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David S Alberts

Publications and source records attributed to David S Alberts.

89 records · Page 5Linked to original sources
PubMed2002

Baseline dietary fiber intake and colorectal adenoma recurrence in the wheat bran fiber randomized trial.

BACKGROUND: The Wheat Bran Fiber (WBF) trial was a double-blind, high-fiber versus low-fiber phase III intervention trial in which participants were randomly assigned to receive a cereal fiber supplement of either 2.0 g/day or 13.5 g/day to assess whether a high-fiber supplement could decrease risk of recurrent colorectal adenomas. Although no effect of the supplement on polyp recurrence was observed, participants consumed a baseline average of 17.5 grams of fiber per day, which may have been sufficient to protect against adenoma recurrence. Therefore, we examined whether baseline fiber intake affected colorectal adenoma recurrence or modified the effect of treatment group in the WBF trial participants. METHODS: Quartiles of baseline fiber intake were calculated on the basis of the distribution in the study population. Odds ratios (ORs) for adenoma recurrence were calculated using the lowest quartile of fiber intake as the reference. The effect of fiber from specific food sources on adenoma recurrence was also assessed. All statistical tests were two-sided. RESULTS: Adjusted ORs (95% confidence intervals) for adenoma recurrence were 0.79 (0.56 to 1.12), 0.76 (0.54 to 1.08), and 0.83 (0.57 to 1.19) for the second, third, and fourth quartiles, respectively. Fiber from the three primary food sources (fruits; breads, cereals and crackers; and vegetables) had no appreciable effect on adenoma recurrence. Baseline fiber intake also had little effect on adenoma recurrence when the population was stratified by treatment group. In addition, there was no interaction between treatment group and quartile of baseline fiber intake. CONCLUSIONS: No association was found between amount of fiber consumed at baseline and adenoma recurrence in the WBF trial participants. The baseline fiber intake, whether considered as a whole or from specific sources, did not modify the effect of treatment group.

Adenoma↗
PubMed2002

Simultaneous quantitation of fatty acids, sterols and bile acids in human stool by capillary gas-liquid chromatography.

A simple method for the simultaneous gas-liquid chromatographic quantitation of fatty acids, sterols and bile acids from human fecal samples is described. The various compounds are directly converted into the n-butyl ester-trimethylsilyl ether derivatives, without prior isolation from the stool. Under these conditions, fecal bile acid derivatives are well resolved from each other and from those of fecal fatty acids and sterols without overlaps. The method was found to be reproducible and recoveries were similar to those obtained after exhaustive solvent extraction of fecal sterols, fatty acids and bile acids. Optimum derivatization conditions that allowed maximum recovery of fecal components with minimal destruction and application of the method for simultaneous bile acid, fatty acid and sterol analysis in human stool are described.

Bile Acids and Salts↗
PubMed2002

Prediction of the need for red cell transfusion in newly diagnosed ovarian cancer patients undergoing platinum-based treatment.

OBJECTIVE: The objective of this study was to develop a predictive algorithm for the likelihood of red blood cell transfusion in women with ovarian cancer undergoing platinum-based chemotherapy. METHODS: Patients in this analysis came from two phase III studies conducted by the Southwest Oncology Group and Gynecologic Oncology Group of platinum-based chemotherapy in advanced ovarian cancer patients, SWOG 8412 and SWOG 8501/GOG 104. The probability of packed red blood cell (PRBC) transfusion was modeled as a function of stage of disease, age, weight, creatinine clearance, hemoglobin (Hb) prior to the start of therapy, the platinum agent administered (i.e., cisplatin vs carboplatin), and the route of drug administration (i.e., intravenous vs intraperitoneal). RESULTS: Overall, 16% of patients developed at least grade 3 anemia (Hb < 8 g/dL) during primary chemotherapy, with 2% experiencing grade 4 anemia (Hb < 6.5 g/dL). PRBC transfusions were administered to 32% of patients. Factors that were determined to be predictive of PRBC transfusions were age and baseline Hb. In patients with bulky stage III or stage IV disease, the odds of transfusion increased by 66% for each 10-year increase in age and by 65% for each 1 g/dL decrease in baseline hemoglobin. Thus a patient aged 65 with a baseline Hb of 10.5 g/dL has approximately a 40% chance of transfusion. CONCLUSIONS: Older ovarian cancer patients (>65 years) with low baseline Hb levels (<10.5) at initiation of platinum-based chemotherapy are likely to become more anemic during treatment and should be considered for prophylactic erythropoietin therapy as an alternative to transfusion.

