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At least 1,171 records · Page 65Linked to original sources
PubMed2003

Adjuvant treatment of high-risk stage II breast cancer with doxorubicin followed by high-dose chemotherapy and autologous stem-cell transplantation: a single-institution experience with 132 consecutive patients.

Several studies have shown conflicting results with the use of intensive consolidation chemotherapy for breast cancer. The aim of the present study was to investigate the efficacy, feasibility and toxicity of high-dose chemotherapy with stem cell support in patients with high-risk stage II breast cancer. From February 1994 to November 1998, 132 consecutive patients with multinode positive breast cancer were entered to the study. In total, 86 patients had >or=10 positive axillary lymph nodes, and 46 had 4-9 positive axillary lymph nodes with at least two additional predetermined risk factors at diagnosis. All patients were offered adjuvant chemotherapy (doxorubicin, 75 mg/m(2) x 4) followed by high-dose chemotherapy (cyclophosphamide 6000 mg/m(2), carboplatin 800 mg/m(2) and thio-tepa 500 mg/m(2)) and autologous stem cell support with growth factor. In all, 131 patients also received local radiation therapy and tamoxifen based on receptor status. After a median follow-up of 51 months (range 27-87), the disease-free and overall survival rates were 72 and 81%, respectively. There was no difference in the outcome for high-risk patients with > or < than 10 positive axillary lymph nodes. On Cox regression analysis only progesterone receptor status was predictive of disease-free, but not overall survival. There were no treatment-related deaths; grades III-IV toxicity was relatively low. This combined approach of doxorubicin followed by high-dose chemotherapy and stem-cell support, followed by locoregional radiotherapy, was safe and seems to be effective in patients with multinode positive stage II breast cancer. In previous trials of adjuvant high-dose therapy in this patient population, treatment-related morbidity and mortality markedly influenced the outcome. For this high-risk patient population, further testing of intensive chemotherapy regimens with a lower toxicity profile is warranted.

Antineoplastic Agents↗
PubMed2005

Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin.

Invasion by colorectal carcinomas is characterized by an epithelial-mesenchymal transition (EMT)-like dedifferentiation of the tumor cells. However, a redifferentiation towards an epithelial phenotype, resembling a mesenchymal-epithelial transition, is detectable in metastases. This indicates that malignant progression is based on dynamic processes, which cannot be explained solely by irreversible genetic alterations, but must be additionally regulated by the tumor environment. The main oncoprotein in colorectal cancer is the Wnt pathway effector beta-catenin, which is overexpressed due to mutations in the APC tumor suppressor in most cases. EMT of the tumor cells is associated with a nuclear accumulation of the transcriptional activator beta-catenin, which is reversed in metastases. Nuclear beta-catenin is involved in two fundamental processes in embryonic development: EMT and stem cell formation. Accumulating data demonstrate that aberrant nuclear expression of beta-catenin can also confer these two abilities to tumor cells, thereby driving malignant tumor progression.

Cell Nucleus↗
PubMed2006

Human metapneumovirus infection in a hematopoietic stem cell transplant recipient with relapsed multiple myeloma and rapidly progressing lung cancer.

Human metapneumovirus (HMPV) was isolated from a 63-year-old multiple myeloma patient who had undergone hematopoietic stem cell transplantation and who presented with lower respiratory tract infection several weeks prior to the diagnosis of lung cancer. The isolate was phylogenetically and biologically characterized and compared to HMPV prototypes and recent pediatric isolates. Remarkably, it belonged to the novel genomic subgroup A2b.

Animals↗
PubMed2000

Immunological properties of mononuclear cells from blood stem cell harvests following mobilization with erythropoietin + G-CSF in cancer patients.

