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Biomedical subjects

L C Stephens

Publications and source records attributed to L C Stephens.

At least 55 records · Page 3Linked to original sources
PubMed1996

Apoptosis and downstaging after preoperative radiotherapy for muscle-invasive bladder cancer.

PURPOSE: To determine the relationship between pretreatment apoptosis levels and clinical-to-pathologic downstaging resulting from preoperative radiotherapy. METHODS AND MATERIALS: Between 1960-1983, 338 patients were dispositioned to receive preoperative radiotherapy 4-6 weeks prior to radical cystectomy for muscle-invasive transitional cell carcinoma of the bladder. Of these, adequate hematoxylin and eosin stained tissue sections for morphologic analysis of apoptosis were available in 158 patients. These patients were treated to a median dose of 50 Gy at 2 Gy per fraction. Median follow-up was 90 months. The apoptotic index (AI) was calculated from the ratio of the number of apoptotic cells divided by the total counted and multiplied by 100. A minimum of 500 cells were counted from each patient. RESULTS: The average AI for the whole group (n = 158) was 2.0 +/- 1.3 (+/- SD), with a median of 1.8. The association of AI to clinical stage was significant with AI averages of 1.8 for Stage T2 (n = 56), 1.9 for T3a (n = 51), and 2.4 for T3b (p = 0.038, Kendall Correlation). The relationship of AI to radiotherapy response also was significant with an average of 2.2 for those who were downstaged (n = 103), 1.9 for those in whom the stage remained unchanged (n = 20), and 1.7 for those who were upstaged (n = 35, p = 0.054, Kendall Correlation). The other significant correlations with AI were for the factors, grade, mitotic index, number of tumors, and gender. The AI was then categorized into three groups ( < or = 1, > 1, and < or = 3, and > 3) to examine the prognostic significance of this parameter. The distributions of patients by clinical stage, grade, mitotic index, number of tumors, radiotherapy response, and hemoglobin level were significantly associated with AI using this grouping. When the analysis of the distribution of patients by radiation response and AI was segregated by stage, a significant correlation was observed only for those with Stage T3b disease (p = 0.006); 93% of T3b patients with an AI > 3 were downstaged, while in 7% the stage remained unchanged and none were upstaged. The relationship of AI to 5-year actuarial patient outcome was investigated using several end points and although no significant correlations were observed, a trend was seen for improved survival when AI was > 3 (71% vs. 41%, p = 0.09) for Stage T3b patients. CONCLUSION: The AI correlated most strongly with radiotherapy response for patients with clinical stage T3b disease, the one subgroup of patients wherein preoperative radiotherapy is likely to be of the most benefit. Further investigation of pretreatment apoptosis levels as a marker of anticancer response is needed, especially for patients treated with chemotherapy and radiotherapy with the goal of bladder preservation.

Aged↗
PubMed1996

Radiation-induced apoptosis in normal and pre-neoplastic mammary glands in vivo: significance of gland differentiation and p53 status.

The tumor suppressor gene p53 maintains the integrity of the genome by stimulating apoptosis in cells that have sustained DNA damage. The p53 gene is frequently altered in human cancers, including breast cancer, and such alterations are thought to result in genomic instability and aneuploidy, 2 hallmarks of anaplastic cells. We used radiation as a DNA-damaging agent to test the role of p53 in controlling apoptosis propensity in pre-neoplastic mammary lesions in mice. Four different pre-neoplastic mammary outgrowth lines, D1, TM2H, TM4 and TM12, were maintained by serial transplantation in the cleared mammary fat pads of syngeneic BALB/c mice. These lines have known alterations in p53 expression: TM12 has normal expression, D1 over-produces wild-type protein, TM2H contains a deletion resulting in a null phenotype and TM4 produces a mutant protein. Mice bearing the various outgrowths were irradiated with 5 Gy, and apoptosis was scored by examination of histological sections prepared from the outgrowths 6 hr after irradiation. The TM12 outgrowths, but not the TM2H outgrowths, exhibited radiation-induced apoptosis. The D1 and TM4 lines expressed radiation-induced apoptosis while the fat pads were being repopulated; however, the induced apoptosis declined to low levels as the mice aged. These results are consistent with the hypothesis that normal p53 function is important if mammary cells with DNA damage are to be deleted by apoptosis.