Aged↗
PubMed2002

Correlation of p53 immunostaining in primary and residual ovarian cancer at the time of positive second-look laparotomy and its prognostic role: a Southwest Oncology Group ancillary study.

OBJECTIVE: The objective of this study was to verify the correlation between p53 immunostaining at initial diagnosis and at positive reassessment after completing platinum-based chemotherapy and to assess prognostic differences between patients whose tumors display positive immunostaining versus those that have negative immunostaining at such reassessment. METHODS: This study made use of samples from patients entered into a prospective randomized study of the Southwest Oncology Group (SWOG 8835) that treated patients with minimal residual disease at second-look laparotomy with either intraperitoneal (ip) mitoxantrone or fluorodeoxyuridine (FUDR). Unstained slides from tumor obtained at the initial diagnosis and at reassessment were retrospectively requested from individual institutions. The degree of nuclear staining was determined using the anti-p53 mouse monoclonal antibody Pab1801 and previously published techniques, with a cutoff of 10% or more staining of tumor cell nuclei for a positive result. Cox model regression analysis was performed for overall survival and progression-free survival, with p53 status, ip treatment, and baseline CA125 as independent variables. RESULTS: p53 determination was feasible in 22 patients both at diagnosis and at the second-look samples; 9 additional patients had only either sample available. Since concordance between the 10 negative and 12 positive immunostained samples was 100%, all 31 patients were considered in the Cox model. The death hazard ratio of p53-positive versus p53-negative patients was 4.18 (two-sided P value of 0.006). CONCLUSION: p53 immunostaining at second-look laparotomy correlates with the immunostaining at diagnosis. In this series confined to patients with minimal residual disease after initial therapy subjected to second-line intraperitoneal treatment, it appears to identify a poor prognostic (positive) subset for survival.

Adult↗
PubMed2002

Chemoprevention of human skin cancer.

The incidence of skin cancer has been rising in recent years with significant effects on public health. Primary prevention has proven inadequate in impacting the incidence of skin cancer, thus stimulating the development of chemopreventive strategies. The majority of skin cancer chemoprevention studies focus on occurrence of new nonmelanoma skin cancers (NMSC) in individuals with a previous NMSC, or on reduction in the number of premalignant skin lesions such as actinic keratoses (AK). Dysplastic nevi, a likely precursor of melanoma, are also potential targets for chemoprevention strategies. Premalignant lesions are especially attractive as endpoints since they are more common than frank cancer, resulting in reduced sample size, length, and cost of clinical trials. Development of new agents that affect the pathogenesis of skin cancer will be discussed, from elucidation of molecular targets to implementation of trials designed to determine the effects of chemopreventive interventions on human skin cancer.

Antineoplastic Agents↗
PubMed2002

Calcium, vitamin D, and risk of adenoma recurrence (United States).

OBJECTIVE: Few data exist regarding the association between calcium intake and adenoma recurrence, and no data exist for vitamin D. We investigated the role of dietary and supplemental sources of calcium and vitamin D in the etiology of adenoma recurrence. METHODS: Analyses were conducted among 1304 male and female participants in the Wheat Bran Fiber (WBF) trial of adenoma recurrence. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In the fully adjusted multivariate model, the OR for participants with dietary calcium intake above 1,068 versus those with intake below 698 mg/day was 0.56 (95% CI = 0.39-0.80; p-trend = 0.007). Calcium supplementation at doses above 200 mg/day did not affect risk of recurrence. Although a borderline inverse association between dietary vitamin D and recurrence was observed after adjustment for age and gender, the association weakened in the fully adjusted model (OR = 0.78 for individuals in the upper compared to the lower quartile; 95% CI = 0.54-1.13). No association was shown for supplemental sources of vitamin D. CONCLUSIONS: Results of this study indicate that a higher intake of calcium decreases the risk of adenoma recurrence by approximately 45%, whereas vitamin D has no significant effect on recurrence rates.

