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Biomedical subjects

F M Stewart

Publications and source records attributed to F M Stewart.

At least 19 recordsLinked to original sources
PubMed1995

Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation.

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady-state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.

Antigens, CD↗
PubMed1995

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Clinical Trials as Topic↗
PubMed1994

Esthesioneuroblastoma. Long-term outcome and patterns of failure--the University of Virginia experience.

BACKGROUND: Esthesioneuroblastoma is a rare tumor arising from olfactory epithelium. This retrospective review analyzed the patterns of failure and long term outcome of patients with esthesioneuroblastoma evaluated at a single institution. METHODS: Forty patients with esthesioneuroblastoma were evaluated at the University of Virginia, with a median follow-up of 130 months. In most cases, treatment consisted of combined-modality therapy, including radiotherapy and surgery for Stages A and B disease and the addition of chemotherapy for Stage C disease. Fifteen patients received chemotherapy that included cyclophosphamide plus vincristine. Thirty-eight patients received radiotherapy, with a median dose of 50 Gy. Initial surgery for 23 patients included craniofacial resection, whereas the remainder had less extensive surgery (3 had no initial surgery). Five patients were salvaged with high dose chemotherapy and autologous bone marrow transplantation (CTX/BMT). RESULTS: Actuarial survivals at 5, 10, and 15 years are 78%, 71%, and 65% respectively. Fifty-five percent of patients failed therapy, and 68% of the failures were locoregional. Thirty-nine percent of recurrences occurred later than 5 years from diagnosis. Three of the five patients were successfully salvaged with CTX/BMT compared with four of seventeen patients who underwent conventional salvage therapy. CONCLUSIONS: Esthesioneuroblastoma is associated with long term survival and late recurrences. Multimodality therapy should be used initially. Durable remissions of failures can be achieved with CTX/BMT:

Adolescent↗
PubMed1994

Seasonal variation in heavy metal levels in tissues of common guillemots, Uria aalge from northwest Scotland.

Mercury, cadmium, zinc, and copper concentrations were analyzed in three samples of common guillemot (in April, June, and November). Levels measured were uniformly low, and not enough to have any toxic effects. Adult guillemots had significantly more cadmium in their livers and kidneys than juveniles, with juvenile levels ranging from 25% to 89% of adult levels. Mercury concentrations in liver and kidney were also higher in adults. Juvenile levels represented from 80% to 94% of adults, but there were no age differences in feather and muscle mercury. Mercury levels declined throughout the year in internal tissues from April through June to November. There was a strong seasonal fluctuation in cadmium levels in liver and kidney, rising significantly between April and June and declining in both adult and juvenile birds. The influences of seasonal processes (namely breeding and moult) and seasonal dietary differences as causative factors in the changes in metal burdens are discussed. These findings have implications for the use of seabirds as monitors of heavy metals in the marine environment.

Animals↗
PubMed1994

Fluctuation tests: how reliable are the estimates of mutation rates?

Fifty one years ago, Luria and Delbrück published in Genetics a paper that was to become a classic. In it they proved, beyond all reasonable doubt, that bacteria were mutating to phage resistance long before they could have encountered any bacteriophage. Luria and Delbrück also showed how the same experimental data could be used to estimate bacterial mutation rates. Since that time and in many different contexts the methods that they introduced have been used to estimate mutation rates. However, little seems to be known about the errors to be expected in such estimates. In what follows I examine how much uncertainty in the estimates is to be expected merely on the basis of the stochastic variability inherent in the sampling process. On the basis of this examination I question a few traditional ideas and conclude with some practical suggestions. The results were obtained by stimulation. It is my hope that they may inspire others to provide a rigorous theoretical basis for such calculations.

Bacteria↗
PubMed1994

An update on non-Hodgkin's lymphomas.

The non-Hodgkin's lymphomas are a diverse group of diseases characterized by enlargement of the lymph nodes and are indolent or aggressive. The histopathologic subtype provides the best guide to the nature of these diseases. In most patients the etiology is unknown. Painless peripheral adenopathy is the usual presenting feature. A careful clinical staging without laparotomy is recommended to establish disease extent, prognosis and treatment. In patients with indolent (low grade) lymphomas, a period of observation prior to treatment may be appropriate if the patient is asymptomatic. Symptomatic patients with low grade lymphoma require therapy. For patients with aggressive disease (intermediate or high grade), immediate treatment with curative intent is indicated. High dose therapy with bone marrow transplantation may be used to cure a small number of patients who relapse following initial chemotherapy.

Antineoplastic Agents↗
PubMed1994

Engraftment of normal murine marrow into nonmyeloablated host mice.

When 200 x 10(6) male BALB/c cells are given by tail vein injection to female nonmyeloablated hosts in one injection, a relatively low engraftment percentage is seen, but when the same total number of cells is given over five injections (separated by 24 hours), the observed engraftment is much higher. A further increase in engraftment appears to occur when the same number of cells is given in 10 injections separated by at least 24 hours. These data suggest that somewhere between 5 and 10% of marrow niches are available at intervals of 24 or more hours and that the keys to high levels of engraftment are the cell cycle status of the engrafting stem cell and the schedule of engraftment.

