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Biomedical subjects

David S Alberts

Publications and source records attributed to David S Alberts.

At least 37 records · Page 2Linked to original sources
PubMed2005

Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers.

Most women with epithelial ovarian cancer are diagnosed with advanced disease. Despite surgery and initial tumor reduction by standard chemotherapy, the tumors frequently recur and the patients eventually die of their disease. New drugs that inhibit tyrosine kinase receptors (TKRs) are being investigated for treatment and this study was undertaken to determine the expression and mutational state for 3 TKRs (c-kit, platelet-derived growth factor receptor [PDGFR] alpha, and PDGFR beta) in ovarian cancer. Tissue arrays containing 84 epithelial ovarian tumors were studied by immunohistochemistry with antibodies specific for c-kit, PDGFR alpha, and PDGFR beta. Immunoreactivity was detected in 78% of the tumor to at least one TKR. PDGFR alpha was expressed in the largest percentage of ovarian tumors (58%) whereas 29% expressed PDGFR beta. Two commercial antibodies against c-kit were studied and 33% of the tumors stained with one but only 6% were interpreted as positive with the second antibody. Activation of TKRs may occur through mutations but, by sequence analysis, no mutations were detected in 6 ovarian tumors with elevated immunoreactivity for each of the TKRs (c-kit, PDGFR alpha, and PDGFR beta). Tyrosine kinase receptors could also be activated through autocrine or paracrine stimulation of receptor by its ligand. Of 43 (35%) tumors tested for both c-kit receptor and its ligand (stem cell factor), 15 expressed both proteins indicating the possibility that this autocrine stimulation feedback loop is a factor in the growth of some ovarian cancers. This study demonstrates that PDGFR alpha, PDGFR beta, and c-kit are expressed in a high percentage of epithelial ovarian cancers suggesting that tyrosine kinase inhibitors may be useful in the treatment of these tumors.

Adenocarcinoma↗
PubMed2005

Role of pegylated liposomal doxorubicin in ovarian cancer.

OBJECTIVES: Safe, effective treatments are needed for relapsed ovarian cancer. Goals include improving symptoms, enhancing quality of life, and prolonging survival. The plethora of agents currently available present difficult choices for physicians. The present effort seeks to examine the role of one of these agents, pegylated liposomal doxorubicin. METHODS: A roundtable meeting of experts in the management of ovarian carcinoma was held to build consensus around the present and future role of pegylated liposomal doxorubicin for ovarian cancer and other gynecologic malignancies. RESULTS: Pegylated liposomal doxorubicin is effective and well tolerated in relapsed ovarian cancer. When compared with topotecan in a phase III randomized trial, pegylated liposomal doxorubicin showed several advantages: improved quality of life, fewer severe adverse events, fewer dose modifications, less hematologic support, and lower total cost per patient. In platinum-sensitive patients, pegylated liposomal doxorubicin also produced a survival advantage. Results from prospective and retrospective studies further demonstrate the improved cardiac safety of pegylated liposomal doxorubicin compared to conventional anthracyclines. CONCLUSIONS: Based on survival and toxicity advantages and a once-monthly administration schedule, pegylated liposomal doxorubicin is the first-choice nonplatinum agent for relapsed ovarian cancer. Pegylated liposomal doxorubicin may also have clinical application in combination regimens for platinum-sensitive ovarian cancer, as consolidation/maintenance therapy for ovarian cancer, as a component of first-line therapy for ovarian cancer, and in the treatment of other gynecologic malignancies. Future clinical trials will further define and maximize the role of pegylated liposomal doxorubicin in the treatment of ovarian cancer and other gynecologic malignancies.

Antibiotics, Antineoplastic↗
PubMed2005

Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial.