Adenocarcinoma↗
PubMed2002

Modulation of biologic endpoints by topical difluoromethylornithine (DFMO), in subjects at high-risk for nonmelanoma skin cancer.

More than one million new skin cancers are diagnosed yearly in the United States creating the need for effective primary and chemopreventive strategies to reduce the incidence, morbidity, and mortality associated with skin cancer. Skin chemoprevention trials often focus on subjects at high risk of nonmelanoma skin cancers and include biological endpoints like number of actinic keratoses (AK) and measures of cell proliferation, apoptosis, and p53 expression and/or mutation. Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses increased polyamine synthesis and inhibits tumors in models of skin carcinogenesis. Thus, DFMO is a good candidate chemopreventive agent in humans at increased risk of NMSC. We reported previously results of a randomized, placebo-controlled trial of topical DFMO in 48 participants with AK. In this study there was a significant reduction in the number of AK (23.5%; P = 0.001) and the polyamine, spermidine (26%, P = 0.04; Alberts, D. S. et al. Cancer Epidemiol. Biomark. Prev., 9: 1281-2186, 2000). In skin biopsies from the same study, we demonstrate that topical DFMO significantly reduces the percentage of p53-positive cells (22%; P = 0.04); however, there were no significant changes in proliferating cell nuclear antigen or apoptotic indices, or in the frequency of p53 mutations (25% at baseline, 21% after placebo, and 26% after DFMO). We conclude that inhibition of the premalignant AK lesions as well as a reduction in the expression of p53 and in spermidine concentrations may serve as surrogate endpoint biomarkers of DFMO and possibly other topically administered skin cancer chemopreventive agents.

Aged↗
PubMed2002

Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development.

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.

Antineoplastic Agents↗
PubMed2002

Karyometry in endometrial adenocarcinoma of different grades.

OBJECTIVE: To characterize nuclei from adenocarcinoma of the endometrium of different grades in order to establish whether significantly different nuclear subpopulations exist. STUDY DESIGN: A total of 1,400 nuclei from 14 cases of adenocarcinoma of the endometrium of grades 1, 2 and 3 were recorded, and 600 nucleifrom normal, secretory phase glandular endometrial epithelium were used as a reference data set. Karyometric features were computed and a discriminant function derived to define a trend in feature values for nuclei from lesions of different grades. The nuclei from lesions of different grades were processed by a nonsupervised learning algorithm in an effort to detect and define subpopulations. RESULTS: Nuclei from grade 1 lesions represented a near-diploid stemline, whereas nuclei from grade 3 lesions formed an aneuploid set with a mode around 3N. The existence of three subpopulations with statistically different nuclear chromatin patterns could be shown for nuclei from each grade. In each grade these three subpopulations occupied the same relative position in feature space. For grade 1 lesions all three subpopulations were near diploid, for grade 3 lesions all three were approximately triploid. CONCLUSION: The nuclei in adenocarcinoma of the endometrium form a heterogeneous set, with subpopulations of distinctly different chromatin patterns and different ploidy. This should be taken into consideration in assessing the efficacy of chemopreventive intervention.

Adenocarcinoma↗
PubMed2002

Effects of perillyl alcohol on melanoma in the TPras mouse model.

This study evaluates the chemopreventive effects of topically applied perillyl alcohol on the development of melanoma in TPras transgenic mice. Our strategy was to target critical pathways in the development of melanoma, in particular, the ras pathway. Ras has been shown in our experimental mouse model, as well as others, to be important in the development and maintenance of melanomas. Perillyl alcohol (POH), a naturally occurring monoterpene, inhibits the isoprenylation of small G protein, including Ras. POH (10 mM) was applied to the shaved dorsal skin of TPras mice starting 1 week before five treatments of dimethylbenz[a]anthracene (50 microg) and was continued for 38 weeks. We observed a delay in the appearance of tumors and a 25-35% reduction in melanoma incidence. POH treatment of melanoma cells in vitro reduced the levels of detectable Ras protein and inhibits the activation of downstream targets, mitogen-activated protein kinases and Akt. POH only minimally induced apoptosis in this system. Pretreatment but not post-treatment of the melanoma cells with POH, however, markedly reduced levels of UV-induced reactive oxygen species. These studies suggest that POH inhibition of the Ras signaling pathway may be an effective target for chemoprevention of melanoma.

