8 ratios, a decreased proliferative response to mitogens, and the development of anergy to recall antigens as measured by delayed-type hypersensitivity testing. The impact on humoral immunity consists of decreased levels of circulating immunoglobulin, impaired immunoglobulin class switching, and a loss of complexity in immunoglobulin gene rearrangement patterns. In this setting, a loss of protective immunity has been demonstrated against viral and bacterial pathogens previously targeted by childhood vaccination. Infections due to encapsulated bacterial organisms such as Streptococcus pneumoniae and Haemophilus influenzae type B remain prevalent even in the late posttransplantation period. The efficacy of vaccination following HSCT is influenced by the time elapsed since transplantation, the nature of the hematopoietic graft, the use of serial immunization, and the presence of graft-versus-host disease. Strategies to enhance vaccine efficacy include pretransplantation immunization of the stem cell donor and the use of cytokine adjuvants.

B-Lymphocytes↗
PubMed2001

Tumor cell depletion of peripheral blood progenitor cells using positive and positive/negative selection in metastatic breast cancer.

BACKGROUND: The clinical relevance of tumor cell purging of hematopoietic progenitor cell grafts has yet to be conclusively determined. Therefore, in addition to the demonstration that a method for graft purification is capable of removing an adequate number of tumor cells, it is critical that the procedure has as benign an impact upon the hematopoietic repopulating potential of the graft as possible. We evaluated tumor cell depletion, recovery of CD34(+) cells and post transplant engraftment kinetics as accepted measures of the effectiveness of an immunomagnetic bead (positive and positive/negative) purging methodology. METHODS: The patients received either positive selection (CD34 selection alone) or a combination of positive and negative (CD34 selection followed by breast cancer cell depletion) using the Isolex 300 (automated and semiautomated) devices. Immunocytochemistry was used to determine the degree of breast cancer cell contamination before and after the selection procedures to determine the efficacy of the procedure. CD34 enumeration was employed to evaluate the recovery and purity of the CD34-selected cellular products and engraftment indices (days to absolute neutrophil count (ANC) recovery and platelet count (Plt) recovery and transfusion requirements) were evaluated to determine the safety of the procedure. RESULTS: A total of 130 aphereses was performed on 101 patients. Ten pairs of collections were pooled before selection to increase the likelihood of achieving CD34 dose goals after selection. In all, 100 positive selections and 20 positive/negative selections were performed. Of the 10 (10.4%) ICC-positive preselection samples, 2 products showed persistent contamination after processing. The majority of patients (85.4%) required one selection procedure to achieve an adequate CD34(+) selected cell dose. Median CD34(+) cell recovery was > 50% for positive selection procedures and > 60% for the positive/negative procedures. The dose of CD34(+) cells infused ranged from 0.76 x 10(6) CD34(+) cells/kg to 27.7 x 106 CD34(+) cells/kg. There were no significant delays in neutrophil or platelet recovery or infections between any of the treatment groups. DISCUSSION: CD34 selection alone or in combination with negative selection can result in a significant reduction of contaminating tumor cells in the peripheral blood progenitor cell autograft. Although there was one engraftment failure with the CD34-positive selected cells, transplantation of the selected products after high-dose chemotherapy for metastatic breast cancer did not result in a clinically significant delay in the hematopoietic reconstitutive capacity of the autografts.

Adult↗
PubMed2001

Lowering the prophylactic platelet transfusion threshold: a prospective analysis.

The 20 x 10(9) /L threshold for prophylactic platelet transfusion may be unnecessarily high. Few prospective studies, however, in which other trigger values were tested have been published. In this study all hospitalized, thrombocytopenic adult hematology-oncology patients in our institution were prospectively evaluated daily for hemorrhage and platelet transfusion during a one year period; no patients were excluded for bleeding or infectious problems. By design, during the initial six-months (baseline period), the prophylactic platelet transfusion trigger was 20 x 10(9) /L; for the second six-months (study period) this threshold was changed to 10 x 10(9) /L. Patients studied during the two periods did not differ significantly in age, gender, diagnosis, blood or marrow transplant status, and duration of neutropenia. Compliance with the thresholds was 95.6% (baseline period) and 93.5% (study period). For patients with platelet counts under 20 x 10(9) /L, the mean use of platelet transfusions per patient per day was significantly lower in the study period (4.47) than in the baseline period (6.48; p<0.001). Both mean prophylactic (1.54/patient-day) and therapeutic (2.93/patient-day) platelet transfusions were reduced in the study period compared with the baseline period (2.26 and 4.22/patient-day, respectively). Hemorrhage was slightly reduced in the study period compared with the baseline period: major hemorrhage, 15.2% vs. 18.4% (p=0.014); minor hemorrhage, 63.6% vs. 70.1% (p<0.001). Thus, hemorrhage was not increased with the lower trigger level. A 10 x 10(9) /L prophylactic platelet transfusion threshold value is safe and effective.

