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A K Stewart

Publications and source records attributed to A K Stewart.

At least 19 recordsLinked to original sources
PubMed1998

Identification of sequence-tagged transcripts differentially expressed within the human hematopoietic hierarchy.

Hematopoiesis is regulated by a complex gene expression program. To gain further insight into the molecular mechanisms underlying this process in humans, we sampled the transcriptional activity of the CD34+ hematopoietic progenitor line KG1a by single-pass sequencing the 5' ends of 1018 clones from a unidirectional cDNA library. Searches of public databases with the resulting expressed sequence tags (ESTs) identified 101 clones that showed no sequence similarity to any of the existing entries and that were therefore considered to derive from previously undescribed genes. Of the remaining 917 ESTs, 553 (a total of 485 distinct transcripts) corresponded to known genes. A further 279 KG1a ESTs matched or exhibited sequence similarity to ESTs or genomic sequences from humans and other species. Among the latter were putative human orthologs of developmental and cell cycle control genes from Caenorhabditis elegans, Drosophila, and yeast, as well as genes whose predicted amino acid sequences showed similarity to mammalian transcription factors. Hybridization of selected novel KG1a ESTs to globally amplified cDNAs prepared from single primary human hematopoietic precursors and homogeneous populations of terminally maturing hematopoietic cells revealed transcripts that are expressed preferentially at a specific stage or in a particular lineage within the hematopoietic hierarchy. Thus, included in the KG1a EST dataset are candidates for new human genes that may play roles in hematopoietic differentiative progression and lineage commitment.

Animals↗
PubMed1998

Trends in the use of radiation and chemotherapy in the initial management of patients with carcinoma of the uterine cervix.

PURPOSE: The Commission on Cancer of the American College of Surgeons conducts Patient Care Evaluation studies to describe practice patterns and trends in disease management. This report surveys changing strategies in the initial treatment of patients with invasive cancer of the uterine cervix. METHODS AND MATERIALS: Using a standard data collection form designed by a multidisciplinary committee of specialists, cancer registrars at 703 hospitals submitted anonymous data on 11,721 total cervical cancer patients diagnosed in 1984 and 1990. RESULTS: Between the two study years, the use of radiation as all, or a component, of the initial course of therapy declined from 70 to 60.3%, coincident with a 32.3% increase in the use of hysterectomy alone and a 33.7% reduction in the use of radiation alone. The percentage of all patients receiving combined hysterectomy and radiation (preoperative or postoperative) remained virtually unchanged--10.2% in 1984, and 9.3% in 1990. However, women who were treated by hysterectomy in 1990 were less likely to receive radiation as part of their treatment than patients treated by hysterectomy in 1984. Among patients treated by radiation without hysterectomy, the use of intracavitary brachytherapy techniques substantially exceeded interstitial brachytherapy techniques in both study years. Among patients treated by local radiation without hysterectomy, the frequency of adjunctive chemotherapy use increased from 6.9% in 1984 to 24.8% in 1990, with chemotherapy and radiation increasingly administered concurrently rather than sequentially. Although differences based on age, histology, race/ethnicity, and insurance status were observed, these general management trends were seen in all groups. CONCLUSIONS: Changes in the utilization of radiation and surgery may reflect the increasing surgical involvement of gynecologic oncologists in the management of early stage cervical cancer, rather than significant alterations in the demographics of the disease. Although brachytherapy is recognized as an important component of radiation treatment, some patients may not receive the potential benefit of this modality. Despite controversy concerning its efficacy, the use of adjuvant systemic chemotherapy to supplement local treatment modalities appears to be increasing rapidly.

Adult↗
PubMed1998

Peptide mimics as substrates for the intestinal peptide transporter.