OBJECTIVE: To retrospectively analyze data from a previously reported randomized trial of either pelvic radiation (RT) or RT + chemotherapy (CT) in patients undergoing radical hysterectomy and pelvic lymphadenectomy with positive pelvic lymph nodes, parametrial involvement, or surgical margins; to explore associations between RT + CT; and to investigate histopathologic and clinical factors which might be predictive of recurrence. METHODS: Histopathologic sections from biopsies and hysterectomies and clinical data were reviewed from patients with stage IA2, IB, or IIA cervical cancer treated with RT or RT + CT (cisplatin 70 mg/m2 plus fluorouracil 1000 mg/m2 every 3 weeks for four cycles). A univariate analysis was performed because the relatively small sample size limited the interpretation of a multivariate analysis. RESULTS: Of the 268 enrolled women, 243 (RT = 116; RT + CT = 127) were evaluable. The beneficial effect of adjuvant CT was not strongly associated with patient age, histological type, or tumor grade. The prognostic significance of histological type, tumor size, number of positive nodes, and parametrial extension in the RT group was less apparent when CT was added. The absolute improvement in 5-year survival for adjuvant CT in patients with tumors < or =2 cm was only 5% (77% versus 82%), while for those with tumors >2 cm it was 19% (58% versus 77%). Similarly, the absolute 5-year survival benefit was less evident among patients with one nodal metastasis (79% versus 83%) than when at least two nodes were positive (55% versus 75%). CONCLUSIONS: In this exploratory, hypothesis-generating analysis, adding CT to RT after radical hysterectomy, appears to provide a smaller absolute benefit when only one node is positive or when the tumor size is < 2 cm. Further study of the role of CT after radical hysterectomy in patients with a low risk of recurrence may be warranted.

Adenocarcinoma↗
PubMed2005

Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the Southwest Oncology Group.

OBJECTIVES: To evaluate the response rate and progression free and overall survival of patients with advanced endometrial cancer treated with paclitaxel, carboplatin and amifostine. To evaluate the toxicity of amifostine when used in combination with carboplatin and paclitaxel. METHODS: Forty-seven eligible patients (median age: 66; range 45-82) with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/M2) and amifostine (740 mg/M2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity. RESULTS: There were 4 CRs (8%) (2 confirmed, 2 unconfirmed) and 15 PRs (32%) (9 confirmed, 6 unconfirmed) for a total response rate of 40% (95% confidence interval [CI], 26% to 56%). The median progression-free survival (PFS) was 7 months (95% CI, 6-9 months) and a 6-month PFS rate of 64% (95% CI, 50% to 78%). The median overall survival was 14 months (95% CI, 12 to 17 months). Toxicity was tolerable. While 79% of patients developed Grade 3/4 neutropenia (30% Grade 3, 49% Grade 4), there were no episodes of Grade 4 febrile neutropenia and one episode of infection with grades 3-4 neutropenia. CONCLUSION: The combination of paclitaxel and carboplatin with amifostine was well reasonably tolerated in this cohort. The regimen demonstrated significant activity in endometrial cancer, comparable to other multi-agent chemotherapy programs in terms of response rate and survival, and with a favorable toxicity profile.

Adenocarcinoma↗
PubMed2005

Exploratory study of ovarian intraepithelial neoplasia.

PURPOSE: This was an exploratory study to test two hypotheses related to potential epithelial precursors to ovarian cancer: (a) histologically normal ovarian surface epithelium exhibited changes in the nuclear chromatin pattern, which indicate an ovarian abnormality, and (b) such changes were detectable in the ovarian surface epithelium of cancer-free subjects who were at high risk for ovarian cancer. EXPERIMENTAL DESIGN: Ovaries were carefully collected to avoid damage to the surface epithelium. Five-micron-thick histologic sections were cut and stained with H&E. High-resolution images were recorded from the ovarian surface epithelium and from the underlying stroma of ovaries from normal women (10 cases), women at high risk of developing ovarian cancer (7 cases), and histologically normal areas adjacent to ovarian cancer (3 cases). Karyometric features and measurements of nuclear abnormality were computed for 3,390 epithelial nuclei. Discriminant function analyses and unsupervised learning algorithms were employed to define deviations from normal and to identify the subpopulations of nuclei exhibiting these changes. RESULTS: Epithelium from ovaries harboring a malignant lesion had changes in the nuclear chromatin pattern consistent with a second phenotype, which were not visually detected with histopathologic surveillance. This phenotype was also present in the ovaries obtained from women at increased risk of ovarian cancer, suggesting that it may represent a premalignant abnormality. These changes were statistically significant. CONCLUSION: The observed changes in karyometric features were sufficiently distinct to warrant further study as both diagnostic and prognostic biomarkers for early detection and prevention of ovarian cancer.