Animals↗
PubMed2002

Current application of selective COX-2 inhibitors in cancer prevention and treatment.

The multistep process of carcinogenesis, which can take many years, provides many opportunities for intervention to inhibit disease progression. Effective chemoprevention agents may reduce the risk of cancer by inhibiting the initiation stage of carcinoma through induction of apoptosis or DNA repair in cells harboring mutations, or they may act to prevent promotion of tumor growth. Similarly, chemoprevention may entail blocking cancer progression to an invasive phenotype. Over the past decade, in vitro, preclinical, and clinical data have supported the hypothesis that cyclooxygenase (COX)-2 plays a central role in oncogenesis and that treatment with COX-2 inhibitors offers an effective chemoprevention strategy, as exemplified by the activity of celecoxib (Celebrex) in familial adenomatous polyposis. These COX-2 data have contributed to initiation of clinical trials testing COX-2 inhibitors for the chemoprevention of a wide variety of cancers that overexpress COX-2.

Clinical Trials as Topic↗
PubMed2002

Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis.

PURPOSE: IFN-based therapy has been shown to be active in the treatmentof squamous cell carcinoma (SCC) of the skin, the most aggressive form of non-melanoma skin cancer. Based largely on this activity, we began programmatically examining the expression of IFN-stimulated gene factor 3 (ISGF-3) proteins (signal transducers and activators of transcription 1alpha/beta, signal transducers and activators of transcription 2, and p48), which are important mediators of IFN-alpha signaling, in skin premalignancy and SCC. Our previous preliminary studies suggested suppression of some or all of the ISGF-3 proteins in skin SCC. EXPERIMENTAL DESIGN: To determine the timing of the suppression of IFN-alpha signaling proteins in squamous skin carcinogenesis, we have now compared ISGF-3 expression by immunohistochemical staining in biopsies of actinic keratosis, a form of skin premalignancy, and matched normal skin. RESULTS: We observed a significant decrease in expression of one or more ISGF-3 proteins in 76% of patients with actinic keratosis (19 of 25 patients). In addition, we found a suppression of one or more ISGF-3 proteins in 67% of skin SCC patients tested (12 of 18 patients), confirming our previous observations. CONCLUSIONS: These data have led to the hypothesis that the suppressed expression of ISGF-3 proteins and consequent reduction in responsiveness to endogenous IFN likely are an early event in skin carcinogenesis.

Aged↗
PubMed2002

Statistical analysis of chemopreventive efficacy of vitamin A in sun-exposed, normal skin.

OBJECTIVE: To develop numeric, statistically secured measures of chemopreventive efficacy and to derive procedures with high sensitivity of detection. STUDY DESIGN: Karyometric features were computed for nuclei from the basal cell layer of biopsies taken from sun-exposed but histologically "normal" skin. Biopsies were collected from placebo-treated subjects and subjects treated for one year with daily, oral doses of 25,000, 50,000 and 75,000 IU of vitamin A. A total of 22,600 nuclei were recorded from 113 cases, at baseline and after one year. RESULTS: Two numeric measures of chemopreventive efficacy were applied: a measure of nuclear abnormality and a measure based on discriminant function scores. Both showed statistically significant chemopreventive effects of vitamin A. Dose-response curves were derived. A novel procedure, second order discriminant analysis, resulted in very high sensitivity for the detection of change in nuclear chromatin patterns. CONCLUSION: Karyometric analysis has increased in sensitivity such that changes on the order of 10%, found in only a low percentage of nuclei in a biopsy specimen, can be reliably documented. The methodology lends itself to cost-efficient screening of compounds for chemopreventive efficacy.

Biopsy↗
PubMed2002

Intake of supplemental and total fiber and risk of colorectal adenoma recurrence in the wheat bran fiber trial.