Animals↗
PubMed1994

In vitro and in vivo studies of stromal niches.

Lymphohematopoiesis occurs in the densely packed environment of the intramedullary spaces. Primitive lymphohematopoietic stem cells exist in close apposition to a variety of supportive cells including both hemopoietic and nonhemopoietic lineages. Using an in vitro long-term Dexter liquid culture system, we have established that a variety of cytokines are produced constitutively by such stromal cells in culture. These cytokines include Steel factor, interleukin-6 (IL-6), and colony-stimulating factor (CSF-1). Granulocyte-CSF and granulocyte-macrophage-CSF mRNA can be detected after refeeding of cultures, although in quiescent cultures message for these factors is difficult to detect. Interleukin-3, IL-4, and IL-5 are not detectable by standard Northern blot analysis or bioassay of condition media. However, IL-3--detectable by reverse-transcriptase PCR and biologic activity--was confirmed by growth of factor-dependent cells on stromal cells with IL-3 antibody blocking of such growth. Stem cells resident on such stromal cells are mirrored by the high proliferative potential colony-forming cell assay and are responsive to a relatively large number of cytokines, with Steel factor being of central importance, appearing to be a critical component of various synergistic combinations. Steel factor allows reduced levels of other factors in such combinations and works early in a temporal sequence. Hematopoietic stem cells can engraft in normal nonmyeloablated hosts. Using a male/female BALB/c transplantation model, we have shown high rates of engraftment into normal animals, out after marrow infusion to 25 months, after marrow infusion and that post-5-fluorouracil bone marrow is quite deficient in such engraftment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice.

We report the successful long-term engraftment of normal male donor bone marrow (BM) transfused into noncytoablated female mice, challenging the assumption that "niches" need to be created for marrow to engraft. We have used chromosomal banding and Southern blot analysis to identify transplanted male marrow cells, and shown the long-term stability of the chimeric marrows. Balb/C, BDF1, or CBA-J female hosts (no irradiation) received for 5 consecutive days 40 x 10(6) male cells (per day) of the same strain, and repopulation patterns were observed. Parallel studies were performed using tibia/femur equivalents of normal marrow or marrow from Balb/C mice pretreated 6 days previously with 150 mg/kg 5-fluorouracil (5-FU). Chromosome banding techniques showed that 5% to 46% of marrow cells were male 3 to 9 months posttransplant with normal donor marrow. Southern blot analysis, using the pY2 probe, showed continued engraftment at 21 to 25 months posttransplant, ranging from 15% to 42% male engrafted cells in marrow. Normal donor male marrow engrafted significantly better than 5-FU-pretreated male marrow as shown 1 to 12 months posttransplant in non-cytoablated female recipients. Percentages of male engrafted cells in BM ranged from 23% to 78% for recipients of normal donor marrow and from 0.1% to 39% for recipients of 5-FU marrow. Mean engraftment for 6 mice receiving normal marrow was 38%, whereas that for 6 mice receiving post-5-FU marrow was 8%, as assayed 1 to 3 months posttransplant. At 10 to 12 months, mean engraftment for the normal donor group was 46%, compared with 16% for the 5-FU group. The patterns of engraftment with normal and 5-FU marrow were similar for spleen and thymus. These results show that long-term chimerism can be established after transplantation of normal donor marrow to normal nonirradiated host mice and indicate that marrow spaces do not have to be created for successful engraftment. They suggest that transplanted marrow competes equally with host marrow for marrow space. Finally, these data show that post-5-FU Balb/C male marrow is markedly inferior in the repopulation of Balb/C female host marrow, spleen, and thymus, and suggest that this population of cells may not be the ideal population for gene transfer studies.

Animals↗
PubMed1993

Indications and relative indications for stem cell transplantation in non-Hodgkin's lymphoma.

High dose chemotherapy with or without total body irradiation and autologous stem cell rescue has proven to be effective treatment to cure patients with relapsed intermediate grade and high grade non-Hodgkin's lymphoma. Important factors for selection of candidates most likely to do well with these approaches include patients whose disease is responsive to conventional therapy and those who have minimal disease volume at the time of transplant. The treatment-related mortality of autologous stem cell transplantation has diminished from 20% to less than 5% with improved supportive care and selection of patients with less advanced disease. Although the treatment-related mortality of allogeneic stem cell transplantation may be as high as 20-40%, a graft versus lymphoma effect may decrease relapse with the result that overall survival is not substantially different between autologous and allogeneic transplantation. The definitive indications for stem cell transplantation include patients who have relapsed with intermediate or high grade NHL. Relative indications include intermediate/high grade non-Hodgkin's lymphoma patients, "high risk" first complete remission (CR), resistant relapse; low grade non-Hodgkin's lymphoma in sensitive or resistant relapse, advanced disease (sensitive or resistant relapse, transformation), first CR (younger patients). Relative contraindications include specific patient profiles such as bulky high grade lymphoma which progresses on appropriate conventional therapy, poor performance status, active serious infection, serious cardiac, renal, pulmonary or liver dysfunction, active, central nervous system (CNS) disease unresponsive to cranial irradiation/intrathecal therapy. For patients with previous marrow involvement or active marrow involvement at the time of harvest or transplant, "purged" autografts, peripheral blood stem cell transplantation and allografts have been used successfully.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