Carcinoma in Situ↗
PubMed2005

Fatty acid composition of red blood cell membranes and risk of squamous cell carcinoma of the skin.

Differential effects of fatty acids on carcinogenesis suggest that fatty acid composition is important in tumor development. Arachidonic acid and its metabolites elicit inflammation and promote tumor formation in mouse skin. Inhibitors of the arachidonic cascade inhibit tumor incidence. A population-based case control study in Southeastern Arizona tested the hypothesis that lower levels of arachidonic acid in RBC membranes were associated with decreased risk of skin squamous cell carcinoma (SCC; n = 335 SCC cases and 321 controls). Extracted and esterified RBC fatty acids were analyzed using capillary gas chromatography. Individual peaks for 14 fatty acids were measured as a percentage of total fatty acids. Logistic regression was used to estimate odds ratios (OR), adjusting for SCC risk factors (age, gender, actinic keratosis history, freckling, and tanning ability). Increased levels of arachidonic acid in RBC membranes were associated with increased risk of SCC [odds ratio (OR), 1.08 per mg/100 mL change; 95% confidence interval (95% CI), 1.02-1.15] and this association remained when controls with actinic keratosis precursor lesions were excluded. SCC risk was highest among the upper quartile of arachidonic acid (OR, 2.38; 95% CI, 1.37-4.12). In contrast, increasing proportions of palmitic acid (OR, 0.94; 95% CI, 0.89-1.00) and palmitoleicacid (OR, 0.49; 95% CI, 0.30-0.81) were associated with reduced SCC risk. More studies are needed to elucidate the function of RBC fatty acids so that recommendations can be made to alter the human diet for cancer prevention.

Aged↗
PubMed2005

Adherence assessment using medication weight in a phase IIb clinical trial of difluoromethylornithine for the chemoprevention of skin cancer.

OBJECTIVE: Adherence is a common and essential measurement in clinical trials. This study evaluates the association between participant self-reported study diary records and the weight of the medication vessel at each study visit, in the setting of a phase IIb topical chemoprevention trial. METHODS: One hundred and twenty-four eligible participants were randomized to one of four arms [34 to difluoromethylornithine (DFMO) plus triamcinolone, 31 to DFMO plus placebo, 31 to placebo plus triamcinolone, and 28 to double placebo] for 6 months of treatment for actinic keratosis. Adherence was assessed at each clinic visit by weighing each tube of dispensed and returned medication and the participant's study diary. RESULTS: Self-reported adherence was consistently higher than adherence measured by returned medication weight (96.5% versus 71.3%, 94.6% versus 82.4%, 95.3% versus 69.5%, and 95.8% versus 66.8% for DFMO, DFMO placebo, triamcinolone, and triamcinolone placebo, respectively; P < 0.001). Most participants (59.2%) recorded 100% adherence on the study diary; however, using the weight adherence, only 10.2% were completely adherent to the study regimen. CONCLUSIONS: Self-reported diary measures seem to overestimate adherence when compared with weighing the returned medication vessel. It is recommended that future clinical trials involving topical applications incorporate medication weights as a primary measure of adherence because it is objective, quantitative, inexpensive, noninvasive, and easy to use.

Administration, Topical↗
PubMed2005

Diet and biomarkers of oxidative damage in women previously treated for breast cancer.