4-Aminophenylacetic acid (4-APAA), a peptide mimic lacking a peptide bond, has been shown to interact with a proton-coupled oligopeptide transporter using a number of different experimental approaches. In addition to inhibiting transport of labeled peptides, these studies show that 4-APAA is itself translocated. 4-APAA transport across the rat intact intestine was stimulated 18-fold by luminal acidification (to pH 6.8) as determined by high performance liquid chromatography (HPLC); in enterocytes isolated from mouse small intestine the intracellular pH was reduced on application of 4-APAA, as shown fluorimetrically with the pH indicator carboxy-SNARF; 4-APAA trans-stimulated radiolabeled peptide transport in brush-border membrane vesicles isolated from rat renal cortex; and in Xenopus oocytes expressing PepT1, 4-APAA produced trans-stimulation of radiolabeled peptide efflux, and as determined by HPLC, was a substrate for translocation by this transporter. These results with 4-APAA show for the first time that the presence of a peptide bond is not a requirement for rapid translocation through the proton-linked oligopeptide transporter (PepT1). Further investigation will be needed to determine the minimal structural requirements for a molecule to be a substrate for this transporter.

Aniline Compounds↗
PubMed1998

Retrovirus-mediated gene transfer into human hematopoietic stem cells.

Human hematopoietic stem cells genetically modified by retroviral-mediated gene transfer may offer new treatment options for patients with genetic disease. The potential of gene-modified hematopoietic stem cells as vehicles for gene delivery was first illustrated by the demonstration that hematopoietic systems of lethally irradiated mice can be reconstituted with retroviral vector transduced syngeneic bone marrow, and that these cells can in turn provide genetically marked progeny which persist in blood and marrow over extended time periods. In contrast, hematopoietic stem cells from large animals prove difficult to transduce with retroviral vectors and are consequently less likely to function as vehicles for long-term gene therapy. Indeed, clinically relevant levels of gene transfer into large animal and human hematopoietic stem cells has not been widely achieved. The need for improved retroviral vector systems and for understanding the biology of hematopoietic stem cell gene transfer continue to fuel intense research activity. Preliminary results from human stem cell gene marking and gene therapy trials currently underway are encouraging. This contribution reviews the underlying concepts relevant to retroviral-mediated gene transfer into hematopoietic stem cells. We survey the evolution of approaches for gene transfer into hematopoietic stem cells, from murine and large animal models to the first human clinical trials. Finally, we discuss new strategies which are currently being pursued.

Animals↗
PubMed1998

Superior survival of young women with malignant melanoma.

BACKGROUND: The Commission on Cancer data from the National Cancer Data Base (NCDB) relating to patients with malignant melanoma are used to examine patterns of long-term survival by patient gender and age, stage of disease, disease morphology, and anatomic subsite. METHODS: Five calls for data have yielded more than 3,700,000 cases of cancer for the years 1985 through 1993, including 23,341 cases of malignant melanoma between 1985 and 1989, from hospital cancer registries across the US, representing slightly less than a quarter of all melanoma cases diagnosed in the US between 1985 and 1989. RESULTS: Three statements can be made from this data: (1) There is little difference in the frequency of malignant melanoma between men and women with respect to stage of disease or morphology. However, differences between the genders do appear with respect to the anatomic subsite of melanotic tumors. (2) Overall, young women (45 years of age and under) enjoy superior survival rates when compared with older women (55 years of age and older) and men of any age. (3) The survival advantage held by young women is particularly pronounced among patients diagnosed with advanced stage disease. CONCLUSIONS: These data suggest that factors present in younger women may be critical in the superior survival rates seen among premenopausal women and might be hormonal in nature.

Age Factors↗
PubMed1998

Ovarian function after autologous bone marrow transplantation.

PURPOSE: To determine the frequency of return of ovarian function after autologous bone marrow transplantation (ABMT), and the major factors that predict recovery. PATIENTS AND METHODS: Records of 200 consecutive women who underwent ABMT at the University of Toronto Autologous Blood and Marrow Program (Toronto, Canada) were reviewed. Seventeen patients met the inclusion criteria, which were (1) alive at the time of evaluation, (2) disease-free at least 18 months after transplantation, (3) age younger than 50 years at transplantation, and (4) premenopausal before transplantation. Recovery of ovarian function was determined by pregnancy or regular menses, with no menopausal symptoms and an estradiol level greater than 20 pmol/L off hormonal therapy. RESULTS: All 17 patients became menopausal immediately after ABMT. Five patients (29%) recovered ovarian function a median of 24 months post-ABMT (range, 6 to 48 months). The median age at transplantation of women with restored ovarian function was 19 years (range, 19 to 28 years) versus 30 years (range, 22 to 48 years) for those who did not regain function. Younger age at transplantation predicted ovarian recovery (P = .03) by means of a log-rank test. Only one of five women who regained ovarian function received total-body irradiation (TBI) compared with five of 12 women who did not. Univariate analysis suggested a trend for TBI to predict a sustained loss of ovarian function (P = .067). The number of regimens of induction or salvage chemotherapy that contained an alkylating agent ranged from none to five and was not predictive (P = .45). CONCLUSION: All women became menopausal after ABMT but 29% recovered ovarian function. Younger age at transplantation predicted return of ovarian function, whereas TBI may have had a negative effect.