BACKGROUND: Although the recombinant granulocyte colony-stimulating factor (G-CSF) is a good CD34 cell mobilizer, the effects of G-CSF mobilization on the immune effector function of the individual is not always optimal. We studied the functional and phenotypic properties of peripheral blood stem cells (PBSC) collected from 15 cancer patients mobilized with G-CSF plus recombinant erythropoietin (EPO). METHODS: The patients received EPO (300 U/kg) and (G-CSF 1 microg/kg) per day as mobilizing cytokines and an autologous graft product was collected with at least daily apheresis procedures until a target number of CD34 cells and mononuclear cells were obtained. Mononuclear cells from the first four PBSC collections were tested for their natural killer (NK), activated NK and lymphokine activated killer (LAK) cytotoxicity in vitro against K562 and Raji tumor target cells. RESULTS: There was a significant increase in NK, activated NK and LAK cytotoxicity in EPO + G-CSF mobilized cells when compared to mononuclear cells from premobilization blood baseline values. Although there was no increase in CD3+ T cells, there was a significant increase in myeloid cells (CD14+), B-cells (CD20+) and NK cells (CD56+) following mobilization. There was no difference in T cell response to the mitogens PHA and Con-A, but there was an increase in B-cell response to PWM following mobilization. Thus, the combination of EPO + G-CSF not only mobilized hematopoietic precursor cells but also increased the number of immune effector cells in the PBSC collections.

Adult↗
PubMed1999

Initial clinical experience evaluating Yttrium-90-chimeric T84.66 anticarcinoembryonic antigen antibody and autologous hematopoietic stem cell support in patients with carcinoembryonic antigen-producing metastatic breast cancer.

cT84.66 is a human/murine IgG1 with high affinity and specificity for carcinoembryonic antigen (CEA). An earlier Phase I trial defined the maximum tolerated dose for 90Y-diethylenetriaminepentaacetic acid (DTPA)-cT84.66 at 22 mCi/m2. Dose-limiting toxicities were reversible leukopenia and thrombocytopenia. The purpose of this Phase I trial was to evaluate the feasibility and toxicities of administering higher activities of 90Y-DTPA-cT84.66 with stem cell support in patients with CEA-producing breast cancer. Patients with CEA-producing breast cancer refractory to standard therapies underwent peripheral stem cell collection followed by infusion of 111indium-DTPA-cT84.66. Those patients demonstrating tumor targeting received a single therapy dose of 90Y-DTPA-cT84.66, followed by Ca-DTPA infusion for 72 h posttherapy. Stem cells were reinfused following a divided schedule. To date, seven patients have been accrued to this trial. Each patient received an imaging dose of (111)In-cT84.66. Six patients demonstrated tumor imaging and received a single cycle of 90Y-cT84.66 at 15 mCi/m2 (three patients) and 22.5 mCi/m2 (three patients). One patient did not demonstrate tumor imaging and was not treated. At these administered activities, 90Y-cT84.66 was well tolerated. No dose-limiting toxicities have been observed. All patients demonstrated hematopoietic recovery after stem cell infusion. One patient demonstrated stable disease for 4 months; one patient had stable disease and reduction of bone pain for 3 months; and a third patient experienced >50% reduction of an ovarian metastasis, resolution of malignant pleural effusion, stable pleural metastases, and stable bone scan for 14 months. Preliminary results from this ongoing Phase I trial are promising and demonstrate the feasibility and potential for antitumor effects of stem cell supported 90Y-cT84.66 therapy in patients with CEA-producing breast cancers.

Animals↗
PubMed1984

5-Fluorouracil and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) followed by hydroxyurea, misonidazole, and irradiation for brain stem gliomas: a pilot study of the Brain Tumor Research Center and the Childrens Cancer Group.

Twenty-eight evaluable children with the diagnosis of brain stem glioma were treated with 5-fluorouracil and CCNU before posterior fossa irradiation (5500 rads); during irradiation, the children received hydroxyurea and misonidazole. The treatment was well tolerated, and minimal toxicity was produced. The median relapse-free survival was 32 weeks, and the median survival was 44 weeks. Analysis of covariates showed that, in patients between the ages of 2 and 19 years, survival was longest in the older children (P less than 0.02). Tumor histology, sex, extent of operation (if any), Karnofsky score, and radiation dose did not correlate with survival.

Adolescent↗
PubMed1998

Investigating stem cells in the lung.

