Elevated prevalence of nodal positivity in carcinoid tumours of the appendix smaller than 2 cm has a negative impact on overall survival.

AIM: The current standard of care for clinically node-negative carcinoid tumours of the appendix < 2.0 cm in size is appendectomy alone. The aim of this analysis was to evaluate the prevalence of pathological nodal positivity in clinically node-negative appendiceal tumour specimens < 2.0 cm and quantify the impact of occult pathological nodal positivity on overall survival following resection. METHOD: A retrospective database review of the 2019 US National Cancer Database for appendiceal cancer identified 2007 cases of clinically node-negative appendiceal carcinoid tumours based on SEER histology codes 8240, 8241, 8242, 8243, 8243, 8244, 8245, 8246 and 8249. Kaplan-Meier with log-rank testing and multivariate Cox regression analysis evaluated the impact of occult nodal positivity on overall survival following resection for clinically node-negative appendiceal carcinoma. RESULTS: The prevalence of occult nodal positivity increased from 1.9% for sub-centimetre tumours to 7% for tumours between 1.0 and 1.5 cm, 16.5% for tumours between 1.5 and 2.0 cm and to >29.5% for tumours > 2.0 cm. Rates of metastatic spread were similar for tumours < 2.0 cm but increased for larger tumours. Over two-thirds of patients received a segmental colectomy as definitive surgical therapy. After controlling for differences in cohorts, multivariate analysis showed an increased hazard ratio for mortality of 162% (HR 2.62, CI 1.884-3.541) for patients with pathological node-positive disease. CONCLUSION: Clinically node-negative carcinoid tumours of the appendix bigger than 1.5 cm have an increased rate of occult nodal spread which has a negative impact on overall survival.

Systemic IFN-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.

Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-beta (hIFN-beta) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-beta in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-beta gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-beta (mIFN-beta) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-beta in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.

Intra-arterial delivery of a recombinant adenovirus does not increase gene transfer to tumor cells in a rat model of metastatic colorectal carcinoma.

Hepatic artery infusion of adenoviral vectors has been shown to increase transduction of certain hepatocellular malignancies in preclinical studies. In addition, clinical trials have begun evaluating the efficacy of gene transfer of cytotoxic genes to metastatic colorectal tumors through hepatic artery infusion. Here we evaluate the extent of gene expression and therapeutic effect following various routes of administration of recombinant adenovirus in a rat model of metastatic colorectal carcinoma. We administered adenovirus (AdCMVlacZ) to rats with established colorectal metastases through infusion into the hepatic artery, intravenous infusion, or direct injection into a tumor. Intravenous administration resulted in transduction of hepatocytes, but not tumor cells. Hepatic arterial administration failed to substantially increase transduction of tumor cells. In addition, ligation of the hepatic artery following infusion of adenovirus or the addition of lipiodol infusion had no effect on the transduction of tumor cells. We administered AdCMVp53 by direct injection into tumors, intravenous administration, or hepatic artery infusion to evaluate the delivery of a therapeutic gene. Direct injection of AdCMVp53 into established hepatic colorectal metastases resulted in a therapeutic response in comparison with both hepatic arterial and intravenous infusion of vector. These preclinical studies fail to support a strategy of infusion through the hepatic artery of recombinant adenovirus targeting tumor cells in the treatment of colorectal cancer liver metastases.

Postexercise nutrient intake timing in humans is critical to recovery of leg glucose and protein homeostasis.

Although the importance of postexercise nutrient ingestion timing has been investigated for glycogen metabolism, little is known about similar effects for protein dynamics. Each subject (n = 10) was studied twice, with the same oral supplement (10 g protein, 8 g carbohydrate, 3 g fat) being administered either immediately (EARLY) or 3 h (LATE) after 60 min of moderate-intensity exercise. Leg blood flow and circulating concentrations of glucose, amino acids, and insulin were similar for EARLY and LATE. Leg glucose uptake and whole body glucose utilization (D-[6,6-2H(2)]glucose) were stimulated threefold and 44%, respectively, for EARLY vs. LATE. Although essential and nonessential amino acids were taken up by the leg in EARLY, they were released in LATE. Although proteolysis was unaffected, leg (L-[ring-2H(5)]phenylalanine) and whole body (L-[1-13C]leucine) protein synthesis were elevated threefold and 12%, respectively, for EARLY vs. LATE, resulting in a net gain of leg and whole body protein. Therefore, similar to carbohydrate homeostasis, EARLY postexercise ingestion of a nutrient supplement enhances accretion of whole body and leg protein, suggesting a common mechanism of exercise-induced insulin action.