Actuarial Analysis↗
PubMed1998

Efficient adenovirus-mediated gene expression in malignant human plasma cells: relative lymphoid cell resistance.

Although adenoviruses offer several potential advantages as gene transfer vectors, some hematopoietic cells, particularly lymphoid cells, are considered relatively resistant to adenovirus-mediated gene transfer. To examine the role of adenovirus-mediated gene transfer in the lymphoid malignancy multiple myeloma (MM), we used E1- and E3-deleted adenoviral vectors to infect myeloma and lymphoma cell lines and subsequently primary bone marrow plasma cells and lymphocytes from patients with MM. Adenoviral vectors expressing LacZ or luciferase (AdCA18) reporter genes were used initially. Subsequently, we studied adenoviral vectors expressing genes of potential value in therapeutic immunomodulation, i.e., CD80 (AdB7-1) and interleukin-2 (AdIL-2). A human plasma cell line (OCI-My5) infected with LacZ or AdB7-1 vectors expressed the corresponding gene product in 95% and 85% of exposed cells, respectively. Time course experiments indicated that maximum expression of adenoviral transgenes in plasma cells was reached 3 days after infection. IL-2 was detected in the supernatant of AdIL-2-infected plasma cells, was functional, and could be detected for at least 30 days after infection. In contrast, three lymphoma cell lines (OCI-Ly2, OCI-Ly13.2, and OCI-Ly17) were significantly less sensitive to adenovirus infection, with relatively low efficiencies of gene transfer even using high adenoviral titers: Surface CD80 expression (13-25% of infected cells) and positive LacZ staining (0-5% of infected cells). Indeed, expression of luciferase was 96-168 times higher in AdCA18-infected OCI-My5 cells than in the OCI-Ly2 lymphoma cell line. Similar patterns were observed in primary plasma cells and lymphocytes from 19 MM patient bone marrow samples. After infection with AdB7-1, increased levels of CD80 expression on CD38 bright bone marrow plasma cells were observed in 84% of patients, with a 33% average increase in the number of plasma cells expressing CD80. In contrast, although increased CD80 expression was also detected on AdB7-1-infected CD19+ B lymphocytes from 63% of the MM patients, an average of only 14% of the infected lymphocytes demonstrated increased expression of CD80. Circulating T lymphocytes could not be transduced with AdB7-1. The relative resistance of B and T lymphocytes to adenovirus-mediated gene transfer warrants further investigation. Adenoviral vectors can efficiently infect malignant plasma cells and may be useful vehicles for therapeutic gene transfer.

Adenoviridae↗
PubMed1998

Testicular plasmacytoma following chemical orchiectomy: potential role of hypogonadism in myeloma proliferation.

We present a case of a 55 year old man with multiple myeloma who underwent autologous stem cell transplantation and subsequently developed testicular myeloma. Testicular enlargement was observed only after treatment of an incidental prostatic adenocarcinoma with chemical orchidectomy at a time when myeloma was controlled systemically. A subsequent bilateral surgical orchiectomy revealed plasmacytoma in both testis. Enhanced production of B-lymphocytes after castration has been reported and implicates testosterone as a possible negative regulator of B-cell production. We propose that the androgen deficient state may have contributed to the development of plasmacytoma of the testes in our patient. The regulatory role of sex steroids in B-cell development is discussed.

Adenocarcinoma↗
PubMed1997

The National Cancer Data Base: report on kidney cancers. The American College of Surgeons Commission on Cancer and the American Cancer Society.

