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PubMed2005

Rhabdomyosarcoma: molecular diagnostics of patients classified by morphology and immunohistochemistry with emphasis on bone marrow and purged peripheral blood progenitor cells involvement.

Two histologically distinct subtypes of rhabdomyosarcomas (RMS), embryonal and alveolar, are different in many aspects, such as age distribution, primary site, and clinical outcome. We analyzed a group of 30 patients with RMS. The aim was to broaden the spectrum of diagnostic tools in evaluating the primary tumors, their recurrences and/or metastases, and to extend the diagnostic boundary to bone marrow and purged peripheral progenitor blood cell samples. We have performed the RT-PCR assay to analyze RMS for the presence of expression of MyoD1 gene and for the presence of chimeric transcripts PAX3/FKHR or PAX7/FKHR. MyoD1 gene expression was found in all 30 patients in samples from primary tumors. The chimeric transcripts PAX/FKHR were identified in 13 of 15 patients with alveolar RMS. Furthermore, the fusion transcript PAX7/FKHR was identified in 2 of 15 patients with RMS classified as embryonal by histology. Bone marrow samples (12) and peripheral blood progenitor cell specimens (13) in ten patients were examined by RT-PCR. We were able to identify 7 patients with bone marrow involvement and/or with contamination of peripheral blood progenitor cells by the tumor cells. We demonstrate that employing molecular diagnostics has an impact on staging, therapy monitoring and recognition of malignant cells at the tumor resection margins.

Adolescent↗
PubMed1993

Administration of human recombinant granulocyte colony-stimulating factor (filgrastim) accelerates granulocyte recovery following high-dose chemotherapy and autologous marrow transplantation with 4-hydroperoxycyclophosphamide-purged marrow in women with metastatic breast cancer.

Stem cell contamination by tumor is common in many diseases for which autologous bone marrow transplantation is used. In in vitro models chemotherapeutic purging reduces contamination and may have an impact on clinical outcome. Purging, however, delays engraftment. Little is known about the ability of granulocyte colony-stimulating factor (G-CSF) to accelerate myelopoiesis after purged autologous bone marrow transplantation. We treated 22 women with metastatic breast cancer with high-dose cyclophosphamide and thiotepa and, following the infusion of 4-hydroperoxycyclophosphamide-purged marrow, administered G-CSF, 16 micrograms/kg daily, from day 0 to engraftment. Results were compared with a control population of 24 women with breast cancer who received identical chemotherapy and purged marrow but not growth factor. Neutrophil recovery was accelerated in the G-CSF-treated population. An absolute neutrophil count of 500 was reached in 19 days compared with 29 for the historic controls. The median number of days febrile was reduced (8 versus 5.5) as were the number of days of hospitalization from marrow infusion (33 versus 25). There was no difference in the number of days on antibiotics or time to last platelet transfusion. G-CSF was administered without any notable toxicity. G-CSF accelerates myelopoiesis following the infusion of 4-hydroperoxycyclophosphamide-purged autologous marrow and shortens hospitalization.

Adult↗
PubMed1993

Successful mafosfamide purging of bone marrow from chronic myelogenous leukemia (CML) cells.