Gene therapy of metastatic disease: progress and prospects.

Gene therapy remains a new and exciting therapy that holds the potential to impact the care of many diseases. Cancer gene therapy strategies encompass a major part of this developing field. Initial preclinical and phase I clinical trials have demonstrated the ability to transfer genetic material to cells in vitro and in vivo with resultant expression of biologically active protein. Most of these studies have involved direct injection or local installation of vector. A majority of patients succumbing to cancer do so because of metastatic disease. Clearly, to broaden the impact of cancer gene therapy on these patients' outcome, new strategies for targeting regional or systemic disease are required. This article offers a review of current vectors and therapeutic strategies along with the application of these in human cancers.

Percutaneous coronary intervention versus medical therapy for coronary heart disease.

Medical therapy reduces myocardial infarction and death in patients with stable coronary heart disease (CHD). In contrast, there is little evidence available to evaluate the impact of percutaneous coronary intervention (PCI) on hard endpoints in such patients. Four randomized, controlled trials have compared PCI with medical therapy. These studies have demonstrated that PCI results in an improvement in angina and exercise tolerance compared with medical therapy, but they also suggest that medical therapy may be preferable to PCI with respect to the risk of cardiac events. Interpretation of these studies has been limited by small sample size, exclusion of high-risk subjects, no or reduced use of stents, lack of a cost- effectiveness evaluation, and absence of risk factor intervention (except for Atorvastatin versus Revascularization Treatment, which used aggressive low-density lipoprotein lowering with atorvastatin in the medical group only). The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial will permit better definition of the role of PCI in the treatment of stable or recently stabilized patients with CHD.

Current perspectives on statins.

Statins (HMG-CoA reductase inhibitors) are used widely for the treatment of hypercholesterolemia. They inhibit HMG-CoA reductase competitively, reduce LDL levels more than other cholesterol-lowering drugs, and lower triglyceride levels in hypertriglyceridemic patients. Statins are well tolerated and have an excellent safety record. Clinical trials in patients with and without coronary heart disease and with and without high cholesterol have demonstrated consistently that statins reduce the relative risk of major coronary events by approximately 30% and produce a greater absolute benefit in patients with higher baseline risk. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis, and inflammation. Mechanisms independent of LDL lowering may play an important role in the clinical benefits conferred by these drugs and may ultimately broaden their indication from lipid-lowering to antiatherogenic agents.

Self-reported cardiac risk factors in emergency department nurses and paramedics.

STUDY OBJECTIVE: Our objective was to assess the prevalence of cardiac risk factors in a sample of urban paramedics and emergency department (ED) nurses. METHODS: We asked 175 paramedics and ED nurses working at a busy, urban ED to complete a cardiovascular risk assessment. The survey asked subjects to report smoking history, diet, exercise habits, weight, stress levels, medication use, history of hypertension or cardiac disease, family history of cardiovascular disease (CVD), and cholesterol level (if known). RESULTS: 129 of 175 surveys were returned (74% return rate) by 85 paramedics and 44 nurses. The percentages of paramedics and nurses at high or very high risk for cardiac disease were 48% and 41%, respectively. Forty-one percent of female respondents and 46% of male respondents were at high or very high risk. Cigarette smoking was reported in 19% of the paramedics and 14% of the nurses. The percentages of paramedics and nurses who reported hypertension were 13% and 11%, respectively. High cholesterol was reported in 31% of paramedics and 16% of nurses. CONCLUSIONS: Forty-eight percent of paramedics and 41% of ED nurses at this center are at high or very high risk for cardiovascular disease, by self-report. Efforts should be made to better educate and intervene in this population of health-care providers in order to reduce their cardiac risk.

The epidemiology of low levels of high-density lipoprotein cholesterol in patients with and without coronary artery disease.