Adult↗
PubMed2000

High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: an autologous blood and marrow transplant registry report.

BACKGROUND: Autologous transplantation is increasingly used to treat epithelial ovarian cancer. However, it is not clear which patients may benefit. OBJECTIVE: To determine overall and progression-free survival and factors associated with favorable outcome after autotransplantation for ovarian cancer. DESIGN: Observational cohort study. SETTING: 57 centers reporting to the Autologous Blood and Marrow Transplant Registry (ABMTR). PATIENTS: 421 women who received transplants between 1989 and 1996. INTERVENTIONS: High-dose chemotherapy using diverse regimens with hematopoietic stem-cell rescue. MEASUREMENTS: Primary outcomes were progression-free survival and overall survival. Multivariate analyses using Cox proportional hazards regression considered the following factors: age, Karnofsky performance score, initial stage, histologic characteristics, previous therapy, remission status, extent of disease, graft source, transplant regimen, and year of transplantation. RESULTS: Most patients had extensive previous chemotherapy. Forty-one percent had platinum-resistant tumors, and 38% had tumors at least 1 cm in diameter. Only 34 patients (8%) received transplants as part of initial therapy. The probability of death within 100 days was 11% (95% CI, 8% to 14%). Two-year progression-free survival was 12% (CI, 9% to 16%), and 2-year overall survival was 35% (CI, 30% to 41%). Younger age, Karnofsky performance score of at least 90%, non-clear-cell disease, remission at transplantation, and platinum sensitivity were associated with better outcomes. Progression-free and overall survival were 22% (CI, 12% to 33%) and 55% (CI, 42% to 66%), respectively, for women with a high Karnofsky performance score and non-clear-cell, platinum-sensitive tumors. CONCLUSIONS: Some subgroups of patients with ovarian cancer seem to have good outcomes after autotransplantation, although several biases may have affected these observations. Phase III trials are needed to compare such outcomes with outcomes of conventional chemotherapy.

Age Factors↗
PubMed2000

Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission.

Allogeneic bone marrow transplantation is an effective postremission strategy for patients with acute myelogenous leukemia (AML) in first complete remission (CR). The value of administering consolidation chemotherapy before human leukocyte antigen (HLA)-identical sibling transplantation is not established. Outcomes of patients with AML in first CR receiving no consolidation therapy, standard-dose cytarabine consolidation therapy, and high-dose cytarabine consolidation therapy before HLA-identical sibling transplantation were compared. Five-year treatment-related mortality rates were 30% (95% confidence interval [CI], 18% to 42%) in patients receiving no consolidation chemotherapy, 22% (95% CI, 17% to 28%) in those receiving standard-dose cytarabine consolidation, and 24% (95% CI, 17% to 31%) in those receiving high-dose cytarabine (P = NS). Five-year cumulative incidences of relapse were 19% (10% to 30%), 21% (16% to 27%), and 17% (11% to 24%), respectively (P = NS). Five-year probabilities of leukemia-free survival were 50% (36% to 63%), 56% (49% to 63%), and 59% (50% to 66%), respectively (P = NS). Five-year probabilities of overall survival were 60% (46% to 71%), 56% (49% to 63%), and 60% (51% to 67%), respectively (P = NS). The data indicate that postremission consolidation with cytarabine before allogeneic transplantation for AML in first CR is not associated with improved outcome compared to proceeding directly to transplantation after successful induction. (Blood. 2000;96:1254-1258)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group.

BACKGROUND: We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. METHODS: Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. RESULTS: The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem cells and 89 were assigned to receive conventional-dose chemotherapy. In an intention-to-treat analysis, we found no significant difference in survival overall at three years between the two treatment groups (32 percent in the transplantation group and 38 percent in the conventional-chemotherapy group). There was no significant difference between the two treatments in the median time to progression of the disease (9.6 months for high-dose chemotherapy plus hematopoietic stem cells and 9.0 months for conventional-dose chemotherapy). CONCLUSIONS: As compared with maintenance chemotherapy in conventional doses, high-dose chemotherapy plus autologous stem-cell transplantation soon after the induction of a complete or partial remission with conventional-dose chemotherapy does not improve survival in women with metastatic breast cancer.