This study sought to evaluate the relationship between dietary intake of fat, polyunsaturated fat, saturated fat, arachidonic acid, and selected dietary antioxidants and levels of oxidative damage as measured by urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2alpha (8-iso-PGF2alpha) in women previously treated for breast cancer. Two hundred two study subjects participating in the Women's Healthy Eating and Living (WHEL) study were included in this ancillary study. Dietary intakes and concentrations of urinary 8-OHdG and 8-iso-PGF2alpha were measured at baseline and 12 mo in the 179 women included in the analytical cohort. Study subjects demonstrated a significant reduction in dietary total, polyunsaturated, and saturated fat intake and a significant increase in vitamins E and C and beta-carotene intake from baseline to 12 mo. Linear mixed-models analysis using baseline and Year 1 data indicated that vitamin E intake was inversely associated with both 8-OHdG and 8-iso-PGF2alpha. 8-Iso-PGF2alpha is increased with increased body mass index (BMI) and polyunsaturated fatty acid (PUFA) intake, indicating an increase in lipid peroxidation with greater BMI and higher PUFA intake. 8-OHdG was inversely related to age but positively related to arachidonic acid, indicating an increase in DNA damage with higher intake of arachidonic acid (meat). The results of this nested case-controlled study provide potential mechanisms by which a high fruit and vegetable, low-fat diet might reduce the recurrence rate of or early-stage breast cancer.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Second order discriminant analysis in chemopreventive efficacy measurement.

OBJECTIVE: To describe the use of second order discriminant analysis as a classification methodology along with the underlying assumptions and sampling requirements, with special emphasis on the use of this analysis in chemopreventive efficacy studies. STUDY DESIGN: The discriminant function score distributions derived in an analysis of 2 diagnostic groups may show such overlap that a statistically significant difference in mean values cannot be shown and, more important, that a useful case-based classification cannot be attained. By using the discriminant function score distributions from each case, it is frequently possible to derive a second order discriminant function based on case-specific characteristics, rather than characteristics of nuclei, thereby attaining improved case classification. RESULTS: Second order discriminant analysis has proven very useful in the documentation of case-level efficacy in chemopreventive trials. In a study of orally administered vitamin A, a first order discriminant analysis did not achieve a statistically significant difference in the score distributions for nuclei, but a second order discriminant analysis allowed a correct recognition of intervention effects in 85% of submitted cases. In a chemopreventive study of triamcinolone, a similarly inadequate discrimination based on discriminant function scores for nuclei resulted. After a second order discriminant analysis, a reduction in solar-actinic damage could be shown in 14/15, or 93%, of treated cases. CONCLUSION: Second order discriminant analysis can be highly effective when the discriminating information offered at the nuclear level is inadequate due to high dispersion and small differences in mean values of discriminant function scores for the diagnostic groups. Second order analysis utilizes case-specific characteristics of the discriminant function score distributions to document diagnostic group separation and/or efficacy of chemopreventive intervention by a reduction in case discriminant function scores.

Administration, Oral↗
PubMed2005

Karyometry of infiltrating breast lesions.

OBJECTIVE: To characterize nuclei from well-differentiated, moderately differentiated and poorly differentiated lesions of invasive breast cancer by karyometry and to test the hypothesis that these diagnostic categories form homogeneous sets. STUDY DESIGN: Histopathologic sections from 6 cases of well-differentiated, 11 cases of moderately differentiated and 17 cases of poorly differentiated ductal carcinomas were digitally recorded. From each case 100 nuclei were segmented and analyzed by karyometry. A discriminant analysis was performed, and nuclear and lesion signatures were computed. The nonsupervised learning algorithm P-index was applied. A progression curve per diagnostic category based on mean nuclear abnormality and a discriminant function score was derived. RESULTS: The well-differentiated lesions formed a homogeneous set, but both the moderately and poorly differentiated lesions showed 2 significantly different subpopulations with nuclei of substantially different nuclear abnormality and progression. CONCLUSION: The visual histopathologic diagnostic assessment of these lesions was based on an evaluation of both tissue architectural criteria and nuclear criteria. Here, only the pattern of nuclear chromatin was evaluated. Cases belonging to the same diagnostic category as assessed by their differentiation may be further characterized by the extent to which the nuclei deviate from normal. There was substantial case-to-case heterogeneity in these invasive lesions.