Low levels of high-density lipoprotein cholesterol (HDL-C), and elevated total cholesterol-to-HDL-C ratios are independently associated with increased risk of coronary artery disease. In observational studies, every 1-mg/dL increment in HDL-C is associated with a 2% decreased risk of coronary artery disease in men and 3% decreased risk in women. On average, HDL-C levels are lower in men than in women, and are lower in whites than in blacks. Low HDL-C has also been found to be linked to higher risk of ischemic stroke, degree of carotid atherosclerosis, increased atherosclerotic progression as measured by coronary arteriography, higher coronary mortality among people with cardiovascular disease, and the development of coronary artery disease among patients with diabetes mellitus.

Nonlipid primary and secondary prevention strategies for coronary heart disease.

Widespread application of proven primary and secondary preventive strategies for coronary heart disease would result in substantial savings of life and health care dollars. Proven strategies (excluding lipid therapy) include quitting smoking, treating hypertension, physical activity, aspirin therapy, and appropriate use of anticoagulants, beta blockers, and angiotensin-converting enzyme inhibitors in survivors of myocardial infarction. Estrogen replacement therapy is currently under clinical investigation. Avoidance of obesity and tight control of diabetes are prudent interventions as yet unproved by clinical trials. Unfortunately, preventive strategies are frequently underutilized. The greatest challenge for preventive cardiology is to put into practice what we already know to prevent the development and progression of atherosclerosis.

Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).

BACKGROUND: Recent clinical trials have shown that modification of plasma lipoprotein concentrations can favorably alter progression of coronary atherosclerosis, but no data exist on the effects of a comprehensive program of risk reduction involving both changes in lifestyle and medications. This study tested the hypothesis that intensive multiple risk factor reduction over 4 years would significantly reduce the rate of progression of atherosclerosis in the coronary arteries of men and women compared with subjects randomly assigned to the usual care of their physician. METHODS AND RESULTS: Three hundred men (n = 259) and women (n = 41) (mean age, 56 +/- 7.4 years) with angiographically defined coronary atherosclerosis were randomly assigned to usual care (n = 155) or multifactor risk reduction (n = 145). Patients assigned to risk reduction were provided individualized programs involving a low-fat and -cholesterol diet, exercise, weight loss, smoking cessation, and medications to favorably alter lipoprotein profiles. Computer-assisted quantitative coronary arteriography was performed at baseline and after 4 years. The main angiographic outcome was the rate of change in the minimal diameter of diseased segments. All subjects underwent medical and risk factor evaluations at baseline and yearly for 4 years, and reasons for all hospitalizations and deaths were documented. Of the 300 subjects randomized, 274 (91.3%) completed a follow-up arteriogram, and 246 (82%) had comparative measurements of segments with visible disease at baseline and follow-up. Intensive risk reduction resulted in highly significant improvements in various risk factors, including low-density lipoprotein cholesterol and apolipoprotein B (both, 22%), high-density lipoprotein cholesterol (+12%), plasma triglycerides (-20%), body weight (-4%), exercise capacity (+20%), and intake of dietary fat (-24%) and cholesterol (-40%) compared with relatively small changes in the usual-care group. No change was observed in lipoprotein(a) in either group. The risk-reduction group showed a rate of narrowing of diseased coronary artery segments that was 47% less than that for subjects in the usual-care group (change in minimal diameter, -0.024 +/- 0.066 mm/y versus -0.045 +/- 0.073 mm/y; P < .02, two-tailed). Three deaths occurred in each group. There were 25 hospitalizations in the risk-reduction group initiated by clinical cardiac events compared with 44 in the usual-care group (rate ratio, 0.61; P = .05; 95% confidence interval, 0.4 to 0.9). CONCLUSIONS: Intensive multifactor risk reduction conducted over 4 years favorably altered the rate of luminal narrowing in coronary arteries of men and women with coronary artery disease and decreased hospitalizations for clinical cardiac events.

Saturated fat intake and insulin resistance in men with coronary artery disease. The Stanford Coronary Risk Intervention Project Investigators and Staff.