Adolescent↗
PubMed2000

Management of cancer treatment-related diarrhea. Issues and therapeutic strategies.

The cancer treatment-related diarrhea caused by acute graft-versus-host disease (GVHD) and chemotherapeutic agents, particularly fluoropyrimidines and irinotecan, significantly affects patient morbidity and mortality. The mechanisms causing cancer treatment-related diarrhea are not fully understood, but histopathologic evidence points to a multifactorial process that causes an absorptive and secretory imbalance in the small bowel. Cancer treatment-related diarrhea could be life-threatening, yet assessment and treatment are not currently standardized. Several clinicians participated in a closed roundtable meeting to review the mechanisms of chemotherapy-induced diarrhea (CID) and GVHD-induced diarrhea, management issues in cancer treatment-induced diarrhea, and pharmacologic approaches to treatment. The meeting produced a proposal for new treatment guidelines and an algorithm, which include the use of octreotide for the management of CID- and GVHD-induced diarrhea. The development of diarrhea assessment guidelines that expand on the current National Cancer Institute criteria and allow for better patient management was also proposed.

Antineoplastic Agents↗
PubMed2000

Treatment of primary resistant or relapsed multiple myeloma with high-dose chemoradiotherapy, hematopoietic stem cell rescue, and granulocyte-macrophage colony-stimulating factor.

In this prospective, multicenter, phase 2 study, multiple myeloma (MM) patients with primary resistant disease or recurrent chemosensitive disease, in chemoresistant relapse, or in second or subsequent remission were treated with high-dose chemoradiotherapy followed by autologous peripheral blood stem cell (PBSC) rescue. PBSCs were collected using granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 microg/kg per day subcutaneously for 3 days. Patients underwent high-dose chemoradiotherapy consisting of melphalan (140 mg/m2 x 1 day), cyclophosphamide (60 mg/kg per day x 2 days), methylprednisolone (2 g/d x 7 days), and total body radiation (150 cGy bid x 3 days) followed by peripheral blood stem cell reinfusion (> or = 1.2 x 10(9) mononucleated cells per kg) and GM-CSF support (5 microg/kg per day) and were evaluated for response, survival, and toxicity. Thirty-six patients, median age 53.4 years, completed the study. The mean pretransplantation cumulative melphalan dose was 464 +/- 72 mg. Excluding the 3 patients (8.3%) who failed to engraft, the median times to engraftment and platelet recovery were 10 days (range, 8-39 days) and 17 days (range, 7-67 days), respectively. Four patients (11.1%) died of complications related to the regimen (main causes of death, sepsis and acute respiratory distress syndrome) within the first 100 days. Twenty-two patients (61.1%) achieved complete response (CR), 8 (22.2%) partial response, and 2 (5.5%) no response. Two patients developed myelodysplastic syndrome after achieving CR. For all 36 patients, the probability of overall survival at 5 years was 27.3%. Median survival was 31 months (range, 0.3-81 months) in all patients and 42 months (range, 3.4-81 months) in those with CR. The probabilities of overall and disease-free survival at 5 years for the 22 patients who achieved CR were 43.6% and 15.7%, respectively. This high-dose chemotherapy regimen coupled with PBSC rescue is associated with a high CR rate and is capable of inducing long-term survival in a subset of heavily pretreated patients with primary resistant or recurrent MM.

Adolescent↗
PubMed2000

CD34+ selection of hematopoietic blood cell collections and autotransplantation in lymphoma: overnight storage of cells at 4 degrees C does not affect outcome.

