Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS.

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Avonex Combination Trial in relapsing--remitting MS: rationale, design and baseline data.

OBJECTIVE: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNbeta-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >or=1 relapse or gadolinium-enhancing MRI lesion in the prior year while on IM IFNbeta-1a monotherapy. Subjects continued IFNbeta-1a 30 mcg IM weekly and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without IVMP 1,000 mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center. RESULTS: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNbeta neutralizing antibodies. ACT's management and operational structures functioned well. CONCLUSION: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.

Analysis of clinical trials involving non-cavitated caries lesions.

Treatments to halt or reverse the progression of non-cavitated caries lesions are of increasing interest. Diagnostic technologies under development offer potential for the assessment of gradual progression and regression of such lesions. Many therapies directed at correcting demineralization-remineralization imbalance should, in principle, protect enamel similarly across lesion severities from initiation to near cavitation. If this is so, and if acceptable reproducibility and predictive validity can be demonstrated for a diagnostic of acceptable cost, then clinical trials of agents to prevent cavitation can become more efficient by the use of outcome indices that reflect, in addition to cavitation, the expansion and regression of non-cavitated lesions. However, to achieve such a benefit will require data analyses that fully exploit ordinal or continuous-scale outcome measures. We consider comparison of such measures of lesion status between treatment groups, with most attention to ordinal categorical data. Interim data from a clinical trial in Lithuanian children are used for illustration.

Infectious disease consultation and microbiologic surveillance for intensive care unit trauma patients: a pilot study.

Infection remains a major cause of posttrauma morbidity. We retrospectively reviewed 2 cohorts of trauma patients admitted to a regional trauma center before and after a policy change integrating prospective microbiologic surveillance and infectious disease (ID) consultation into management of trauma admissions. Primary interests were effects of this policy change on antimicrobial use and diagnostic precision (particularly differentiation of infection from colonization). Associated costs, microflora, survival, and disability were also compared. Patients were stratified for risk of infection. ID consultation was associated with a 49% increased odds that an infection diagnosis was microbiologically based (P=.006) and 57% reduction of antibiotics costs per hospitalized day (P=.0008). Costs of consultation and an 86% increase (P<10(-6)) in total cultures combined to minimally exceed that financial saving. The observed improvements in diagnostic precision and antimicrobial usage, however, suggest consideration of prospective microbiologic surveillance and multidisciplinary physician teams including ID physicians for high-risk trauma patients.

Nasopharyngeal carcinoma in Malaysian Chinese: occupational exposures to particles, formaldehyde and heat.

BACKGROUND: During 1990-1992, 282 Chinese residents of Selangor and the Federal Territory, Malaysia with histologically confirmed nasopharyngeal carcinoma (NPC) were interviewed about occupational history, diet, alcohol consumption, and tobacco use, as were an equal number of Malaysian Chinese population controls, pair-matched to cases by age and sex. METHODS: Exposures to 20 kinds of workplace substances, solar and industrial heat, and cigarette smoke, were analysed by univariate and multivariate methods. RESULTS: Nasopharyngeal carcinoma was associated with occupational exposures to construction, metal and wood dusts; motor fuel and oil; paints and varnishes; certain other chemicals; industrial heat; solar heat from outdoor occupations; certain smokes; cigarette smoking; and childhood exposure to parental smoking. After adjustment for risk from diet and cigarette smoke, only wood dust (OR = 2.36; 95% CI : 1.33- 4.19), and industrial heat (OR = 2.21; 95% CI : 1.12-4.33) remained clearly associated. Wood dust remained statistically significant after further adjustment for social class. No significant crude or adjusted association was found between NPC and formaldehyde (adjusted OR = 0.71; 95% CI : 0.34-1.43). CONCLUSIONS: This study supports previous findings that some occupational inhalants are risk factors for NPC. The statistical effect of wood dust remained substantial after adjustment for diet, cigarette smoke, and social class. Intense industrial heat emerged as a previously unreported risk factor, statistically significant even after adjustment for diet and cigarette smoke. No association was found between NPC and formaldehyde.