BACKGROUND: To determine whether there is an association between diet and plasma insulin concentration that is independent of obesity, we studied the relation of dietary composition and caloric intake to obesity and plasma insulin concentrations in 215 nondiabetic men aged 32-74 years with angiographically proven coronary artery disease. METHODS AND RESULTS: After adjusting for age, the intake of saturated fatty acids and cholesterol were positively correlated (p less than 0.05) with body mass index (r = 0.18, r = 0.16), waist-to-hip circumference ratio (r = 0.21, r = 0.22), and fasting insulin (r = 0.26, r = 0.23). Carbohydrate intake was negatively correlated with body mass index (r = -0.21), waist-to-hip ratio (r = -0.21), and fasting insulin (r = -0.16). Intake of monounsaturated fatty acids did not correlate significantly with body mass index or waist-to-hip circumference ratio but did correlate positively with fasting insulin (r = 0.24). Intake of dietary calories was negatively correlated with body mass index (r = -0.15). In multivariate analysis, intake of saturated fatty acids was significantly related to elevated fasting insulin concentration independently of body mass index. CONCLUSIONS: These cross-sectional findings in nondiabetic men with coronary artery disease suggest that increased consumption of saturated fatty acids is associated independently with higher fasting insulin concentrations.

Psychosocial predictors of physical activity in adolescents.

Regular physical activity consistently demonstrates an inverse relationship with coronary heart disease and has positive effects on quality of life and other psychological variables. Despite the benefits of exercise, many youth and adults maintain a sedentary lifestyle. Interventions are needed, particularly with youth, to increase levels of physical activity. A better understanding of the psychosocial predictors of physical activity will aid in structuring these interventions. Longitudinal data from a cohort of 743 10th-grade students from the control condition of the Stanford Adolescent Heart Health Program were analyzed. Regression analysis indicated that psychosocial variables were significantly related to physical activity after controlling for baseline levels of physical activity and BMI. Associations with physical activity were found for intention to exercise, self-efficacy, stress, and direct social influence. The designers of future interventions should consider including program components that target these variables.

Temporal representation of clinical algorithms using expert-system and database tools.

The HyperLipid Advisory System combines a rule-based implementation of a clinical algorithm (the NIH Cholesterol Education Program Expert Panel recommendations) with a temporal representation that facilitates reasoning over time while maintaining efficient storage in a standard database. The temporal representation consists of objects that model point events such as visits and interval events such as specific therapies. These objects are combined into abstractions called phases, which correspond to higher level clinical concepts such as a diet or drug treatment. The time-oriented data objects are referenced in the rules using a custom-tailored operator query language. Between user sessions relevant clinical data are stored in external files. When the advisory system is reconsulted, this information is retrieved and mapped back into an object-oriented format. Use of a commercially available expert-system shell for such tasks allows algorithm implementation in standard personal computing environments.

The Stanford Adolescent Heart Health Program.

This study was designed to create, implement, and test a school-based multiple risk factor reduction program for high school students. All tenth graders in four senior high schools (N = 1447) from two school districts participated in the study. Within each district, one school was assigned at random to receive a special 20-session CVD risk reduction intervention and one school served as a control. The schools were matched for size and distribution of racial groups before randomization. At a two-month follow-up, knowledge gains were significantly greater for students in the treatment group on each of the risk factor domains tested: nutrition/diet (p less than 0.0001), physical activity (p less than 0.0001), and cigarette smoking (p less than 0.0001). Compared to controls, a higher proportion of those in the treatment group who were not exercising regularly at baseline, reported regular exercise at follow-up (p less than 0.0003). Almost twice as many baseline experimental smokers in the treatment group reported quitting at follow-up while only 5.6% of baseline experimental smokers in the treatment group graduated to regular smoking compared to 10.3% in the control group (p = 0.009). Students in the treatment group were more likely to report that they would choose heart healthy snack items (p less than 0.0001). Beneficial treatment effects were observed for resting heart rate (p less than 0.0001), BMI (p = 0.05), triceps skinfold thickness (p = 0.003), and subscapular skinfold thickness (p = 0.01). The results suggest that it is feasible to provide CVD risk reduction training to a large segment of the population through school-based primary prevention approaches.

Depressive symptoms and substance use among adolescent binge eaters and purgers: a defined population study.