Animals↗
PubMed1996

Visual laser ablation of the canine prostate with a diffusing fiber and an 805-nanometer diode laser.

BACKGROUND AND OBJECTIVE: Although the popularity of visual laser ablation of the prostate (VLAP) as a treatment for symptomatic, benign prostatic hyperplasia (BPH) is increasing, the perceived advantages of VLAP over conventional transurethral electroresection of the prostate (TURP) is being debated because optimal technique and dosimetry for surgical lasers are still being refined. At this time, the 1.06 neodymium:yttrium-aluminum-garnet (Nd:YAG) laser and a laterally deflecting delivery system is the hardware combination most widely used for VLAP. STUDY DESIGN/MATERIALS AND METHODS: Reported here is a study of an alternate system, a 805-nm diode laser (Diomed 25 Diomedics, The Woodlands, TX) with a cylindrically diffusing fiber (Surgimedics Inc., The Woodlands, TX). Eight mongrel dogs were prostatectomized by transurethral irradiation of the prostate with 15,000 J of diode laser energy delivered via a fiber that diffuses the energy in a 1.5-cm-long cylindrical pattern. The dogs were sacrificed and prostates harvested at 3 hours and 1,4,7,14,21,35, and 49 days after the procedure, fixed with 10% buffered formalin, and examined histologically. RESULTS/CONCLUSIONS: It was found that this laser/fiber combination created volumes of tissue coagulation similar to those encountered in our previous work with the Nd:YAG laser in combination with both laterally deflecting and diffuser fibers, while offering the distinct advantages of simplified technique, lower cost hardware, and fewer postoperative complications in the dog model.

Animals↗
PubMed1996

Programmed cell death and radioresistance.

Whereas apoptosis is a critical mode of cell deletion in normal organism development, apoptotic cells are also observed in tumors, especially following cytotoxic treatments, leading to questions about their role in tumor response to therapy. We have conducted a series of studies using murine tumor models and found that the ability of the tumor cells to undergo apoptosis correlates with tumor response to radiation. The best correlation was with the pretreatment apoptotic index, suggesting that apoptosis in some tumors may govern radiocurability by regulating the number of tumor clonogens. However, other roles for apoptosis in tumor response to radiation have not been ruled out. One of the important observations that has come from this work has been the heterogeneity in apoptosis propensity both within the cell population of a given tumor and among different types of tumors. Such findings underscore the fact that apoptosis is under complex genetic control and that some of the same oncogenes and tumor suppressor genes that are responsible for tumor initiation and progression to malignancy also dictate the apoptotic response to treatment. Understanding the biochemical and molecular pathways that govern this process may ultimately allow the development of strategies for modulating apoptosis for therapeutic benefit.

Animals↗
PubMed1996

Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.

A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.

Aged↗
PubMed1996

Strain difference in jejunal crypt cell susceptibility to radiation-induced apoptosis.

Levels of radiation-induced jejunal crypt cell apoptosis were compared in C57BL/6J, C3Hf/Kam and C3H/HeJ mice. Apoptosis levels were consistently lower in the C3H strains than in C57BL/6J. Although other explanations are possible, the strain difference is most likely to have a genetic basis, and in fact a preliminary analysis of the F2 progeny of C3H/HeJ and C57BL/6J mice indicates that more than one gene is involved. Both C3H strains also had lower levels of radiation-induced thymocyte apoptosis than C57BL/6J mice. Jejunal crypt cell apoptosis levels did not co-segregate with thymocyte apoptosis levels in the F2 progeny of C57BL/6J and C3H/HeJ mice. These results imply that the genes responsible for the difference in radiation-induced thymocyte apoptosis levels between these two strains are not the same as those responsible for the strain difference in radiation-induced jejunal crypt cell apoptosis levels. The experiments reported here identify strain-specific differences in levels of radiation-induced crypt cell apoptosis and are a first step towards identifying genetic polymorphisms that influence sensitivity of the small intestine to damage from ionizing radiation.

Analysis of Variance↗
PubMed1996

Silver iontophoretic catheter: a prototype of a long-term antiinfective vascular access device.