Nasopharyngeal carcinoma in Malaysian Chinese: salted fish and other dietary exposures.

We interviewed 282 histologically confirmed cases of nasopharyngeal carcinoma (NPC) in Chinese residents of Selangor and the Federal Territory, Malaysia, and an equal number of Chinese age-, sex-, and length-of-residence-matched controls sampled from the general population. Consumption of 55 dietary items during childhood, and 5 years pre-diagnosis of NPC, was analyzed by univariate and multivariate methods. Four salted preserved foods (fish, leafy vegetables, egg and root), fresh pork/beef organ meats and beer and liquor consumption exhibited strong positive associations, and 4 vegetable/fruit combinations strong negative associations with NPC. Factor analysis and multivariable modeling using estimated factor scores strongly supported separate effects on NPC of vegetables/fruits, salted preserved foods, pork/beef organ meats and beer/liquor consumption. Multivariable modeling associated NPC most clearly with high consumption of salted fish, salted eggs, pork/beef liver and beer and low consumption of Chinese flowering cabbage, oranges/tangerines and shrimp. A strong residual association of social class with NPC remained after adjustment for diet, which is consistent with a substantial role for non-dietary environmental factors.

Outbreak of serogroup C meningococcal disease associated with campus bar patronage.

Between February 1991 and April 1992, eight undergraduates at a US residential university and one at a nearby 2-year college contracted serogroup C meningococcal disease. A case-control investigation with 20 controls per case, oropharyngeal carriage surveys, and multilocus enzyme electrophoresis (MEE) of serogroup C isolates were used to identify factors contributing to the outbreak. All eight sterile-site isolates from cases were closely related by MEE and were similar (though not identical) to the strain associated with the 1991-1992 epidemic of meningococcal disease in eastern Canada. Disease was associated with cigarette smoking (p = 0.012), recent patronage of campus-area bars (p = 0.034), estimated amount of time spent in campus-area bars (p = 0.0003), and, especially, recent patronage of one specific bar, bar A (p = 0.0006; odds ratio = 23.1, 95% confidence interval 3.0-571.5). In carriage surveys, 1,528 throat cultures taken from (primarily student) noncases yielded only five (0.3%) strains that were identical by MEE to those from cases. Two of these were found among 22 cultures obtained from bar A employees in spring 1992. Some cases in this outbreak may have followed transmission of the epidemic strain in bar A. Campus bar environments may facilitate the spread of meningococcal disease among teenagers and young adults.

Meningococcal carriage, alcohol consumption, and campus bar patronage in a serogroup C meningococcal disease outbreak.

Community outbreaks of serogroup C invasive meningococcal disease are increasing in North America (L. H. Harrison, JAMA 273:419-421, 1995; L. A. Jackson, A. Schuchat, M. W. Reeves, and J. D. Wenger, JAMA 273:382-389, 1995; C. M. Whalen, J. C. Hockin, A. Ryan, and F. Ashton, JAMA 273:390-394). In a recent 15-month university outbreak, disease was linked to patronage of a specific campus-area bar, suggesting that aspects of a campus bar environment might promote meningococcal transmission (P. B. Imrey, L. A. Jackson, P. H. Ludwinski, et al., Am. J. Epidemiol., in press). To investigate this hypothesis, oropharyngeal carriage results from samples taken from 867 university health service clients and 85 campus-area bar employees during the last 3 months of the outbreak were analyzed to determine factors correlated with carriage of any strain of Neisseria meningitidis. Results were validated with data from samples from 344 health center clients and 211 campus bar employees taken 8 months after the last outbreak case. Recent alcohol consumption (adjusted prevalence odds ratio = 3.8 for > 15 versus 0 drinks in last week [P = 0.0012]) and campus bar patronage (adjusted odds ratio = 1.9 for any versus no patronage in last 2 weeks [P = 0.0122]) showed separate effects in both univariate and multiple logistic regression analyses of data from the 1992 health center clients. Prevalence of meningococcal carriage among 1992 campus bar workers was 3.8 times that among health center clients; this prevalence ratio was roughly 2.5 after adjustment for alcohol consumption and bar patronage. Recent antibiotic usage was protective (prevalence odds ratio = 0.3) among health center clients and bar workers. These findings were generally supported by the validation samples. If alcohol consumption and other aspects of the campus bar environment facilitate transmission of and/or colonization by N. meningitidis, then the introduction of a highly pathogenic substrain into the campus bar environment may provide an unusual opportunity for invasive meningococcal disease within a campus community.