The in vitro sensitivity of human chronic myeloid leukemia-blast crisis and chronic phase (CML-BC and CML-CP, respectively) cells as well as adherent cell-depleted, T lymphocyte-depleted normal bone marrow cells (A-T-NBMC) to various concentrations of mafosfamide (ASTA Z7654), was examined by colony formation assay in the presence of IL-3 and GM-CSF, to test the possibility of purging of BMC from CML cells. Colony formation by CML cells was inhibited more efficiently than by NBMC. After the incubation with 50 micrograms/ml or 100 micrograms/ml of mafosfamide, the growth of leukemic CFU-GM was totally abrogated in 2/11 or 9/11 cases of CML-BC and in 1/7 or 6/7 cases of CML-CP, respectively. At the same time the CFU-GM arising from normal BMC were not inhibited totally with 50 or 100 micrograms/ml of the drug in any of five experiments. CML cells were still unable to form secondary colonies, while normal BMC were capable of regrowth. The CD34+ cells isolated form CML-BC and CML-CP patients were also more susceptible to mafosfamide cytotoxicity in comparison to CD34+ cells derived from NBMC. To confirm the possibility of purging, CML-BC cells were mixed with NBMC (1:1) and incubated with mafosfamide. Finally, the growing colonies were examined for the presence of bcr/abl hybrid gene by reverse transcriptase-Taq polymerase chain reaction (RT-PCR) and specific hybridization. The bcr/abl gene was not detected in the colonies growing after 100 micrograms/ml, and the signal was diminished after incubation with 50 micrograms/ml of mafosfamide, as compared to control. These results strongly suggest that high concentrations of mafosfamide may be useful for the purging of autologous BMC from CML cells.

Antineoplastic Agents↗
PubMed1989

The use of recombinant cytokines for enhancing immunohematopoietic reconstitution following bone marrow transplantation. I. Effects of in vitro culturing with IL-3 and GM-CSF on human and mouse bone marrow cells purged with mafosfamide (ASTA-Z).

Enhanced colony formation (CFU-GM) in vitro was observed in murine and human bone marrow (BM) cells following pre-incubation for 2-3 days with recombinant murine GM-CSF or natural purified murine IL-3, and recombinant human GM-CSF or IL-3, respectively. Pre-incubation in the presence of both GM-CSF and IL-3 produced additive stimulatory effects. BM cells previously treated in vitro with mafosfamide (ASTA-Z) under conditions identical to those used in the purging of autologous BM grafts, also demonstrated an enhanced cumulative response to combinations of GM-CSF and IL-3, with up to 100-fold increase in CFU-GM as compared with controls (p less than 0.001). In mice, the number of CFU-S was also significantly increased (2-20 times) following incubation of unpurged and purged BM cells in murine IL-3 and/or GM-CSF. Interestingly, the frequency of both CFU-GM and CFU-S in BM cells first purged with ASTA-Z and then cultured with both cytokines was significantly higher (p less than 0.01) than that in fresh, intact BM cells. In addition, mice transplanted with unpurged or purged, cytokine cultured syngeneic BM cells exhibited a significantly (p less than 0.01) earlier reconstitution of peripheral white blood cells and of BM CFU-GM, and a significantly enhanced anti-sheep red blood cell plaque-forming cell response. Overall, the data suggest that it might be possible to enhance immunohematopoietic reconstitution in recipients of unmanipulated, as well as ASTA-Z purged autologous BM following short-term culture of BM cells with recombinant colony stimulating factors prior to bone marrow transplantation.

Animals↗
PubMed1988

Successful clinical use of an anti-HLA-DR monoclonal antibody for autologous bone marrow transplantation.

It has been widely assumed that anti-HLA-DR antibodies react with pluripotent stem cells and cannot be used in bone marrow purging. We report a case of non-Hodgkin's lymphoma in which an anti-HLA-DR antibody (AB4) was used for immunomagnetic purging and the subsequent autologous bone marrow transplantation resulted in rapid marrow engraftment with no serious complications. The results indicate that the AB4 antibody, which binds to an antigen encoded by the B3 gene of the DR region, can be safely used in the clinic in the purging of bone marrow from patients with AB4-positive tumors (non-T-cell acute lymphocytic leukemia, non-Hodgkin's lymphoma, and some cases of acute myelogenous leukemia.

Adult↗
PubMed1994

Photosensitizers in photodynamic therapy.