The Wheat Bran Fiber (WBF) trial was a double-blind Phase III clinical trial in which participants were randomized to a cereal fiber supplement of either 13.5 or 2.0 g/day. No protective effect for adenoma recurrence was observed for those randomized to the high-fiber group as compared with those in the low-fiber group. However, the high-fiber group had significantly lower adherence to the supplement as assessed by cereal box counts. The aim of this study was to determine whether reported supplemental and total fiber intake affected colorectal adenoma recurrence in the WBF trial population, regardless of treatment group assignment. A total of 1208 participants who completed the WBF trial had a colonoscopy before the date of the last cereal box count and/or at least one colonoscopy within 90 days after it and, thus, were eligible for the current analyses. Statistical analyses were done using multivariate logistic regression models that included potentially confounding variables. Compared with individuals consuming less than 1.8 g/day of supplemental fiber, the adjusted odds ratio (95% confidence interval) for adenoma recurrence for those consuming greater than 11.0 g/day was 0.94 (0.66-1.33). The odds ratio (95% confidence interval) for participants whose total fiber intake was greater than 30.3 g/day was 0.98 (0.68-1.42) compared with those whose intake was less than 17.9 g/day. The results of this study show that neither fiber intake from a wheat bran supplement nor total fiber intake affects the recurrence of colorectal adenomas, thus lending further evidence to the body of literature indicating that consumption of a high-fiber diet, especially one rich in cereal fiber, does not reduce the risk of colorectal adenoma recurrence.

Adenoma↗
PubMedDate not supplied

Reducing the risk of colorectal cancer by intervening in the process of carcinogenesis: a status report.

Risk factors for colorectal cancer have been identified, and significant advances have been made in understanding the process of colorectal carcinogenesis. The transition from normal colonic mucosa to adenomatous polyp to adenocarcinoma is a gradual process involving genetic and epigenetic instability that can take decades, offering numerous opportunities for early detection (e.g., colonoscopy screenings), lifestyle changes (e.g., reduced red meat intake, increased physical activity, and reduced alcohol/ tobacco exposure), and chemopreventive interventions. Aspirin and various other nonsteroidal anti-inflammatory drugs may have chemopreventive benefits for colorectal cancer and other human epithelial carcinomas, butthe long-term use of nonsteroidal anti-inflammatory drugs is associated with serious gastrointestinal side effects. Recently, overexpression of cyclooxygenase-2 has been documented in colorectal tumors and numerous other pre-cancers and cancers. The development of selective cyclooxygenase-2 inhibitors, such as celecoxib, provides an opportunity for preventive intervention in the carcinogenic process. Celecoxib has been approved for the management of familial adenomatous polyposis and is under investigation for the management of sporadic colorectal polyps and for its potential as a chemopreventive agent for other cancers.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Analysis of cyclooxygenase 2 (COX-2) expression during malignant melanoma progression.

Cyclooxygenase 2 (COX-2) is an inducible enzyme involved in the production of prostaglandins and thromboxanes during inflammation. There are now several lines of evidence indicating that increased expression of COX-2 plays a functional role in the development and progression of malignant epithelial cancers. However, there is only limited data regarding the role of COX-2 in melanoma pathogenesis. In the present work, we retrospectively examined lesions through out the development of melanoma and metastatic disease (dysplastic nevi n = 10, melanoma in situ n = 4, stage II melanoma n = 10, stage III n = 4, stage IV n = 3, stage V n = 2, melanoma metastasis lymph nodes n = 13 metastasis to other sites n = 3). COX-2 was consistently observed in keratinocytes, dermal fibroblasts, and inflammatory cells in regions adjacent to benign evi and primary cutaneous melanomas. However, no COX-2 staining was detected in the nevi nor in the primary skin melanoma cells. In addition, COX-2 was undetected in all vertical and radial growth phase cases Interestingly, 13 out of 13 of the lymph node metastasis expressed extremely high levels of COX-2 in overlying epithelium and inflammatory cells, and COX-2 was strongly detected in the metastatic cancer cells per se. For additional information on the expression of COX-2 in malignant melanoma, we determined the expression of COX-2 protein in several different melanoma cell lines. We found that 3We found that 5 out of 7 of the melanoma cells over expressed COX-2 compared to normal melanocytes. Collectively, these data suggest that COX-2 may play a functional role in metastases of melanoma, and treatment with COX-2 inhibitors may be efficacious for malignant melanoma.

Adult↗