The combined effects of dietary fat and estrogen on survival, 7,12-dimethylbenz(a)anthracene-induced breast cancer and prolactin metabolism in rats.

The relationships between dietary fat concentration (10 or 40% of energy), fat source (corn oil or beef tallow) and estrogen (control, ovariectomy or ovariectomy with estrogen replacement) to 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis and survival in rats were studied in a 2 x 2 x 3 factorial experiment. Female Sprague-Dawley rats given DMBA (2.5 mg/100 g body wt, intragastric) at 55 d of age were randomly allocated to three groups 48 h later: sham ovariectomy (control), ovariectomy (OVX) or ovariectomy with a subcutaneous estrogen implant (OVX+E). Each group was subdivided into dietary groups fed 10 and 40% of energy as corn oil or beef tallow for 70 wk. OVX+E rats exhibited serum estrogen concentrations in excess of physiologic values. Survival at 70 wk for the 3 hormonal groups was control 51%, OVX 67% and OVX+E 13%. Mortality in controls was doubled by feeding a high fat diet; no diet effect was detected in OVX or OVX+E rats. Palpable tumors developed in 74, 14 and 60% of control, OVX and OVX+E rats, respectively. High fat diets approximately doubled the hazard of developing a palpable tumor. Adenocarcinoma prevalence was 58, 12 and 63% in control, OVX and OVX+E rats, respectively. The odds of having any tumor, an adenocarcinoma or an adenoma were multiplied by 3.6, 2.8 and 2.3, respectively, for rats fed high vs. low fat. Additional studies showed that diet had no effect on serum prolactin or estrogen concentrations or metabolism and clearance of intravenously administered radiolabeled prolactin. We demonstrated that high dietary fat concentration enhances breast carcinogenesis independently of cyclic ovarian function, although the presence of estrogen may be a prerequisite for significant dietary modulation. The effect of fat on breast cancer is not mediated by major changes in systemic prolactin metabolism.

Proposed guidelines for American Dental Association acceptance of products for professional, non-surgical treatment of adult periodontitis. Task Force on Design and Analysis in Dental and Oral Research.

Guidelines are suggested for determining efficacy of products to supplement scaling and root planing in professional, non-surgical treatment of adult periodontitis. They result from an extended process including a conference on clinical trials in gingivitis and periodontitis, a subsequent workshop, and commentary from industrial, academic, professional and governmental members of the periodontal research community on two drafts. Recommendations are made in the broad areas of basic study design, subject and periodontal site selection, clinical management, choice of outcome variables, statistical summarization and analysis, and criteria for acceptance. Prominent dissenting views, with justifications for positions taken here, are also provided. Groundwork is laid for possible future guidelines addressing products for primary prevention or over-the-counter uses, or for determining superiority or equivalence of competing products. However, issues are identified which require further exploration before responsible and widely acceptable recommendations can be made in these areas. The guidelines suggested here are meant to form the basis of an evolving document rather than a static standard. It is suggested that they be reviewed frequently in the light of improvement in the technology available for periodontal research, and the emergence of products representing new approaches to periodontal therapy.