Breast Neoplasms↗
PubMed2005

The evolution of scanning microphotometry: a historical review.

This article traces the evolution of scanning microphotometry from its beginning, with an emphasis on the developing technologies that have made feasible the rapid and detailed capture of high-resolution image information. Consideration is given to future directions that may prove fruitful to clinical practice.

History, 20th Century↗
PubMed2004

Selenium and colorectal adenoma: results of a pooled analysis.

BACKGROUND: Secondary analyses of data from a large randomized clinical trial have suggested that intake of the trace element selenium reduces risk of colorectal neoplasia, but epidemiologic studies have not shown a consistent protective association. METHODS: We conducted a combined analysis of data from three randomized trials--the Wheat Bran Fiber Trial, the Polyp Prevention Trial, and the Polyp Prevention Study--which tested the effects of various nutritional interventions for colorectal adenoma prevention among participants who recently had an adenoma removed during colonoscopy. Selenium concentrations were measured from blood specimens from a total of 1763 trial participants, and quartiles of baseline selenium were established from the pooled data. To estimate the association between baseline selenium and colorectal adenoma risk, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression modeling. All statistical tests were two-sided. RESULTS: Individual study results among participants whose blood selenium concentrations were in the highest versus the lowest quartile varied in magnitude (Polyp Prevention Trial: OR = 0.67, 95% CI = 0.43 to 1.05; P(trend) = .21; Wheat Bran Fiber Trial: OR = 0.66, 95% CI = 0.40 to 1.10; P(trend) = .13, and Polyp Prevention Study: OR = 0.57, 95% CI = 0.34 to 0.95, P(trend) = .04). Analyses of the pooled data showed that individuals whose blood selenium values were in the highest quartile (median = 150 ng/mL) had statistically significantly lower odds of developing a new adenoma compared with those in the lowest quartile (OR = 0.66, 95% CI = 0.50 to 0.87; P(trend) = .006). CONCLUSIONS: The inverse association between higher blood selenium concentration and adenoma risk supports previous findings indicating that higher selenium status may be related to decreased risk of colorectal cancer.

Adenoma↗
PubMed2004

Longitudinal changes in body weight and body composition among women previously treated for breast cancer consuming a high-vegetable, fruit and fiber, low-fat diet.

BACKGROUND: Excess adiposity has been shown to be associated with increased risk for breast cancer recurrence, and a plant-based eating pattern has been hypothesized to be protective. Whether a plant-based diet without specific energy goals will result in weight loss or changes in body composition in women who have been diagnosed with breast cancer has not been fully explored. AIM OF THE STUDY: This study was conducted to identify changes in body weight, anthropometric measures, and body composition over a four year period in a sub-sample of breast cancer survivors participating in a dietary intervention targeting increased intake of vegetables, fruit and fiber and decreased dietary fat intake. METHODS: This randomized, controlled dietary intervention study compared longitudinal changes in intakes, body weight, waist:hip ratio (WHR), body mass index (BMI) and body composition by treatment group among fifty-two women previously treated for Stage I, II, or IIIA breast cancer from the Arizona site of the Women's Healthy Eating and Living Study. The dietary intervention aimed for eight servings of fruit and vegetables, 30 g fiber, < or = 20% total energy from fat per day, as well as daily intake of vegetable juice. The comparison group was advised to follow general dietary guidelines for cancer prevention. RESULTS: The dietary intervention resulted in a significant and sustained increase in fiber, fruit, vegetable, and vegetable juice consumption (p < 0.05) among intervention group subjects as compared to comparison group subjects. The first 6 months resulted in a reduction in body weight and body fat among the intervention group subjects while the comparison group subjects remained stable. Subsequent measurements, at 12, 24 or 36, and 48 months, showed no significant differences in mean body weight, BMI, WHR, or body composition by study group. Also, no significant changes in these measures were demonstrated for either study group between baseline and 48 months. CONCLUSIONS: The dietary intervention efforts resulted in significant changes in diet toward an increase in plant foods and a decrease in dietary fat. Changes in weight, WHR, BMI, and body composition were not different over time or by study group assignment. Interventions that promote a plant-based diet without specific energy restriction do not appear to promote changes in body weight or body composition in women who have been diagnosed with breast cancer. To adequately examine the role of energy restriction in reducing obesity-associated breast cancer recurrence, future interventions should include prescribed energy imbalance either through reduced intake and/or increased expenditure.

