Randomized trial of IV dexamethasone for acute migraine in the emergency department.

BACKGROUND: It is not yet clear if corticosteroids are useful for the treatment of migraine. We determined the efficacy of 10 mg of IV dexamethasone as adjuvant therapy for patients presenting to an emergency department (ED) with acute migraine. METHODS: This was a randomized, double-blind, placebo-controlled multicenter trial. Subjects were randomized to dexamethasone 10 mg IV or placebo. As primary treatment for their migraine, all subjects received IV metoclopramide. Our primary hypotheses were the following: a greater percentage of patients with migraine who received dexamethasone would 1) achieve a headache-free state in the ED and maintain it for 24 hours and 2) have no headache-related functional impairment after ED discharge when compared to placebo. RESULTS: A total of 656 patients were approached for participation and 205 were randomized. The persistent pain-free outcome was achieved in 25% of those randomized to dexamethasone and 19% of placebo (p = 0.34). No functional impairment after ED discharge occurred in 67% of those randomized to dexamethasone and 59% of placebo (p = 0.20). In the subgroup of subjects with migraine lasting longer than 72 hours, 38% of those randomized to dexamethasone were persistently pain-free vs 13% of placebo (p = 0.06). Side effect profiles were similar, with the exception of acute medication reactions, which occurred more commonly in the dexamethasone group. CONCLUSION: A moderate dose of IV dexamethasone should not be administered routinely for the emergency department-based treatment of acute migraine, although it might be useful for patients with migraine lasting longer than 72 hours.

Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma.

Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case-control study, four polymorphisms in the Cox-2 gene (two in the promoter, -663 insertion/deletion, GT/(GT) and -798 A/G; one in intron 5-5229, T/G; one in 3'untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at -663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR)=0.59, confidence interval (CI): 0.34-1.02 and OR=0.48, CI: 0.24-0.99, respectively), whereas the heterozygous genotype T/C at 3'UTR-8494 had a positive association (OR=1.31, CI: 1.01-1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3'UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR=1.35, CI: 1.07-1.70), but the one with a risk allele at 3'UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR=0.85, CI: 0.66-1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.

Cancer risk and diet in India.

India is a developing country with one of the most diverse populations and diets in the world. Cancer rates in India are lower than those seen in Western countries, but are rising with increasing migration of rural population to the cities, increase in life expectancy and changes in lifestyles. In India, rates for oral and oesophageal cancers are some of the highest in the world. In contrast, the rates for colorectal, prostate, and lung cancers are one of the lowest. Studies of Indian immigrants in Western societies indicate that rates of cancer and other chronic diseases, such as coronary heart disease and diabetes, increase dramatically after a generation in the adopted country. Change of diet is among the factors that may be responsible for the changing disease rates. Diet in India encompasses diversity unknown to most other countries, with many dietary patterns emanating from cultural and religious teachings that have existed for thousands of years. Very little is known, however, about the role of the Indian diet in causation of cancer or its role, if any, in prevention of cancer, although more attention is being focused on certain aspects of the Indian diet, such as vegetarianism, spices, and food additives. Of particular interest for cancer prevention is the role of turmeric (curcumin), an ingredient in common Indian curry spice. Researchers also have investigated cumin, chilies, kalakhar, Amrita Bindu, and various plant seeds for their apparent cancer preventive properties. Few prospective studies, however, have been conducted to investigate the role of Indian diet and its various components in prevention of cancer. From a public health perspective, there is an increasing need to develop cancer prevention programs responsive to the unique diets and cultural practices of the people of India.

Effect of age on acute pain perception of a standardized stimulus in the emergency department.

STUDY OBJECTIVE: The study was undertaken to determine whether pain perception is different in elderly patients than in younger patients. METHODS: A cross-sectional, observational study was conducted at 2 urban academic emergency departments. Adult patients (> or =18 years of age) who required an 18-gauge intravenous catheter as part of their ED care were eligible. Patients were excluded for the following conditions: more than one attempt at intravenous catheter placement, altered mental status, visual impairment, intoxication, distracting pain, or abnormal upper extremities. Patients were asked to indicate on a 10-cm visual analog scale (VAS) the amount of pain they had at baseline immediately before intravenous catheter placement. They were then asked to indicate on a separate VAS the amount of pain caused by intravenous catheter placement. Patients aged 65 years and older were defined a priori as elderly. RESULTS: Of 100 patients enrolled in the study, 32 (32%) were elderly. Elderly patients reported significantly less pain than nonelderly patients (Delta = -15 mm, 95% confidence interval -26 to -4 mm). Pain of intravenous catheter placement was not associated with sex, baseline pain, site of intravenous catheter insertion, or level of training of the individual placing the intravenous catheter. CONCLUSION: Elderly patients experienced less acute pain than their younger counterparts in response to a standardized stimulus in a clinical setting. This difference is both statistically and clinically significant. This may have clinical implications for the assessment and treatment of acute pain in the elderly.