A silver iontophoretic catheter (SIC) was developed consisting of two electrically charged parallel silver wires helically wrapped around the proximal segment of a vascular catheter. In vitro and in vivo activities of this catheter were compared with those of an aseptic catheter coated with chlorhexidine and silver sulfadiazine (CH/SS). The SIC demonstrated broad-spectrum in vitro inhibitory activity against bacteria and Candida albicans comparable to that of the CH/SS-coated catheter. The durability of activity was determined by incubating catheters in serum at 37 degrees C for various time intervals. After 30 days, the antimicrobial activity of the SIC did not change significantly, while that of the CH/SS-coated catheter was reduced to a suboptimal level. In a rabbit model, the SIC was safe and significantly more efficacious than the CH/SS-coated catheter in preventing colonization with Staphylococcus aureus (P < .05). The SIC has broad-spectrum inhibitory activity of long durability and is highly efficacious in preventing colonization in vivo.

Animals↗
PubMed1996

Glioblastoma multiforme arising in the irradiated spinal cord of a rhesus monkey (Macaca mulatta).

An adult female rhesus monkey that had received 44.0 Gy of cobalt 60 radiation to 8 cm of the cervical and upper thoracic spinal cord approximately 2.8 years postirradiation developed a sudden onset of self-mutilation and loss of function of the right arm followed progressively by loss of function of the left arm and terminally bilateral paresis of the legs. Histopathologic examination of the cervical spinal cord revealed a glioblastoma multiforme that extended from the cervical medullary junction to the sixth cervical vertebrae. Because of the infrequent occurrence of spontaneous neoplasia in rhesus monkeys and the location in the radiation field, the glioblastoma is believed to be radiation induced.

Animals↗
PubMed1996

Associations between lymphocytic thyroiditis, hypothyroidism, and thyroid neoplasia in beagles.

The thyroids were evaluated in 276 control Beagles that were allowed to live out their full life span (mean = 12 years) in a closed breeding colony. Lymphocytic thyroiditis was found in 26.3% of the dogs. This lesion was characterized by lymphoplasmacytic inflammation accompanied by follicular destruction. The thyroiditis was progressive, resulting in severe atrophy of follicular tissue, and 44 dogs (15.9%) were diagnosed as hypothyroid at the time of death. In accordance with the experimental protocol, hypothyroid dogs were not given thyroxine replacement therapy. There was a high degree of heritability for the hypothyroidism. Hypothyroid dogs had an increased risk for thyroid follicular epithelial neoplasia and, in particular, for follicular adenocarcinomas. Twenty-four of the 44 hypothyroid dogs (54.5%) had one or more follicular thyroid neoplasms, whereas only 53 of the 232 (22.8%) clinically euthyroid dogs had similar tumors. Multiple thyroid tumors were present in 14 of the 44 (31.8%) hypothyroid dogs but in only 12 of the 232 (5.2%) euthyroid dogs. One or more follicular adenocarcinomas were present in 15 of the 44 (34.1%) hypothyroid dogs but in only 16 of the 232 (6.9%) euthyroid dogs. There was no difference in prevalence of hypothyroidism or tumors between the sexes. The strong association between progressive lymphocytic thyroiditis, hypothyroidism, and thyroid follicular neoplasia in these Beagles probably relates to promotion of residual follicular epithelium by chronic excess thyrotropin stimulation.

Adenoma↗
PubMed1996

Genetic basis of strain variation in levels of radiation-induced apoptosis of thymocytes.

Levels of radiation-induced apoptosis of thymocytes were compared in C57BL/6J and C3Hf/Kam mice. For up to 8 h after irradiation, levels of apoptosis were higher in the C57BL/6J strain for all doses assayed. The heritability of the strain difference in the extent of apoptosis resulting from irradiation was investigated using a breeding study. Analysis of the F1 and F2 intercross progeny of these two strains provided strong evidence for a maternal effect but little evidence of sex linkage. The results indicate that in this strain combination the level of apoptosis of thymocytes after irradiation is a heritable trait that is likely to be controlled by few genes. These genes should be detectable in a mapping study.

Animals↗
PubMed1996

Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat.