The purpose of this study was to investigate whether storing mobilized peripheral blood progenitor cell (PBPC) collections overnight before CD34+ selection may delay platelet count recovery after high-dose chemotherapy and CD34+-enriched PBPC re-infusion. Lymphoma patients underwent PBPC mobilization with cyclophosphamide 4 g/m2 i.v. and G-CSF 10 microg/kg/day subcutaneously. Patients were prospectively randomized to have each PBPC collection enriched for CD34+ cells with the CellPro CEPRATE SC System either immediately or after overnight storage at 4 degrees C. Thirty-four patients were randomized to overnight storage and 34 to immediate processing of PBPC; 15 were excluded from analysis due to tumor progression or inadequate CD34+ cell mobilization. PBPC from 23 patients were stored overnight, while 30 subjects underwent immediate CD34+ selection and cryopreservation. Median yield of CD34+ enrichment was 43.6% in the immediate processing group compared to 39.1% in the overnight storage group (P = 0.339). Neutrophil recovery >500 x 10(9)/l occurred a median of 11 days (range 9-16 days) in the overnight storage group compared to 10.5 days (range 9-21 days) in the immediate processing group (P = 0.421). Median day to platelet transfusion independence was 13 (range 7-43) days in the overnight storage group vs 13.5 (range 8-35) days in those assigned to immediate processing (P = 0.933). We conclude that storage of PBPC overnight at 4 degrees C allows pooling of consecutive-day collections resulting in decreased costs and processing time without compromising neutrophil and platelet engraftment after infusion of CD34+-selected progenitor cells. Bone Marrow Transplantation(2000) 25, 559-566.

Adolescent↗
PubMed2000

Multi-purpose silastic dual-lumen central venous catheters for both collection and transplantation of hematopoietic progenitor cells.

Autologous peripheral blood progenitor cell (PBPC) transplantation frequently requires sequential placement and use of two separate central venous catheters: (1) a short-term, large-bore, stiff device inserted for leukapheresis, and after removal of that device, (2) a long-term, multi-lumen, flexible, Silastic catheter for administration of high-dose chemotherapy, re-infusion of hematopoietic cells, and intensive supportive care. We reviewed our recent experience with two dual-lumen, large-bore, Silastic multi-purpose ('hybrid') catheters, each of which can be used as a single device for both leukapheresis and long-term supportive care throughout the transplant process. Quinton-Raaf PermCath and Bard-Hickman hemodialysis/apheresis dual-lumen catheters were used as the sole venous access device in 112 consecutive patients who underwent autologous PBPC collection and transplantation. The catheter exit site was monitored three times a week, and lumen patency was assessed using clinical and radiologic techniques. Catheters were removed prematurely for persistent thrombus, positive blood cultures despite appropriate antibiotics, or mechanical dysfunction. There were no intra-operative or immediate post-operative complications relating to insertion. Thirty-two patients experienced catheter occlusion necessitating urokinase instillation. Persistent occlusive problems were noted in 16 patients, and in 10 patients the catheter had to be removed. Two exit site infections and 17 bacteremias occurred. Catheters had to be removed for persistent infection in two subjects and for mechanical problems in five others. Cost analysis comparing the hybrid catheters alone vs conventional devices revealed a charge of $4230 in patients with hybrid catheters vs. $7530 in those requiring a temporary non-Silastic dialysis catheter in addition to a flexible, long-term Silastic catheter. Hybrid, Silastic, dual-lumen, large-bore central venous catheters are safe, cost-effective and convenient multi-purpose venous access devices that may be used in the setting of autologous PBPC collection and transplantation. The rate of thrombotic, infectious and mechanical complications appears comparable to other central venous access devices.

Adolescent↗
PubMed2000

Autologous CD34+ enriched peripheral blood progenitor cell (PBPC) transplantation is associated with higher morbidity in patients with lymphoma when compared to unmanipulated PBPC transplantation.

High-dose chemotherapy followed by CD34+ enriched peripheral blood progenitor cell (PBPC) transplantation is used for the treatment of primary refractory or relapsed Hodgkin's and non-Hodgkin's lymphomas. The CD34+ enrichment procedure, while reducing tumor burden, may compromise immunological reconstitution in the transplanted patient and result in increased rates of post-transplant infection. We compared infectious complications in patients with lymphoma who were treated with high-dose chemotherapy and supported either with CD34+ enriched PBPC (n = 19) or unmanipulated PBPCs (n = 24). Analysis was limited to patients discharged from initial hospitalization for transplantation with a minimum of 1 year followup and free of lymphoma recurrence. We found a statistically significant increase in the number of patients with one or more infectious events in the CD34+ transplant group (14/19) compared with the unmanipulated PBPC group (9/24, P < 0.01). Greater numbers of patients with two or more infectious events were observed in the CD34+ group (7/19 vs 2/24, P < 0.03) and an increased incidence of bacterial infections was observed in the CD34+ group (10/19 vs 5/24, P < 0.05). Two deaths due to infectious complications were observed in the CD34+ group. There was no significant difference in blood lymphocyte or monocyte recovery between the groups. These data demonstrate a significant increase in the long-term incidence of infectious events in lymphoma patients transplanted with autologous CD34+ enriched PBPCs compared to unmanipulated PBPCs. Thus, patients who undergo CD34+ enriched PBPC transplantation should be followed closely for infectious complications and prolonged infectious prophylaxis should be considered.