Disruption of the lung architecture by genetic events, environmental insults, or transformation can lead to respiratory diseases such as acute respiratory distress syndrome and lung cancer. Identification of the stem cells of the lung and the processes by which they regulate homeostasis may lead to better targets for treatment of these diseases. There are a number of approaches to study stem cell biology. Development of the lung and the major pulmonary cells of the bronchioles and alveolar regions of the lung is discussed in this review. Likewise, identifying the proteins that are critical for cell-specific expression and differentiation may identify approaches for manipulation of gene expression for use as therapy or treatment of lung diseases. Furthermore, strategies for studying stem cells in the lung are addressed by using the mouse as a model system. Gaining a more detailed understanding of the stem cells of the lung may provide new insight into the processes that govern lung biology and may lead to better treatments for lung diseases. Enthusiasm for the use of exogenous stem cells to replace tissue, organs, or other defective or deficient cells is boundless. Before stem cells can be used indiscriminately for these purposes, understanding tissue genetics and immunology is essential. Progress has been made in these areas for pulmonary disease. Attention to these models will be applicable to other organs and diseases.

Animals↗
PubMed2001

Biological purging of breast cancer cells using an attenuated replication-competent herpes simplex virus in human hematopoietic stem cell transplantation.

Autologous hematopoietic stem cell transplantation after myelosuppressive chemotherapy is used for the treatment of high-risk breast cancer and other solid tumors. However, contamination of the autologous graft with tumor cells may adversely affect outcomes. Human hematopoietic bone marrow cells are resistant to herpes simplex virus type 1 (HSV-1) replication, whereas human breast cancer cells are sensitive to HSV-1 cytotoxicity. Therefore, we examined the utility of G207, a safe replication-competent multimutated HSV-1 vector, as a biological purging agent for breast cancer in the setting of stem cell transplantation. G207 infection of human bone marrow cells had no effect on the proportion or clonogenic capacity of CD34+ cells but did enhance the proliferation of bone marrow cells in culture and the proportion of CD14+ and CD38+ cells. On the other hand, G207 at a multiplicity of infection of 0.1 was able to purge bone marrow of contaminating human breast cancer cells. Because G207 also stimulates the proliferation of human hematopoietic cells, it overcomes a limitation of other purging methods that result in delayed reconstitution of hematopoiesis. The efficient infection of human bone marrow cells in the absence of detected toxicity suggests that HSV vectors may also prove useful for gene therapy to hematopoietic progenitor cells.

Bone Marrow Cells↗
PubMed2006

Umbilical cord blood transplantation: newer trends.

During last ten years, over 4000 umbilical cord blood transplantations have been performed worldwide. The interest in this modality of transplantation has been growing as this provides easy access to an alternative source of stem cells for treating cancer and serious genetic disorders with otherwise fatal outcome or immense morbidity. Umbilical cord blood is a commonly discarded source of useful stem cells. The outcome of transplantation using cells from this source in children mirrors the results of unrelated donor transplantation and hence the procedure is widely accepted by paediatric transplant community. Results are, however, hampered in adults due to low cell dose. Newer techniques, such as pooled or sequential cord blood transplantation, may help to increase progenitor cell numbers and improve immune reconstitution. In near future, non-haematopoietic uses will make this even more exiting area. In this write-up, we will review this treatment including cord blood banking issues and the ethical concerns. We will discuss both paediatric and adult transplantations including certain new indications.

Adult↗
PubMed1996

Regulation of telomerase activity in immortal cell lines.

Telomerase is a ribonucleoprotein whose activity has been detected in germ line cells, immortal cells, and most cancer cells. Except in stem cells, which have a low level of telomerase activity, its activity is absent from normal somatic tissues. Understanding the regulation of telomerase activity is critical for the development of potential tools for the diagnosis and treatment of cancer. Using the telomeric repeat amplification protocol, we found that immortal, telomerase-positive, pseudodiploid human cells (HT1080 and HL60 cells) sorted by flow repressed in quiescent cells. This was true whether quiescence was induced by contact inhibition (NIH 3T3 mouse cells), growth factor removal (bromodeoxyuridine-blocked mouse myoblasts), reexpression of cellular senescence (the reversibly immortalized IDH4 cells), or irreversible cell differentiation (HL60 promyelocytic leukemia cells and C2C12 mouse myoblasts). Taken together, these results indicate that telomerase is active throughout the cell in dividing, immortal cells but that its activity is repressed in cells that exit the cell cycle. This suggests that quiescent stem cells that have the potential to express telomerase may remain unaffected by potential antitelomerase cancer therapies.

3T3 Cells↗
PubMed1989

[Recovery kinetics of hematopoiesis after peripheral blood stem cell autotransplantation].