We assessed the effects of 41 potential chemopreventive agents in the F344 rat using the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon as the measure of efficacy. ACF were induced by the carcinogen azoxymethane in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last azoxymethane injection, animals were evaluated for the number of aberrant crypts detected in methylene blue-stained whole mounts of rat colon. The 41 agents were derived from a priority listing that was based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. The list of agents included representative examples of phytochemicals, vitamins, minerals, inhibitors of proliferation, inducers of Phase 1 and Phase 2 metabolism systems, nonsteroidal anti-inflammatory agents, and differentiation agents. Eighteen agents were positive in the assay, significantly reducing the incidence of ACF at least in one of two doses tested. As a chemical class, the nonsteroidal anti-inflammatory drugs, which included ibuprofen, ketoprofen, piroxicam, and indomethacin, were most active; other less potent agents were arginine, butylated hydroxyanisole, curcumin, diallyl sulfide, difluoromethylornithine, 18 beta-glycyrrhetinic acid, indole-3-carbinol, oltipraz, purpurin, rutin, and the sodium salts of butyrate, selenite, and thiosulfate. Twenty-three agents did not inhibit ACF; included among these were several agents that promoted the development of ACF at one or both doses tested: benzyl isothiocyanate,calcium glucarate, catechin, dihydroepiandosterone, fluocinolone acetonide,folic acid, levamisole, 2-mercaptoethanesulfonic acid, nordihydroguiaretic acid, potassium glucarate, propyl gallate, beta-sitosterol, sodium cromolyn, sodium molybdate, and sulfasalazine. The aberrant crypt assay demonstrates reasonable specificity and sensitivity in predicting which agents are likely to prevent colon cancer.

Animals↗
PubMed1996

Increased apoptosis accompanies neoplastic development in the human colorectum.

A disturbance in the balance between cell proliferation and cell loss, or apoptosis, may underlie neoplastic development. Therefore, we determined spontaneous apoptotic and proliferative rates in normal, hyperplastic, adenomatous, and malignant colorectal epithelia. In paired sections, DNA strand breaks were detected using the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, and apoptotic cells were also identified in H&E-stained slides by morphological criteria. Cell proliferation, bcl-2, and p53 expression were analyzed using specific monoclonal antibodies. In normal mucosa, luminal epithelial cells demonstrated higher rates of apoptosis compared to cells in the proliferative zone. Neoplastic transformation was associated with a significant increase in rates of apoptosis and proliferation. However, apoptosis, but not proliferation, decreased at the adenoma-to-carcinoma transition coincident with expression of mutant p53. In carcinomas, both mutant p53 and bcl-2 protein levels were associated with attenuated apoptotic rates. In conclusion, apoptosis is an important regulator of growth in normal and neoplastic colorectal epithelia. Increased apoptosis and proliferation accompany neoplastic transformation, suggesting that an alteration in apoptotic rates is an important event in colorectal carcinogenesis. Furthermore, the imbalance in these processes found in carcinomas may facilitate tumor growth and progression.

Apoptosis↗
PubMed1995

Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats.

Apoptosis in tumor and normal tissues was examined in rats treated with whole-body hyperthermia (WBH; 41.5 degrees C for 2 h). WBH alone produced 0.5 day of tumor growth delay (TGD) in a fibrosarcoma and 5.8 days of TGD in the Ward colon carcinoma. This difference in WBH-induced TGD indicates that the fibrosarcoma is relatively resistant to WBH, whereas the Ward colon carcinoma is relatively heat sensitive. A quantitative histological assay for apoptosis demonstrated that the extent of apoptosis in the fibrosarcoma reached a maximum level of 19% 4 h after WBH and returned to the control level by 24 h. In contrast, WBH induced apoptosis with a peak value of 43% at 8 h in the Ward colon carcinoma, and the apoptotic level remained elevated above the control level until 48 h after WBH. Within normal tissues, the spleen and the lymph nodes showed WBH-induced apoptosis; however, the highest level of WBH-induced apoptosis as well as the most prolonged increase in apoptotic levels occurred in the thymus. The WBH-induced apoptosis in the thymus remained elevated above the control level until 48 h after WBH. Within the entire gastrointestinal tract, the small intestine was the most sensitive to WBH. Apoptotic cells were observed in the small bowel mucosa following WBH exposure. We also noted a minor WBH-induced increase in the apoptotic level in the bone marrow. Except for the case of the thymus, increased apoptotic levels in the normal tissues declined after peak levels at 4 h, and apoptosis above control levels was not seen beyond 12 h following WBH. Thus, within the normal tissues, WBH-induced apoptosis declined to basal levels within 12-48 h. These data indicate that both the extent and the kinetics of WBH-induced apoptosis differ between the two tumors and, meaningfully, between tumor and normal tissues. The extent and duration of apoptosis seem to correlate with tumor response to WBH.