BACKGROUND: The National Cancer Data Base (NCDB) examining current time trends (1993) in stage of disease, treatment patterns, and survival of patients with kidney cancer are reported. METHODS: Five calls for data have yielded a total of 3,700,000 cancer cases for the years 1985 through 1993, including 8140 kidney cancer cases in 1988 and 10,617 in 1993 from hospital cancer registries across the U.S. These data represent 36% and 39% of all cases of kidney cancers diagnosed in the U.S. in 1988 and 1993, respectively. RESULTS: Three trends were observed. 1) Stage II disease is being diagnosed with increasing frequency. 2) There has been an overall increase in the frequency with which surgery alone is utilized as the primary treatment for patients with Stage I, II, and III disease; however, surgical treatment of patients with Stage IV kidney cancer has declined. 3) Partial nephrectomy rather than total nephrectomy is performed with increasing frequency as surgical treatment of patients with Stage I renal carcinoma. CONCLUSIONS: The NCDB data have important implications for analyzing cancer treatments and outcomes in the U.S. These data suggest that kidney cancers are being diagnosed at an earlier stage and with greater precision. As a result, changes in surgical practice are apparent in the treatment of patients with lower stage disease (Stage I and II). Stage for stage, surgery remains the most effective form of treatment for patients with kidney cancer.

Aged↗
PubMed1997

Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation.

BACKGROUND: The role of intensive chemotherapy with autologous blood and marrow transplantation (ABMT) for patients with relapsed or refractory intermediate grade non-Hodgkin's lymphoma has recently been established. However, conventional dose salvage chemotherapy is frequently used to determine chemotherapy sensitivity and reduce tumor bulk prior to intensive therapy. Different salvage regimens have been proposed but none appears significantly superior. The purpose of this study was to determine the efficacy of mini-BEAM salvage chemotherapy in patients referred for AMBT and to define prognostic factors of response. PATIENTS AND METHODS: One hundred four patients referred for consideration of AMBT after failure of primary anthracycline-based chemotherapy received BCNU 60 mg/m2 day 1, etoposide 75 mg/m2 day 2-5, ara-C 100 mg/m2 q12 h day 2-5, melphalan 30 mg/m2 day 6 (mini-BEAM) until maximum tumor reduction. Median age was 52 (range 18-65), 57% had failed to achieve a complete response (CR) to doxorubicin-based chemotherapy at diagnosis and only 13% had a previous CR lasting > 12 months. Seventy-six received mini-BEAM as first salvage chemotherapy. RESULTS: The overall response rate (RR) was 37% (95% confidence interval (CI) 28-46%) with 12 patients achieving CR and 25 achieving PR. The response rate among patients treated as first salvage was 43% compared to 20% for patients who had failed to respond to a previous salvage regimen. Only 15% of patients who failed to respond to mini-BEAM responded to another conventional dose salvage regimen. Thirty-eight of 104 patients ultimately demonstrated sufficient response to proceed to ABMT. Actuarial survival at four years is 22% for all 104 patients, and 36% for those who went on to AMBT. For those who were not transplanted, four-year survival was 18%. B symptoms and tumor burden at relapse were significant predictors of response to mini-BEAM in multivariate analysis, and identified a poor prognosis group of patients unlikely to be cured by the approach. CONCLUSIONS: Mini-BEAM does not appear to be a superior salvage regimen in this high-risk group of relapsed or refractory NHL patients for whom ABMT was the ultimate treatment intention. Only one-third of patients referred for ABMT ultimately proceed to transplant; alternative treatment strategies should be developed for those with a low likelihood of cure by this approach.

Adolescent↗
PubMed1997

Autologous and allogeneic transplantation for multiple myeloma at a single centre.