Hematopoietic recovery kinetics was evaluated in five children with therapy-refractory cancers who received peripheral blood stem cell autotransplantation (PBSCT) following marrow-ablative chemotherapy. Four children received graft containing more than 1.5 X 10(4) CFU-GM/kg and days required to achieve granulocyte counts of greater than 0.5 X 10(9)/l were 6, 10, 13, and 18, respectively. One patient received 0.9 X 10(4) CFU-GM/kg, but, recovery of granulopoiesis was retarded (greater than 30 days). The days required to achieve platelet count of greater than 50 X 10(9)/l were 12, 15, 16, 195, and greater than 240, respectively. Transient decrease of blood cell counts developed 3 to 5 weeks after transplantation and thereafter, the recovery of hematopoiesis became stable. With the use of a large number of progenitors, PBSCT seems to be safe and effective new type of stem cell rescue operation as an alternative to bone marrow transplantation.

Acute Disease↗
PubMed1998

High-dose therapy with peripheral blood stem cell (PBSC) support using an innovative mobilization regimen in patients with high-risk primary or chemoresponsive metastatic breast cancers.

High-dose therapy followed by peripheral blood stem cell (PBSC) support was performed in 29 patients with primary high-risk (Group I) or chemoresponsive metastatic (Group II) breast cancer patients. Group I patients had received PBSC mobilization within 4 weeks of modified radical mastectomy. Group II patients had to achieve minimal residual disease (MRD) by induction chemotherapy before being considered eligible for PBSC mobilization and high-dose therapy. An innovative FE120C regimen (5-FU 600 mg/m2, i.v., day 1; epirubicin 120 mg/m2, i.v., day 1; cyclophosphamide 600 mg/m2, i.v., day 1) plus G-CSF (300 microg/day, subcutaneous injection for 9 days, from day 4 post-FE120C) was used to mobilize PBSCs. After high-dose CTCb (cyclophosphamide 6,000 mg/m2, thiothepa 500 mg/m2, carboplatin 800 mg/m2, in 4 days), patients received PBSC infusion and daily C-CSF 300 microg subcutaneous injection. There were 19 and 16 patients enrolled into Group I and Group II, respectively. Ten of the Group II patients had achieved minimal residual disease (MRD) after induction chemotherapy. The median numbers of mobilized total CD34 + cells for Group I and Group II patients were 27.3 (9.2 to 114.1) x 10(6)/kg and 17.1 (5.9 to 69.1) x 10(6)/kg respectively. The median time to neutrophil recovery (ANC > or = 500/microL) was 8 and 9 days in Group I and II, respectively. The median time to platelet recovery (> or = 50,000/microL) was 10 and 15 days in Group I and II, respectively. No major treatment-related toxicities were noted. In Group I, 13 out of 19 patients (68.4%; 43-87%, 95% C.I.) remained recurrence-free with a median follow-up of 31 months (6 + to 55 + months). In Group II, 3 out of 10 patients (30%; 7-65%, 95% C.I.) remained progression-free at 33 +, 35 +, 39 + months from induction therapy. We suggest that the FE120C plus G-CSF is an effective and innovative regimen for PBSC mobilization in breast cancer patients, and high-dose CTCb therapy with PBSC support is a safe and well-tolerated treatment modality.

Adult↗
PubMed1992

Experience with peripheral blood stem cell collection for autografts in children with active cancer.

This report examines laboratory and clinical experience with peripheral blood stem/progenitor cell harvest for autografts in 71 consecutively referred children with various types of cancer from one institution. The age of the patients ranged from 7 months to 17 years with a median of 8 years. Ten of the 71 referred children were removed from the collection procedure because of failure to induce clinical remission (nine) or deteriorating chemotherapy-induced liver failure (one). A total of 215 aphereses were performed on a CS 3000 cell separator in 61 patients, including 18 children aged 4 years or less. The methylcellulose progenitor assay was used as an index of stem cell collection. A minimum of greater than or equal to 3 x 10(5) colony-forming units-granulocyte/macrophage (CFU-GM)/kg body weight were collected in 31 of 71 children (44%) with a mean of 3.1 (range, 1-5) aphereses, and greater than or equal to 1 x 10(5) CFU-GM/kg in 46 children (65%). The incidence of serious morbidity was low. When apheresis or chemotherapy was repeated, the progenitor yields decreased rapidly. By multivariate analysis, the age of the patients was the only significant predictor of CFU-GM yield (p = 0.009). In our experience with 12 children with acute leukemia or non-Hodgkin's lymphoma, regimens containing high-dose cytarabine (2.0 g/m2 x 10) were effective for mobilization. Our results extend the earlier findings that harvesting PBSCs for autografts in children with active cancer is a safe and reliable procedure with a low incidence of serious morbidity.