Photodynamic therapy (PDT) is based on the use of light-sensitive molecules called photosensitizers. Photoactivation causes the formation of singlet oxygen, which produces peroxidative reactions that can cause cell damage and death. Porfimer sodium (Photofrin, manufactured by Lederle Parenterals, Carolina, Puerto Rico, under license from Quadra Logic Technologies, Inc, Vancouver, BC, Canada) is the photosensitizer that has been studied most extensively. Patients generally have to be hospitalized for 2 days prior to light treatment after administration of porfimer sodium; it takes approximately 48 hours after injection to reach optimal concentration in tumor tissue. The tumoricidal capacity of PDT with porfimer sodium is determined in part by the maximum depth of penetration of light having a wavelength of 630 nm. Porfimer sodium causes cutaneous photosensitivity that may last for up to 6 weeks. Benzoporphyrin derivative (BPD verteporfin; BPD-Quadra Logic Technologies, Inc, Vancouver, BC, Canada), another photosensitizer, accumulates more rapidly in tumor tissue, permitting optimal PDT 30 to 150 minutes following intravenous administration. It is rapidly cleared from the body, and skin photosensitivity does not extend beyond a few days. The primary mechanism of action of PDT is related to the selective accumulation of photosensitizers in cancer tissue. Photodynamic therapy also shows promise in the treatment of a number of nonneoplastic conditions, including psoriasis, macular degeneration of the retina, atherosclerotic plaque and restenosis, bone marrow purging for treatment of leukemias with autologous bone marrow transplantation, inactivation of viruses in blood or blood products, and several autoimmune conditions, including rheumatoid arthritis. Physiologic characteristics shared by this disparate group of diseases, and the mechanisms by which they may mediate photoactivation, are discussed.

Antiviral Agents↗
PubMed1993

Chromosome abnormalities in patients treated with 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation.

Autologous bone marrow transplantation (ABMT) offers potentially curative therapy for patients with acute leukemia and lymphoma, yet little information exists about the chromosome abnormalities observed in ABMT recipients. Clonal abnormalities of chromosome 1 were reported by van den Akker. We report the cytogenetic results of 55 patients who underwent ABMT between November 1987 and July 1990: acute nonlymphocytic leukemia (ANLL, 22), acute lymphocytic leukemia (ALL, eight), Hodgkin's disease (seven), lymphoma (16), other (two). ANLL patients received busulfan and cytoxan, and the others received cytoxan and total body irradiation as their preparative regimen before transplant. BM was purged ex vivo with 4-hydroperoxycyclophosphamide (4-HC) at 30-100 micrograms/ml before reinfusion to kill tumor cells. Cytogenetic analysis was performed before and after transplant. Between one and four posttransplant specimens of BM were analyzed per patient (range 36-921 days). Chromosome abnormalities were observed in 14 of 55 patients after transplant. Seven had clonal abnormalities; all were in leukemic relapse, and one karyotype had complex rearrangements. Clonal abnormalities of chromosome 1 were not observed. Seven patients had nonclonal changes, and three of these have had overt clinical relapse. Our data suggest that clonal abnormalities observed posttransplant are best explained by clinical relapse of tumor and that ex vivo marrow purging with 4-HC is not likely to induce clonal chromosome abnormalities in normal cells. Long-term observation of these patients will be required to answer that question definitively, however.

Adolescent↗
PubMed1992

Interactions among colony-stimulating factors, IL-1 beta, IL-6, and kit-ligand in the regulation of primitive murine hematopoietic cells.

We have investigated the regulation of primitive murine hematopoietic progenitors by the cytokines interleukin 1 (IL-1), interleukin 6 (IL-6), and kit-ligand (KL). Individually these cytokines have a limited ability to stimulate the growth of high proliferative potential colony-forming cells (HPP-CFC) from 5-fluorouracil (5-FU)-purged bone marrow, but in combination these cytokines demonstrate synergism in promoting the growth of HPP-CFC. Furthermore, IL-1, IL-6, and KL, alone or in combination, synergized with the colony-stimulating factors (CSFs) granulocyte CSF (G-CSF), macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-CSF), or interleukin 3 (IL-3) in clonal and liquid cultures of 5-FU-purged bone marrow. The pattern of HPP-CFC growth that was observed with 40 different cytokine combinations demonstrated the unique roles of IL-1, IL-6, and KL in the regulation of HPP-CFC proliferation. Short-term liquid cultures (delta-cultures), with secondary recloning, of 5-FU-purged bone marrow were stimulated to greatly expand the numbers of progenitor cells generated in response to cytokine stimulation. The greatest expansion, over 1800-fold, of the more mature progenitor compartments took place in delta-cultures stimulated with IL-1, IL-6, and KL plus IL-3. However, the combination of IL-1 and IL-6 plus KL was optimal in expanding HPP-CFC, increasing their numbers by 700-fold. The ability to expand early progenitor cells in delta-cultures was further demonstrated by the greater than 100-fold expansions of day-12 spleen colony-forming units (CFU-S) by the synergistic interactions of IL-1 with IL-3 or KL.