Adult↗
PubMed2000

Impaired growth and elevated fas receptor expression in PIGA(+) stem cells in primary paroxysmal nocturnal hemoglobinuria.

The genetic defect underlying paroxysmal nocturnal hemoglobinuria (PNH) has been shown to reside in PIGA, a gene that encodes an element required for the first step in glycophosphatidylinositol anchor assembly. Why PIGA-mutated cells are able to expand in PNH marrow, however, is as yet unclear. To address this question, we compared the growth of affected CD59(-)CD34(+) and unaffected CD59(+)CD34(+) cells from patients with that of normal CD59(+)CD34(+) cells in liquid culture. One hundred FACS-sorted cells were added per well into microtiter plates, and after 11 days at 37 degrees C the progeny were counted and were analyzed for their differentiation pattern. We found that CD59(-)CD34(+) cells from PNH patients proliferated to levels approaching those of normal cells, but that CD59(+)CD34(+) cells from the patients gave rise to 20- to 140-fold fewer cells. Prior to sorting, the patients' CD59(-) and CD59(+)CD34(+) cells were equivalent with respect to early differentiation markers, and following culture, the CD45 differentiation patterns were identical to those of control CD34(+) cells. Further analyses of the unsorted CD59(+)CD34(+) population, however, showed elevated levels of Fas receptor. Addition of agonist anti-Fas mAb to cultures reduced the CD59(+)CD34(+) cell yield by up to 78% but had a minimal effect on the CD59(-)CD34(+) cells, whereas antagonist anti-Fas mAb enhanced the yield by up to 250%. These results suggest that expansion of PIGA-mutated cells in PNH marrow is due to a growth defect in nonmutated cells, and that greater susceptibility to apoptosis is one factor involved in the growth impairment.

Antigens, CD34↗
PubMed2000

Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy.

PURPOSE: Multipotential mesenchymal stem cells (MSCs) are found in human bone marrow and are shown to secrete hematopoietic cytokines and support hematopoietic progenitors in vitro. We hypothesized that infusion of autologous MSCs after myeloablative therapy would facilitate engraftment by hematopoietic stem cells, and we investigated the feasibility, safety, and hematopoietic effects of culture-expanded MSCs in breast cancer patients receiving autologous peripheral-blood progenitor-cell (PBPC) infusion. PATIENTS AND METHODS: We developed an efficient method of isolating and culture-expanding a homogenous population of MSCs from a small marrow-aspirate sample obtained from 32 breast cancer patients. Twenty-eight patients were given high-dose chemotherapy and autologous PBPCs plus culture-expanded MSC infusion and daily granulocyte colony-stimulating factor. RESULTS: Human MSCs were successfully isolated from a mean +/- SD of 23.4 +/- 5.9 mL of bone marrow aspirate from all patients. Expansion cultures generated greater than 1 x 10(6) MSCs/kg for all patients over 20 to 50 days with a mean potential of 5.6 to 36.3 x 10(6) MSCs/kg after two to six passages, respectively. Twenty-eight patients were infused with 1 to 2.2 x 10(6) expanded autologous MSCs/kg intravenously over 15 minutes. There were no toxicities related to the infusion of MSCs. Clonogenic MSCs were detected in venous blood up to 1 hour after infusion in 13 of 21 patients (62%). Median time to achieve a neutrophil count greater than 500/microL and platelet count >/= 20,000/microL untransfused was 8 days (range, 6 to 11 days) and 8.5 days (range, 4 to 19 days), respectively. CONCLUSION: This report is the first describing infusion of autologous MSCs with therapeutic intent. We found that autologous MSC infusion at the time of PBPC transplantation is feasible and safe. The observed rapid hematopoietic recovery suggests that MSC infusion after myeloablative therapy may have a positive impact on hematopoiesis and should be tested in randomized trials.

Adult↗