We report the results of a consecutive series of patients who underwent autologous (auto) (40), allogeneic (allo) (22) or syngeneic transplantation (2) for multiple myeloma (MM) at our centre. Median age at diagnosis was 45.5 (auto) and 43 (allo) years. Most patients had stage 2 (27% auto; 27% allo) or stage 3 (62% auto; 50% allo) disease and 73% demonstrated chemosensitivity prior to transplant. Median time from diagnosis to transplant was 18.6 months (auto) and 16.4 months (allo). Standard conditioning regimens were used. Median time to neutrophil engraftment was 11 days (7-18) (auto) and 18 days (13-24) (allo) and median time to platelet engraftment was 11 days (6-60) and 18 days (13-105), respectively. Ninety-day mortality was 5% (auto) and 27% (allo). Median follow-up was 15 months (6-48) (auto) and 42 months (24-52) (allo). Three-year progression-free survival (PFS) was 17 +/- 10% (auto) and 22 +/- 9% (allo) and 3-year overall survival (OS) was 74 +/- 11% (auto) and 32 +/- 10% (allo). Autologous transplantation for MM is a safe procedure with good OS although disease progression following transplant is frequent. Allogeneic transplantation has a high procedure-related mortality and PFS comparable to autologous transplantation but OS is poor. The early mortality and high OS of autologous transplantation in MM compares favourably with both the results of allogeneic transplantation and published results of standard therapy in this retrospective analysis.

Adult↗
PubMed1997

A phase I study of interleukin-6 after autologous bone marrow transplantation for patients with poor prognosis Hodgkin's disease.

We performed a pilot study of human recombinant IL-6 (SDZ ILs 969) in 6 patients with poor prognosis Hodgkin's disease following autologous bone marrow transplantation (ABMT) to determine its safety and tolerability. IL-6 was administered the day following bone marrow infusion by subcutaneous injection once daily at a dose of 1 micro/kg/day to 3 patients and 2.5 microg/kg/day to 3 patients and was continued for 6 weeks or until platelet engraftment (>50 x 10(9)/L independent of transfusion). No severe or life threatening toxicities were seen at either dose level. A reversible elevation in alkaline phosphatase occurred in 4 patients and all patients complained of headache, myalgias, and fever. Gastrointestinal toxicity was low, grade 3-4 mucositis occured less frequently than in similarly-treated historical controls receiving GM-CSF. Serum concentrations of other cytokines such as IL-3 and G-CSF after ABMT differed from results obtained in transplant recipients given GM-CSF. The median time to an ANC >0.5 x 10(9)/L was 25.5 days and to a platelet count of >20 x 10(9)/L independat of transfusion was 35.5 days. Engraftment was no different from controls. Five patients relapsed at a median of 5 months post-ABMT and four remain alive at a median of 12 months post-ABMT. We conclude that IL-6 administration is safe and well tolerated in patients following ABMT. Further efforts to evaluate its effect on hematopietic recovery as well as relapse following transplantation in a larger patient series are warranted.

Adult↗
PubMed1997

Castleman's disease in a 44-year-old male with neurofibromatosis and pheochromocytoma.

A case of Castleman's disease in a patient with type I neurofibromatosis and pheochromocytoma is reported. The association of pheochromocytoma and neurofibromatosis is well documented, but uncommon. Castleman's disease has not been previously documented in a patient with neurofibromatosis or pheochromocytoma and may represent a previously unrecognized association of this disease. Castleman's disease is an interleukin-6 (IL-6) mediated B-cell proliferation. We postulate a relationship between pheochromocytoma IL-6 secretion and Castleman's disease. The relevant literature relating to this unusual case is reviewed.

Adrenal Gland Neoplasms↗
PubMed1997

Role of splenectomy in gastric cancer surgery: adverse effect of elective splenectomy on longterm survival.