Recommended revisions to American Dental Association guidelines for acceptance of chemotherapeutic products for gingivitis control. Report of the Task Force on Design and Analysis in Dental and Oral Research to the Council on Therapeutics of the American Dental Association.

This paper presents suggested revisions to the American Dental Association's 1985 guidelines for acceptance of anti-gingivitis chemotherapeutic agents. The areas of study design, choice and quality control of clinical gingivitis measurements, statistical analysis, and minimum strength of effect, are addressed. The revisions articulate certain aspects of study design which were implicit in the 1985 guidelines, clarify language on cross-over designs and independence of studies, and recommend use of a United States population in at least one trial supporting a product. Separate recording and analysis of a product's effect on gingival bleeding is proposed, and quality control of clinical measurements receives enhanced emphasis. Modestly elaborated statistical reporting guidelines and strengthened approval criteria, based on size of estimated effect as well as statistical significance, are advocated.

Design and analytic concepts for periodontal clinical trials.

Aspects of the design and analysis of periodontal clinical trials are surveyed from a biostatistical perspective. Design issues discussed include protocol preparation, subject selection and its documentation, randomization, problems associated with the sample versus population paradigm in sampling of microbes and gingival fluid constituents, quality control, cross-over and split-mouth versus parallel-arm designs, blinding, and multicenter trials. Analytic discussion deals with the definition and choice of analytic unit, appropriate methods for the analysis of data from multiple sites within the same subject, the nature and application of randomization tests, interim analyses, subgroup analyses, and multiple comparison issues. Examples are provided to illustrate the feasibility of analyzing site-specific data while accounting for intra-subject correlation, which represents the increased similarity of sites chosen from the same mouth as compared to sites from different patients.

Logical and analytic issues in dental/oral product comparison research.

Possible meanings of "superiority" and "equivalence" in comparative dental studies are considered. A proposed refinement of vocabulary is introduced to precisely distinguish between these meanings. Implications for data analysis of different interpretations of "superiority" and "equivalence" are explored, as are implications for study design where design and analytic considerations are inseparable. Conceptual problems of equivalence studies are stressed. Choice of analytic unit(s), scaling of dependent variables, use of surrogate variables, and validity checking are discussed as they pertain to comparative studies. Analytic methods for correlated responses and categorized responses are briefly surveyed, particularly with reference to periodontal research.

The combined effects of dietary fat, protein, and energy intake on azoxymethane-induced intestinal and renal carcinogenesis.

Two 3 x 3 factorial experiments were conducted to examine the effects of dietary protein (8, 16, and 32% of energy from casein) and dietary fat (12, 24, and 48% of energy from corn oil) on the initiation and promotion of azoxymethane-induced carcinogenesis in rats. For the initiation study, 33 weanling male Sprague-Dawley rats were randomized to each of nine diets fed ad libitum. Azoxymethane was administered s.c. between the fourth to sixth weeks of feeding, providing a total dose of 6 mg/100 g body weight. All rats were subsequently fed a common diet containing 16% energy from protein and 24% energy from fat for an additional 30 to 38 weeks. For the promotion study, all rats were fed a common diet containing 16% of energy from protein and 12% of energy from fat until the completion of azoxymethane administration, when 33 rats were randomized to each of nine diets varying in fat and protein content and fed these diets until sacrifice. Low-protein diets during the initiation phase were associated with increased risk of renal adenocarcinomas (P less than 0.001) and mesenchymal (P = 0.005) malignancies. No other statistically significant relationships were found between the levels of dietary fat or protein and the prevalence of malignant lesions of the small intestine, colon, or kidney in either the initiation or promotion study (although polypoid adenocarcinoma of the colon increased suggestively from 13 to 19 to 26% of rats with increasing dietary protein during initiation). Results of a multiple logistic regression analysis, combining both studies, showed that ad libitum energy intake was significantly associated with intestinal carcinogenesis. The odds of finding an intestinal adenocarcinoma increased by 6.2 +/- 2.6% (SE) for each additional kilocalorie of mean daily ad libitum intake (P = 0.014). The quintile of rats which consumed the least averaged 60 kcal/day, while the most voracious quintile averaged 74 kcal/day. This 14 kcal/day difference in mean ad libitum intake corresponded to more than a doubling (146% increase) of the odds of developing an intestinal adenocarcinoma. These studies suggest that ad libitum energy intake is a critical factor modulating experimental colon carcinogenesis.