Animals↗
PubMed1996

Phototoxicity of some bromine-substituted rhodamine dyes: synthesis, photophysical properties and application as photosensitizers.

The synthesis of some bromine-substituted rhodamine derivatives viz., 4,5-dibromorhodamine methyl ester (dye 2) and 4,5-dibromorhodamine n-butyl ester (dye 3) are reported. These dyes were synthesized to promote a more efficient cancer cell photosensitizer for potential use in in vitro bone marrow purging in preparation for autologous bone marrow transplantation. Spectroscopic and photophysical characterization of these dyes together with rhodamine 123 (dye 1) are reported in water, methanol, ethanol and also in a microheterogeneous system, sodium dodecyl sulfate. The possible mechanism of photosensitization is characterized in terms of singlet oxygen efficiency of these dyes. Singlet oxygen quantum yields for bromine-substituted dyes are in the range of 0.3-0.5 depending on the solvent. For dye 1 no singlet oxygen production is found. The photodynamic actions of these dyes in different cell lines are tested. It was found that dye 2 and dye 3 are efficient photosensitizers and mediate eradication of K562, EM2, myeloid cell lines (CML) and the SMF-AI rhabdomyosarcoma line.

Animals↗
PubMed1991

Analysis of factors predicting speed of hematologic recovery after transplantation with 4-hydroperoxycyclophosphamide-purged autologous bone marrow grafts.

We previously described the predictive value of graft colony-forming units granulocyte macrophage (CFU-GM) content after 4-hydroperoxycyclophosphamide (4-HC) purging for the duration of aplasia after autologous bone marrow transplantation. Despite the uniform 4-HC concentration, we observed heterogeneity in CFU-GM survival and the kinetics of engraftment. We have now analysed patient and graft characteristics for 154 patients undergoing autologous transplantation with 4-HC purged grafts to further define this heterogeneity. Patients transplanted for the treatment of malignant lymphoma reached a peripheral blood granulocyte count of greater than 0.5 x 10(9)/l (median, 20 versus 40 days; p less than 0.001) and platelet transfusion independence (median, 30 versus 70 days; p less than 0.001) significantly faster than patients transplanted for acute non-lymphoblastic leukemia. Other diagnostic groups were intermediate. These differences were independent of graft CFU-GM content. Multiple other patient and graft factors including patient age, peripheral blood counts on day of harvest, and amounts of other hematopoietic progenitors also predicted the kinetics of engraftment in univariate and multivariate analysis. Cytomegalovirus infection during the aplastic period predicted a delay in granulocyte (p = 0.024) but not platelet recovery (p = 0.174). This analysis demonstrates that multiple patient, graft, and post-transplant factors predict the engraftment capacity of autografts, and the kinetics of engraftment with 4-HC purged grafts. The multiple predictive factors explain a significant portion of the variability in engraftment kinetics observed after transplantation with 4-HC purged autografts.

Adolescent↗
PubMed1993

Role of autologous bone marrow transplantation in non-Hodgkin's lymphoma.