BACKGROUND: Splenectomy, and in some cases pancreatico splenectomy, has been advocated by surgeons in an effort to improve clearance of metastatic nodes to splenic hilum (node 10) and splenic artery (node 11). Although splenectomy has known effects on increasing morbidity and even mortality after a variety of surgical maneuvers including gastrectomy, the longterm effect on survival is controversial. The purpose of this study is to review and analyze the effect of splenectomy on survival in patients having curative gastrectomy for stomach cancer. METHODS: We reviewed the role of splenectomy in patients having curative gastrectomy in a data base of stomach cancer patients that had been collected in 1987 as part of an American College of Surgeons Patterns of Care Study. This analysis had involved 18,344 patients, of whom 11,252 were first diagnosed in 1982 as part of a longterm study, and 7,092 were first diagnosed in 1987 as part of a shortterm study. From the two data collection periods information was available on 12,439 patients who received cancer directed abdominal surgery; 21.2% of these patients received a splenectomy. Among the 3,477 patients reported as having a curative gastrectomy (pathologically clear margins), 26.2% received a splenectomy. RESULTS: The operative mortality was 9.8% with splenectomy and 8.6% without splenectomy. In patients having a curative gastrectomy, the 5-year observed survival rate was 20.9% in patients having splenectomy versus 31% in patients who did not receive splenectomy (p < 0.0001). Examination of differences in survival by stage of diagnosis showed significantly reduced survival outcomes among patients with stage II and III, but not for those diagnosed with stage I or IV disease. The pattern of recurrence was moderately different with a larger proportion of patients having distant metastases among the group of patients who had undergone splenectomy compared with the patients who had not, 29% and 15.5%, respectively. Whether these differences are inherent in the splenectomy or in the associated cofactors was not determined in this study. CONCLUSIONS: The data suggest elective splenectomy should generally be avoided in patients with stage II and III gastric cancer. In patients with resectable proximal advanced (stage IV) cancer or who have extension to spleen and pancreas or macroscopic nodal metastases to splenic hilum, splenectomy might be necessary to facilitate complete removal of the tumor in an effort to achieve longterm tumor control. The importance of surgical judgment is emphasized as the major deciding factor in determining the need for splenectomy in the individual cancer patient.

Elective Surgical Procedures↗
PubMed1996

Preclinical assessment of human hematopoietic progenitor cell transduction in long-term marrow cultures.

Long-term marrow cultures (LTMCs) were established from 27 human marrows. Hematopoietic cells were subjected to multiple rounds of exposure to retroviral vectors during 3 weeks of culture. Seven different retroviral vectors were evaluated. LTMCs were assessed for viability, replication-competent retrovirus, progenitors capable of proliferating in immune-deficient mice, and gene transfer. The average number of adherent cells and committed granulocyte-macrophage progenitors (CFU-GM) recovered from LTMCs was 28% and 11% of the input totals, respectively. There was no evidence by marker rescue assay or polymerase chain reaction (PCR) of replication-competent virus production during LTMC. No toxicity to cellular proliferation due to the transduction procedure was observed. The adherent layers of LTMCs exposed to retroviral vectors were positive for proviral DNA by PCR and by Southern blot analysis. Fifty-three percent of 1,427 individual CFU-GM from transduced LTMC adherent layers were positive for vector-derived DNA. For neocontaining vectors, the average G418 resistance was 28% of 1,393 LTMC-derived CFU-GM. Forty percent of 187 tissues from 30 immune-deficient mice injected with human LTMC cells were positive for human DNA 4-5 weeks after adoptive transfer. These studies indicate that multiple exposures of human LTMCs to retroviral vectors result in consistent and reproducible LTMC viability and gene transfer into committed progenitors. Our results further support the use of transduced LTMC cells in clinical trials of hematopoietic stem cell gene transfer.

Animals↗
PubMed1996

The National Cancer Data Base report on bladder carcinoma. The American College of Surgeons Commission on Cancer and the American Cancer Society.

BACKGROUND: Previous Commission on Cancer Data from the National Cancer Data Base (NCDB) have examined time trends in stage of disease, treatment patterns, and survival for selected cancers. The most current (1993) data relating to patients with bladder carcinoma are described here. METHODS: Five calls for data have yielded a total of 3,700,000 cases for the years 1985 through 1993, including 447,679 cases for 1988 and 608,593 cases for 1993, from hospital cancer registries across the U.S. Data were received on 18,053 bladder carcinoma cases in 1988 and 22,606 cases in 1993. RESULTS: Interesting trends are 1) younger patients (49 years of age and younger) present with earlier stages of disease than do older patients; 2) women are slightly more likely to be diagnosed with later stages (II, III, and IV) of bladder carcinoma than men; 3) African Americans are less likely to be diagnosed with Stage 0 or Stage I disease than either Hispanic or non-Hispanic whites; and 4) National Cancer Institute designated centers treat more patients with advanced disease than do other types of hospitals. CONCLUSIONS: The NCDB data are important for analyzing what cancer treatments and outcomes are used and occurring in the country. The data suggest that African Americans are diagnosed at later stages of disease progression. The relative survival rates among African Americans are lower than among Hispanics or non-Hispanic whites. Also, the decreasing utility of adjuvant chemotherapy is being recognized.

Adult↗