Adolescent↗
PubMed2004

High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial.

PURPOSE: Investigation of high-dose chemotherapy (HD-CT) followed by autologous hematopoietic stem-cell support compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more positive axillary lymph nodes. PATIENTS AND METHODS: Between November 1993 and September 2000, 307 patients were randomized to receive (following four cycles of epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), intravenously every 21 days) either HD-CT of cyclophosphamide 1500 mg/m(2), thiotepa 150 mg/m(2), and mitoxantrone 10 mg/m(2), intravenously for 4 consecutive days followed by stem-cell support; or SD-CT in three cycles of cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) intravenously on days 1 and 8, every 28 days. The primary end point was event-free survival. RESULTS: After a median follow-up of 3.8 years, 144 events with respect to event-free survival have been observed (HD-CT: 63 events; SD-CT: 81 events). The first event of failure (HD-CT v SD-CT) was an isolated locoregional recurrence (nine v 11), a distant failure (52 v 68), and death without recurrence (two v two). The estimated relative risk of HD-CT versus SD-CT was 0.75 (95% CI, 0.54 to 1.06; P =.095). Overall survival showed no difference (HD-CT: 40 deaths; SD-CT: 49 deaths). CONCLUSION: There was a trend in favor of HD-CT with respect to event-free survival, but without statistical significance. Further follow-up and a meta-analysis of all randomized studies will reveal the effect of HD-CT as compared with SD-CT as adjuvant treatment in high-risk primary breast cancer.

Adult↗
PubMed1996

Selective transgene expression for detection and elimination of contaminating carcinoma cells in hematopoietic stem cell sources.

Tumor contamination of bone marrow (BM) and peripheral blood (PB) may affect the outcome of patients receiving high dose chemotherapy with autologous transplantation of hematopoietic stem cell products. In this report, we demonstrate that replication defective adenoviral vectors containing the cytomegalovirus (CMV) or DF3/MUC1 carcinoma-selective promoter can be used to selectively transduce contaminating carcinoma cells. Adenoviral-mediated reporter gene expression in breast cancer cells was five orders of magnitude higher than that found in BM, PB, and CD34+ cells. Our results demonstrate that CD34+ cells have low to undetectable levels of integrins responsible for adenoviral internalization. We show that adenoviral-mediated transduction of a reporter gene can detect one breast cancer cell in 5 x 10(5) BM or PB cells with a vector containing the DF3/MUC1 promoter. We also show that transduction of the HSV-tk gene for selective killing by ganciclovir can be exploited for purging cancer cells from hematopoietic stem cell populations. The selective expression of TK followed by ganciclovir treatment resulted in the elimination of 6-logs of contaminating cancer cells. By contrast, there was little effect on CFU-GM and BFU-E formulation or on long term culture initiating cells. These results indicate that adenoviral vectors with a tumor-selective promoter provide a highly efficient and effective approach for the detection and purging of carcinoma cells in hematopoietic stem cell preparations.

Adenoviruses, Human↗
PubMed1995

High-dose therapy with autologous bone marrow stem cell support in primary and metastatic human breast cancer. A review.

A dose-response relationship has been demonstrated for metastatic human breast cancer. This increased response using moderately increased doses is generally not translated into an improved survival. The use of high-dose therapy to selected patients with metastases/recurrence responding to conventional doses of polychemotherapy may lead to an improved survival tail. Conventional doses of polychemotherapy in the adjuvant setting will reduce the relative mortality by around 25% 10 years after primary diagnosis. The use of high-dose therapy supported by autologous bone marrow stem cells may be markedly more effective in the adjuvant setting, especially to high-risk patients, compared with standard polychemotherapy. Several randomized studies are being planned or have already started in order to answer different aspects of this issue.

Antineoplastic Agents↗