Although the conventional therapy of patients with NHL has improved over the past 20 years, approximately 50% of the patients still are not cured of their disease with routine therapy. The use of high-dose chemoradiotherapy and ABMT has now been shown to salvage a portion of this patient population. Despite these advances, there are areas that need further research to improve the long-term disease-free survival. For example, relapses frequently occur in areas of previous disease sites. This may imply that the conditioning regimen was not adequate, or that tumor cells contaminating the infused hematopoietic product tracked to the site of previous disease. Further advances in the dose-intensity of conditioning regimens, or perhaps alternative hematopoietic stem cell sources such as purged bone marrow, allogeneic bone marrow, or autologous peripheral stem cell grafts, may improve these results. Other potential areas for development include the use of hematopoietic growth factors in an attempt to decrease the morbidity and mortality associated with transplant, and the use of ABMT as intensification therapy following conventional therapy in patients with intermediate or high-grade NHL with poor prognostic features. The exact role of high-dose therapy and ABMT for follicular low-grade NHL is not clear at this time and will require further analysis. It is hoped that continued efforts to improve the risks associated with high-dose therapy and ABMT, to identify the optimal regimens and rescue products for certain subtypes of NHL, and to identify earlier in the course of disease those patients who would benefit from ABMT will increase the percentage of long-term disease-free survivors with NHL.

Bone Marrow Purging↗
PubMed1990

Monoclonal antibody 55 (CD10) and complement used for purging autologous bone marrow in common acute lymphoblastic leukemia.

A CD10 monoclonal antibody 55 (McAb55) was intended for purging residual common acute lymphoblastic leukemia antigen (CALLA) positive leukemic cells from autotransplants of common acute lymphoblastic leukemia (C-ALL) patients. It was found that after two rounds of McAb55 and complement treatment, 4-5 logs of CALLA+ cells were removed from bone marrow detected by clonogenic assay. The standardization of separation, purgation and preservation of bone marrow for C-ALL patients' autotransplants was then set as follows: Following the carboxymethyl starch sedimentation and Ficoll-Hypaque gradient separation, the isolated mononuclear cells (MNCs) were treated with McAb55 and complement twice and kept in room temperature for 48-72 hours prior to infusion. This procedure resulted in the removal of more than 99% of CALLA+ cells, recovery of 10-30% MNCs, and leaving the hematopoiesis stem cells intact. After the intensive cytoreductive therapy, 4 patients with C-ALL received the purged autotransplants giving timely recovery of the hematopoietic function. The patients were all remaining in remission status for more than 40-250 days so far.

Adult↗
PubMed1995

Acute cholecystitis after autologous bone marrow transplantation for acute myeloid leukemia.

BACKGROUND: We investigated the incidence of acute cholecystitis in patients with acute myeloid leukemia (AML) undergoing autologous bone marrow transplantation in complete remission. PATIENTS AND METHODS: Thirty-five consecutive acute myeloid leukemia patients were given oral busulfan 4 mg/kg/day for 4 days and IV cyclophosphamide 50 mg/kg/day for 4 days followed by reinfusion of autologous bone marrow purged with 4-hydroperoxycyclophosphamide. RESULTS: Five of 35 patients developed clinical evidence of acute cholecystitis, manifested by fever, nausea, vomiting, right-upper-quadrant pain, and abdominal guarding, within 18 days after autologous bone marrow infusion. Ultrasonography and CT scans of the abdomen supported the diagnosis of cholecystitis. Three patients underwent cholecystectomy, while two patients were treated medically; all recovered uneventfully. A review of 338 consecutive bone marrow transplant patients who underwent marrow transplantation for a variety of diseases and were treated with other high-dose cytotoxic regimens during the same time period revealed significantly fewer cases of cholecystitis, i.e. two, (p < 0.0001). CONCLUSIONS: Five of 35 AML patients undergoing autologous bone marrow transplant using busulfan, cyclophosphamide, and purged bone marrow developed evidence of acute cholecystitis. These findings suggest that the busulfan/cyclophosphamide preparative regimen may be associated with acute cholecystitis. The true incidence of this injury and its pathogenesis remain to be elucidated.