Adolescent↗
PubMed2004

Determination of celecoxib in human plasma using solid-phase extraction and high-performance liquid chromatography.

A simple reversed phase high-performance liquid chromatography (HPLC) method was developed for determination of celecoxib levels in human plasma. The procedure involves solid-phase extraction of celecoxib and the internal standard (SC-236) from plasma using C(18) extraction cartridges. The chromatographic separation of celecoxib and SC-236 was achieved with a Nova Pak C(8) column (3.8 mm x 150 mm) eluted with a mobile phase consisting of acetonitrile-tetrahydrofuran-sodium acetate buffer (pH 5.0) in the ratio of 30:8:62. An ultraviolet light detector with the wavelength set at 215 nm was employed for detection. Celecoxib was well resolved from the plasma constituents and the internal standard. The extraction recovery of celecoxib and SC-236 from human plasma was greater than 88%. Linear calibration curves were established over a concentration range of 40-4000 ng/ml when 0.25 ml aliquots of plasma were used. The inter- and intra-day R.S.D. for the assay was less than 12 and 5%, respectively. This assay has been applied to the analysis of celecoxib levels in plasma samples collected from healthy participants entered into a Phase II clinical study.

Celecoxib↗
PubMed2004

Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers.

OBJECTIVE: Three phase 1 clinical trials of a superpotent melanotropic peptide, melanotan-1 (MT-1, or [Nle(4)-D-Phe(7)]alpha-melanocyte-stimulating hormone) were performed to demonstrate safety for MT-1 therapy combined with UV-B light or sunlight. DESIGN: Open-label studies at 2 dose levels of MT-1 combined with small doses of UV-B to the neck or buttock or full sunlight to half of the back. SETTING: Dermatology clinics at the Arizona Health Sciences Center, Tucson. INTERVENTIONS: The first study randomized 4 subjects to MT-1 (0.08 mg/kg per day subcutaneously) and 4 subjects to injections of isotonic sodium chloride (9%) solution for 10 days, followed by neck irradiation with 3 times the minimal erythema dose (MED) of UV-B light. In the next study (n = 12), the MT-1 dosage was increased to 0.16 mg/kg per day for 10 days, with UV-B radiation (0.25-0.75 MED) given to a buttock site for 5 days during (n = 7) or after (n = 5) MT-1 administration. A final study randomized 8 subjects to 3 to 5 days of sunlight to half of the back or to sunlight plus 0.16 mg/kg of MT-1 for 5 days per week for 4 weeks. RESULTS: Tanning in the first study was achieved in 3 of 4 subjects receiving MT-1, and these subjects also had 47% fewer sunburn cells at the irradiated neck site. More skin sites darkened with the higher dose of MT-1 in the second study. In the third study, there was significantly enhanced tanning of the back in the MT-1 group, and this was maintained at least 3 weeks longer than the tanning in the sunlight-only controls, who required 50% more sun-exposure time for equivalent tanning. MAIN OUTCOME MEASURE: There were no pathologic findings at any UV-B or sun-exposed sites in any subject. Toxic effects due to MT-1 were minor, consisting of nausea and transient facial flushing. CONCLUSION: Melanotan-1 can be safely combined with UV-B light or sunlight and appears to act synergistically in the tanning response to light.

Adult↗