Animals↗
PubMed1995

Multiple organ dysfunction syndrome in bone marrow transplantation.

OBJECTIVE: To define the frequency and outcome of organ dysfunction in bone marrow transplantation (BMT) and to determine if patients with organ dysfunction have lower levels of protein C (PC) and/or antithrombin III (ATIII) than those without organ dysfunction. DESIGN: Inception cohort of patients undergoing BMT, followed for 28 days, until hospital dismissal, or until death. SETTING: Bone marrow transplant department of a university hospital. PATIENTS: A total of 199 consecutive patients admitted for BMT. INTERVENTIONS: Standard supportive care was given to all patients. MAIN OUTCOME MEASURES: Definitions of organ dysfunction were arrived at prior to beginning the study. They include pulmonary, central nervous system (CNS), hepatic, and renal dysfunction. Protein C and ATIII levels were measured prior to beginning the preparative regimen and weekly thereafter. RESULTS: Single organ dysfunction, manifesting as pulmonary, CNS, or hepatic dysfunction, occurred in 93 (48.5%) of the 199 patients and was a strong predictor of multiple organ dysfunction syndrome (MODS) and death. Death occurred in 14 (7.0%) of the patients. Cause of death was precisely identified in only four patients. Low levels of either PC or ATIII were associated with death and pulmonary, CNS, and hepatic dysfunction. Multivariate analysis showed ATIII and PC levels were associated with single organ dysfunction independent of the type of transplant, the type of preparative regimen, and the presence of bacteremia. CONCLUSIONS: Single organ dysfunction during BMT is a marker for a systemic abnormality that has a high likelihood of progressing to MODS, similar to that seen in other critically ill patient populations. MODS is the leading cause of death in series of BMT patients. Low levels of ATIII and PC are markers of and may be involved in the pathogenesis of MODS in BMT.

Adolescent↗
PubMed1995

ASTRO Research Fellowship: apoptosis as a predictor of tumor response to radiation in stage IB cervical carcinoma. American Society for Therapeutic Radiology and Oncology.

PURPOSE: Levels of apoptosis predict for tumor responsiveness to radiation in various animal systems. To investigate the potential role of apoptosis as a predictor of response in human tumors, a retrospective review was undertaken of patients with adenocarcinoma of the cervix whose primary lesion at presentation measured at least 4 cm and who underwent definitive radiation therapy. A previous report had indicated that roughly half this group of patients should have a long-term relapse free survival. METHODS AND MATERIALS: Pretreatment biopsy specimens of 44 patients with Stage IB adenocarcinoma of the cervix, whose primary lesion at presentation measured at least 4 cm in greatest dimension, were scored for apoptosis by two independent investigators without knowledge of the treatment outcome, and the results were averaged. Actuarial methods were used to assess overall survival, disease-free survival, determinate survival, and local control as a function of the baseline level of apoptosis. Patients ranged in age from 21 to 87 years and were treated with definitive radiotherapy between 1964 and 1989. Follow-up for the surviving patients ranged from 1 to 278 months, with a mean of 101 months. RESULTS: Patients whose tumors had a baseline level of apoptosis above the median value (2%) had a better overall survival than those with lower levels of apoptosis (p = 0.056). A similar trend for disease-free survival (p = 0.32) and determinate survival (p = 0.27) did not reach statistical significance, perhaps because of the small number of patients. Because only 6 of the 44 patients (13%) had a local tumor failure, it was not possible to establish a correlation between the pretreatment level of apoptosis and the local tumor control by radiation. CONCLUSION: The baseline level of apoptosis predicted for survival in patients with Stage IB cervical adenocarcinoma. Further investigation of the measurement of apoptosis as a potential predictive assay is warranted in other human tumor systems.

Adenocarcinoma↗