The addition of oatbran to a low fat diet has no effect on lipid values in hypercholesterolaemic subjects.

AIMS: to assess the hypocholesterolaemic effect of adding 50 g of oatbran to the diet of hypercholesterolaemic subjects already prescribed a diet with less than 30% of energy from fat. METHODS: twenty-nine volunteers aged 21-67 years with total serum cholesterol levels 5.59-8.5 mmol/L prescribed a diet containing less than 30% of energy intake as fat, and with a body mass index between 19.8 and 29.3, were enrolled in a crossover study to assess the effect of the addition to the diet of 50 g daily of oatbran. After six weeks of an oat-free control diet, subjects were randomised to eat 50 g daily of oatbran or to continue on the oat-free diet. Six weeks later the subjects crossed to the alternative diet for a further six week period. Lipid levels were assessed in weeks five and six of each study period. RESULTS: twenty-four subjects completed the study consuming 51.7 (SD 15.5) g of oatbran daily during the treatment phase. No significant difference was seen between the oatbran and control diet periods in body mass index, energy or fat intake, or in total cholesterol, LDL and HDL fractions, apolipoprotein A1 and B levels, or triglyceride levels. Considerable variation was observed between the paired lipid results. CONCLUSIONS: ingestion of 50 g of oatbran daily by hypercholesterolaemic subjects on a low fat diet showed no influence on serum lipid levels. The importance of using at least duplicate samples in assessing changes in lipid values is emphasised.

Adult↗
PubMed1992

Hypoplastic/aplastic anemia. Role of bone marrow transplantation.

For young patients with SAA, allogeneic bone marrow transplantation is the best curative approach. Major obstacles to the success of allogeneic bone marrow transplantation include GVHD, infections, and graft rejection. A careful management approach to patients prior to transplant may decrease some of these complications. Immunosuppressive therapy should be utilized in older patients with SAA. Underlying clonal disorders, eg, acute leukemia and recurrent aplasia, are late complications.

Anemia, Aplastic↗
PubMed1991

Fluctuation analysis: the effect of plating efficiency.

This paper supplements an earlier paper which explained how to calculate the probability distribution of the number of mutants that would be observed in a fluctuation test experiment. The formulas in that work give the distributions to be expected under a wide variety of experimental conditions, but the method it uses when only a fraction of the mutants will produce visible colonies are clumsy and inefficient. Here I describe efficient procedures for dealing with that case, provided that the mutation rate per cell division remains constant during the experiment.

Colony Count, Microbial↗
PubMed1991

The role of the chest roentgenogram in febrile neutropenic patients.

In a retrospective review of patients with neutropenia and fever, we sought to determine how often roentgenograms detected pulmonary disease, especially pneumonia, not suggested by signs and symptoms. Further, we sought to determine how often therapy was changed as a result of roentgenographic findings. Overall, 41 (22%) of 187 chest roentgenograms obtained during initial febrile episodes, recurrent fevers, or persistent fevers were abnormal. While most patients had signs and symptoms suggesting the presence of pulmonary disease, 17% had roentgenographic abnormalities detected in the absence of such findings. During initial febrile episodes, therapy was not changed in response to findings on the chest roentgenogram. However, during episodes of persistent or recurrent fever, findings on chest roentgenograms led to changes in therapy in eight (61%) of 13 episodes of which six (40%) resulted in clinical improvement. Chest roentgenograms were therefore found to be an important diagnostic tool in evaluating recurrent or persistent fever in the neutropenic patient but of little use during initial febrile episodes.

Bone Marrow Transplantation↗
PubMed1990

Treatment of small-cell carcinoma of the cervix with weekly combination chemotherapy.

Three patients with small-cell carcinoma of the cervix entered a pilot study of combination chemotherapy with agents that are not cross-resistant. Two patients had local disease and the third had extensive metastatic disease of the liver. The regimen consisted of weekly chemotherapy for 16 weeks with cisplatin, vincristine, methotrexate, doxorubicin, cyclophosphamide and etoposide followed by radiotherapy and/or surgery. The two patients with local disease achieved a pathological complete response, with no evidence of disease at 24 months and 15 months from diagnosis. The third patient achieved a partial response and is alive at 13 months with progressive disease. Side-effects were tolerable.

Adult↗