From carcinogenesis to clinical interventions for cancer prevention.

During the last three decades, the scientific community has made immense progress in acquiring the knowledge needed to prevent cancer. Pioneering research helped to identify potential causes of cancer, particularly environmental factors such as diet, and provided insight regarding their mechanisms-of-action. Concurrently, promising inhibitors of cancer that appeared able to either arrest or reverse cancer development by interfering with one or more steps in the process of carcinogenesis were identified and systematically evaluated for their potential as chemopreventive agents. Numerous agents determined to be safe and effective in preclinical trials have been and continue to be tested in Phase I,II, and III clinical interventions for cancers at various sites, including breast, colon, prostate, esophagus, mouth, lung, cervix, endometrium, ovary, liver, bladder, and skin. The development of valid intermediate biomarkers that can serve as surrogate endpoints for clinical disease is urgently needed to accelerate advances in clinical trials for cancer prevention.

Diet and cancer prevention.

Research from several sources provides strong evidence that vegetables, fruits, and whole grains, dietary fibre, certain micronutrients, some fatty acids and physical activity protect against some cancers. In contrast, other factors, such as obesity, alcohol, some fatty acids and food preparation methods may increase risks. Unravelling the multitude of plausible mechanisms for the effects of dietary factors on cancer risk will likely necessitate that nutrition research moves beyond traditional epidemiological and metabolic studies. Nutritional sciences must build on recent advances in molecular biology and genetics to move the discipline from being largely 'observational' to focusing on 'cause and effect'. Such basic research is fundamental to cancer prevention strategies that incorporate effective dietary interventions for target populations.

Molecular targets for nutrients involved with cancer prevention.

Dietary nutrients can influence cancer risk by inhibiting or enhancing carcinogenesis through diverse mechanisms of action. The identification and elucidation of their sites of action have been a focus of nutrition and cancer research for more than four decades. Transforming nutrition and cancer research from a predominantly observational to a molecular approach offers exciting opportunities for truly identifying those who will and will not benefit from dietary intervention strategies. The emerging field of nutritional genomics, defined here as the study of any genetic or epigenetic interaction with a nutrient, will be key to this evolution. Unraveling which genetic upregulation or downregulation leads to subsequent phenotype changes will not be easy. There is evidence that genetic polymorphisms can influence the dynamics between nutrients and molecular targets and, thus, contribute to variation in response among individuals. Because many molecular targets will likely be identified, it may be necessary to credential nutrients, that is, to determine which specific nutrient-related genetic and epigenetic changes bring about phenotypic changes, to establish which interactions are the most important and under what circumstances. Vitamin D, calcium, folate, selenium, genistein, and resveratrol are highlighted, because they represent specific classes of nutrients and illustrate the need to credential various nutrients to understand their physiological significance in cancer prevention. As the science of nutrition unfolds, a clearer understanding will emerge about how nutrients can modulate cancer risk through molecular interactions and how foods might be changed by agronomic approaches and/or biotechnology. Undeniably, embracing new genomic technologies offers exciting opportunities for advances in the broad area of nutrition, especially those related to cancer prevention.

Creating a new paradigm in nutrition research within the National Cancer Institute.

Almost two decades after Doll and Peto (1981) provided evidence that one third of cancer deaths are related to diet, it remains unclear which dietary components may be key in cancer prevention. Although the complexity of the diet can become overwhelming, the National Cancer Institute (NCI) of the National Institutes of Health (NIH) has remained steadfast in its commitment to defining the roles that diet and nutrition have in the development of cancer and has provided increased research and training support to assist in unraveling this interrelationship. Evidence for this sustained commitment is highlighted by a fourfold increase in NCI expenditures for nutrition research and training from 1983 to 1998; this substantial increase reflects a trend that is occurring in some universities and the private sector. More than one third of the nutrition-related NCI research is funded by the Division of Cancer Prevention. Supported investigations cover the gamut from basic mechanisms of action of dietary constituents, methodology development, human metabolic studies, clinical trials of dietary modification and the chemopreventive potential of individual nutrients to population-based studies.

Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer.

This paper proposes a scientific basis and possible strategy for applying surrogate end points in chemopreventive drug development. The potential surrogate end points for cancer incidence described are both phenotypic (at the tissue, cellular, and molecular levels) and genotypic biomarkers. To establish chemopreventive efficacy in randomized, placebo-controlled clinical trials, it is expected that in most cases it will be critical to ensure that virtually all of the biomarker lesions are prevented or that the lesions prevented are those with the potential to progress. This would require that both the phenotype and genotype of the target tissue in agent-treated subjects, especially in any new or remaining precancers, are equivalent to or show less progression than those of placebo-treated subjects. In the National Cancer Institute chemoprevention program, histological modulation of a precancer (intraepithelial neoplasia) has thus far been the primary phenotypic surrogate end point in chemoprevention trials. Additionally, we give high priority to biomarkers measuring specific and general genotypic changes correlating to the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at a specific microsatellite loci). Other potential surrogate end points that may occur earlier in carcinogenesis are being analyzed in these precancers and in nearby normal appearing tissues. These biomarkers include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers also may be monitored (e.g., prostate-specific antigen) because of their accessibility. Potentially chemopreventive drug effects of the test agent also may be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). These initial studies are expected to expand the list of validated surrogate end points for future use. Continued discussion and research among the National Cancer Institute, the Food and Drug Administration, industry, and academia are needed to ensure that surrogate end point-based chemoprevention indications are feasible.

Cancer chemoprevention: progress and promise.

Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The focus of chemoprevention research in the next millennium will include defining the genotypic and phenotypic (functional and histological) changes during carcinogenesis, the cancer risk conferred by these changes, their modulation in preclinical experimentation and randomised clinical trials by chemopreventive drugs, dietary agents and regimens and treatments resulting from early detection. The key elements of this research effort will be basic and translational risk evaluation programmes; chemopreventive and dietary agent drug discovery and development; development of transgenic animal models; required safety and pharmacology studies; well-designed phase I, II and III chemoprevention studies; and much expanded early detection programmes. The large number of chemoprevention research programmes now ongoing ensures that the promise of chemoprevention will continue to be realised in the next decade.

Cancer chemoprevention: progress and promise.

Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The focus of chemoprevention research in the next millennium will include defining the genotypic and phenotypic (functional and histological) changes during carcinogenesis, the cancer risk conferred by these changes, their modulation in preclinical experimentation and randomised clinical trials by chemopreventive drugs, dietary agents and regimens and treatments resulting from early detection. The key elements of this research effort will be basic and translational risk evaluation programmes; chemopreventive and dietary agent drug discovery and development; development of transgenic animal models; required safety and pharmacology studies; well-designed phase I, II and III chemoprevention studies; and much expanded early detection programmes. The large number of chemoprevention research programmes now ongoing ensures that the promise of chemoprevention will continue to be realised in the next decade.

Fat, caloric intake, and obesity: lifestyle risk factors for breast cancer.

Dietary fat is a likely important determinant of postmenopausal breast cancer as part of an intricate and inseparable interaction of lifestyle cancer risk factors that include dietary fat, type of fat, energy intake and expenditure, and obesity. These factors possibly build upon individual susceptibilities derived from a complex array of polygenetic risk determinants. Epidemiologic studies have not provided conclusive evidence for a dietary fat-breast cancer association, partly because studies that focus on a single nutrient cannot always evaluate readily the interactive effects of other lifestyle factors. Further, persons generally underestimate their usual dietary intake, measured by either food frequency questionnaires (FFQs) or diet records. A dietary measurement model that accounts for this underreporting demonstrated that FFQs and diet records may not be able to detect a dietary fat-breast cancer association because of measurement error biases. Although meta-analysis of epidemiologic data across individual studies suggests only a week association between breast cancer and dietary fat, this result is compatible with the dietary measurement model and does not rule out a contributing role for dietary fat, either alone or with other causative factors. Research is needed that focuses on a comprehensive approach to dietary lifestyle choices and breast cancer risk and that emphasizes a fat-caloric intake-obesity linkage. The best hope for a definitive answer may rest with randomized, controlled clinical trials. Two such trials, the Women's Health Initiative and the Women's Intervention Nutrition Study, are under way.