Dietary protein and chronic toxicity of 1,2-dimethylhydrazine fed to mice.

1,2-Dimethylhydrazine-HCl (DMH-2HCl) is derived from the natural toxin cycasin, and is extensively used to induce cancers in experiments with rodents. We examined the toxicity of DMH-2HCl, incorporated into purified diets varying in protein, to determine concentrations compatible with long-term survival in B6C3H1 mice. Initial studies showed single-dose oral LD50 values (95% confidence intervals) of 26 (18-32) mg DMH-2HCl/kg body weight for males, and 60 (53-65) for females. A 6-wk study was performed with diets containing 10 or 40% soybean protein with doses of 0, 11.25, 22.5, 45, 90, and 180 mg DMH-2HCl/kg diet. All mice fed the highest dose were removed from the study due to severe toxicity. Declines in food consumption and body weight occurred in both sexes, accelerated with increasing log(DMH) dose, and were substantially more severe in groups fed 10% protein. A 5-mo study was subsequently performed with male mice fed 10 or 40% protein diets containing doses of 0, 15, 30, or 45 mg DMH-2HCl/kg diet. In this longer study, dose-related declines of food intake and body weight were also more pronounced with 10% protein. Histopathologic examination of samples from 29 organs/tissues revealed hepatic changes most commonly, and these were more severe at higher DMH levels. Lesions ranged from focal centrilobular hepatocellular necrosis to severe toxic hepatitis, associated with lobular disorganization and hepatocellular hypertrophy. Frequent dose-dependent lesions were also found in kidneys, adrenals, and heart. Renal changes included focal subcapsular fibrosis with atrophy, and hyperplasia of the tubular epithelium. Adrenal cortical hypertrophy was noted at the two highest DMH doses. Focal cardiac myocytolysis was also noted at high DMH doses. Renal damage occurred only rarely in the absence of liver pathology, and adrenal hypertrophy only rarely without renal damage. Cardiac myocytolysis was found in 14% of mice without hepatic, renal, or adrenal damage, but in 62% of those with lesions in each of those organs. No evidence of gastrointestinal toxicity was observed. Hepatic, renal, and adrenal lesions were more frequent and severe in mice fed the low-protein diet. The protective effect of high protein was DMH-dose dependent. The lower doses in these studies could be used to investigate effects of diet, cocarcinogens, or chemopreventative agents on carcinogenesis resulting from chronic, low-level dietary exposure to DMH.

A longitudinal study of aspartate aminotransferase in human gingival crevicular fluid.

Previous studies have shown that aspartate aminotransferase (AST), an established serum marker for cardiac and liver damage in humans, appears in elevated concentrations in samples of gingival crevicular fluid (GCF) from ligated vs. non-ligated teeth in beagle dogs and in elevated quantities in cross-sectional GCF sampling, adjusted for collection time, from human sites with clinical signs of past or present periodontal disease as compared to healthy sites. This paper describes a longitudinal study in which AST was monitored quarterly over a 2-year period at 2 sites/tooth in 31 patients with mild to moderate adult periodontitis. In this study sample, 40 (2.6%) of 1536 sites exhibited confirmed loss of at least 2 mm of attachment during the 2-yr observation period. In comparison with healthy sites within the same patients, AST standardized to a 30-second collection interval (AST30) was elevated at these sites with new confirmed attachment loss, and at sites with past attachment loss or gingivitis in the absence of periodontitis. When both within- and between-patient variation were taken into account, observed odds-ratios associating enzyme with disease were higher for sites with new attachment loss (9-16 depending on test cut-point) than for sites with pre-study attachment loss (3-12), or gingivitis in the absence of periodontitis (5-8). AST in GCF is strongly related to human periodontal disease. The data are consistent with the hypothesis that the relationship is strongest during episodes of cumulative tissue breakdown, but the small numbers of sites with confirmed attachment loss during the study period, or with gingivitis in the absence of periodontitis, means that further clinical studies are necessary to clarify this issue.