Acute Disease↗
PubMed1995

Autografting in chronic myelogenous leukemia: new questions.

In the 1970s, when autografting was started, it was hard to imagine that this procedure would have an application in hematological malignancies. Autografting in patients with CML has been difficult to pursue because their bone marrow is often contaminated by Philadelphia-chromosome positive cells. In recent years, renewed interest has come from this procedure and various in vivo or in vitro techniques of manipulation of Ph-positive cells, such as collection of blood progenitor cells in the early phase of recovery after intensive conventional chemotherapy in untreated or pretreated patients, long-term bone marrow culture and chemical purging of marrow cells. Despite all these interesting trials, we do not have enough data to address the question of whether autografting in CML increases the duration of the chronic phase.

Animals↗
PubMed1992

Leukemic cell kill in autologous bone marrow transplantation: in vivo or in vitro?

Both the contribution of high dose chemo-radiotherapy ("conditioning treatment") prior to autologous bone marrow transplantation (ABMT) and "purging" of autologous marrow grafts to the prevention of leukemia relapse are being addressed in the present communication. Based on both preclinical and clinical studies, it is concluded that cures achieved after ABMT are mainly due to effective eradication of residual leukemic cells in the host. The chance that leukemia will relapse is due to leukemic cells reinfused with the graft is estimated to be less than 10%.

Animals↗
PubMed2001

A midkine promoter-based conditionally replicative adenovirus for treatment of pediatric solid tumors and bone marrow tumor purging.

The treatment of advanced neuroblastoma (NB) or Ewing's sarcoma (ES) is one of the major challenges in pediatric oncology. Both malignancies are refractory to conventional therapies and have an extremely poor prognosis. High-dose myeloablative radiochemotherapy with autologous bone marrow or peripheral blood stem cell rescue is one of the most aggressive treatments attempted for these diseases but is often undermined by residual tumor cells contaminating the graft. Thus, in this approach, purging of tumor cells from the graft is key to the prevention of relapse after transplantation. We investigated a novel approach to eliminate tumor cells from the bone marrow or peripheral blood stem cell graft without causing stem cell damage through the use of a conditionally replicative adenovirus (Ad). ES and NB are sensitive to Ad infection, and advanced NBs express a high level of the growth/differentiation factor midkine (MK). We confirmed in this study that ES cell lines (SK-ES-1 and RD-ES) are also sensitive to Ad infection and express high levels of MK. In contrast, CD34+ stem cells are refractory to Ad infection and express very little MK. A conditionally replicative Ad in which the expression of E1 is controlled by the MK promoter achieved good levels of viral replication in NB or ES and induced remarkable tumor cell killing. On the other hand, this virus caused no damage to CD34+ cells even after 3 h of infection at a dose of 1000 multiplicity of infection. We concluded that application of this replication-competent Ad to hematopoietic grafts could be a simple but effective procedure to achieve complete tumor cell purging.

Adenoviridae↗
PubMed1990

Purged autologous bone marrow transplantation in the treatment of acute leukemia.

Allogeneic bone marrow transplantation is an established treatment for acute leukemia. It is largely limited to patients with HLA-matched sibling marrow donors and those for whom phenotypically HLA-matched unrelated donors can be identified. There therefore exists a significant number of patients for whom this potentially curative therapy is not available. Autologous marrow transplantation might be an alternative approach, but concern about the infusion of leukemic cells with the autologous marrow exists. Multiple methods for removing neoplastic cells from marrow (marrow purging) have been developed. Clinical results using purged marrow in treating patients with acute non-lymphoblastic leukemia in second or greater remission by autologous bone marrow transplantation approach those observed in allogeneic marrow transplantation. Current investigations include the development of more effective cytoreductive regimens, use of recombinant hematopoietic growth factors, improvement of marrow purging techniques, and enhancement of cell-mediated anti-leukemic activity in patients receiving autologous marrow transplants.

Bone Marrow Transplantation↗