A cross-sectional analysis of aspartate aminotransferase in human gingival crevicular fluid.

Previous investigation has shown that the concentration of aspartate aminotransferase (AST), an established serum marker for cardiac and liver damage in humans, is significantly elevated in samples of gingival crevicular fluid (GCF) from ligated teeth in beagle dogs. This paper reports on a cross-sectional study of the relationships between AST in GCF and clinical indices of human periodontal disease in 60 patients with mild to moderate adult periodontitis. AST standardized to a 30-second collection interval (AST30) showed substantial (multiple regression R2 = 0.61) association with summary indices of patient disease status, modest association (partial R2 = 0.22) with tooth disease status within patient, and weaker (partial R2 = 0.12) but statistically significant association with site-to-site variation in disease at the same tooth. AST concentration showed modest (R2 = 0.30) between-patient relationship with clinical indices, but no clinically significant relationship with these indices between sites within patients, suggesting a rough proportionality between accumulated enzyme and GCF volume at sites with varying stages of disease. The relationship between GCF volume and probing depth also appears central to interpretation of enzyme assays. Clinical measures of past periodontitis and current inflammatory disease are cross-sectionally related to variation in AST30, across patients and sites within the same patient. Considerable residual variation, especially elevated AST30 in the absence of clear signs of disease, may result from varying levels of current disease activity, not reflected in clinical measures.

Adult root caries survey of two similar communities with contrasting natural water fluoride levels.

For a comparative study of root caries, 502 adult lifelong residents of a naturally fluoridated community (1.6 ppm F) and 465 such residents of a nearby, comparable nonfluoridated community (0.2 ppm F) were examined. Substantially fewer carious lesions were found among adults in the fluoridated community relative to the nonfluoridated community. This was observed in virtually all age- and gender-specific groups. Given a cross-sectional design and considering only exposed root surfaces, root caries was related to age. In addition, the data from this study show that the number of root caries lesions is underestimated but that root caries prevalence is overestimated by the standard Root Caries Index (RCI). A less restrictive form of the RCI may lead to more valid estimation of root caries prevalence.

The combined effects of dietary protein and fat intake during the promotion phase of 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats.

A 3 X 3 factorial experiment was conducted to examine the effects of dietary protein (8, 16 or 32% of energy from casein) and dietary fat (12, 24 or 48% of energy from corn oil) on the promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis in rats. A purified diet with protein and fat supplying 16 and 24% of energy, respectively, was fed to 360 rats. After 4 wk each rat received DMBA (20 mg/kg) via gastric intubation. Forty rats were then randomly assigned to each of the nine dietary treatments for 28 wk. We observed no effects of protein or interactions between protein and fat on mammary tumorigenesis. At necropsy, rats fed diets containing 12, 24 and 48% of energy from corn oil following DMBA administration showed tumor prevalences of 53, 60 and 70% with 109, 127 and 140 total tumors, respectively. Linear logistic statistical modeling indicated that each doubling of dietary fat concentration multiplied the odds of finding a tumor of any histologic type at necropsy by 1.52. Dietary fat had no significant effects on the prevalence of adenomas or fibroadenomas, whereas those fed corn oil at 12, 24 and 48% of dietary energy showed adenocarcinoma prevalences of 34, 41 and 52% with total adenocarcinoma counts of 66, 75 and 96, respectively. Our results suggest that increasing dietary fat enhanced the promotion of DMBA-induced breast carcinogenesis over a wide range of protein intake.