We surveyed 646 tenth grade females in Northern California to assess the prevalence of binge eating and purging behaviors. Of these, 10.3 per cent met study criteria for bulimia and an additional 10.4 per cent reported purging behaviors for weight control. Bulimics and purgers were heavier, had greater triceps and subscapular skinfold thicknesses, and reported higher rates of drunkenness, marijuana use, cigarette use, and greater levels of depressive symptomatology.

Perspectives on adolescent substance use. A defined population study.

We asked 1447 tenth graders to complete a survey on physical activity, nutrition, stress, and substance use and to undergo basic physical assessments. In a multiple regression analysis, increased level of substance use by both boys and girls was most strongly predicted by friends' marijuana use. For boys, this was followed by perceived safety of cigarette smoking; poor school performance; parents' education; and use of diet pills, laxatives, or diuretics for weight control, accounting for 44% of the overall variation in substance use. For girls, friends' marijuana use was followed by poor school performance; self-induced vomiting for weight control; perceived safety of cigarette smoking; use of diet pills, laxatives, or diuretics for weight control; parents' education; perceived adult attitudes about cigarettes; and nonuse of seat belts, accounting for 53% of the overall variance. Separate multiple regression analyses for each substance produced similar results. The homogeneity of the study population precluded ethnic comparisons. These findings suggest that for many purposes substance use may be considered a single behavior regardless of the specific substance(s) used and that substance use may exist as part of a syndrome of adolescent problem behaviors. In addition, the potent influence of perceived social environment suggests that a social influence resistance model may represent the most successful preventive strategy.

Nicotine yield and measures of cigarette smoke exposure in a large population: are lower-yield cigarettes safer?

We examined the relationship of machine-estimated nicotine yield by cigarette brand with the level of cigarette consumption and two biochemical measures of smoke exposure (expired-air carbon monoxide and plasma thiocyanate) in a large, population-based sample of smokers (N = 713). The lower the nicotine yield of the cigarette, the greater the number of cigarettes smoked per day. Prior to adjusting for number of cigarettes smoked per day, nicotine yield was not related to the actual measures of smoke exposure. Smokers of ultralow-yield cigarettes had laboratory tests of smoke exposure which were not significantly different from those of smokers of higher-yield brands. Only after adjustment for number of cigarettes smoked per day did nicotine yield become significantly related to expired-air carbon monoxide and to plasma thiocyanate. In multivariate analysis, the number of cigarettes smoked per day accounted for 28 per cent and 22 per cent of the variance in observed expired-air carbon monoxide and plasma thiocyanate levels, respectively, whereas nicotine yield accounted for only 1 per cent and 2 per cent of the variance, respectively. The relative lack of an effect of nicotine yield on the biochemical measure appears to be due to the fact that smokers of lower nicotine brands smoked more cigarettes per day, thereby compensating for reduced delivery of smoke products. Our data do not support the concept that ultralow-yield cigarettes are less hazardous than others. Machine estimates suggesting low nicotine yield underrepresent actual human consumption of harmful cigarette constituents.

Correlates of seat-belt use by adolescents: implications for health promotion.

This study examined the psychosocial and behavioral correlates of seat-belt use among 1,728 10th-graders in four Northern California high schools. Parent and friend seat-belt use patterns were most highly correlated with student seat-belt use (r = 0.66 and r = 0.61, respectively) and together accounted for 46% of the variation in use. These relationships held across differences in sex, ethnicity, and socioeconomic status. Failure to wear seat belts was associated with a higher use of alcohol, cigarettes, marijuana, and cocaine; more tolerance toward speeding and drinking while driving; less exercise; and more preference for fat in the diet. Our findings attest to the power of parent and peer influences in shaping seat-belt use by adolescents and suggest that not wearing seat belts can be conceptualized as one facet of a pattern of general risk-taking behavior. These findings suggest several possible educational interventions to increase seat-belt use by adolescents.

Self-induced vomiting and laxative and diuretic use among teenagers. Precursors of the binge-purge syndrome?

Bulimia (binge-purge syndrome) is a recently described but apparently common eating disorder. Purging behaviors associated with bulimia can cause serious medical complications. Prevalence data on purging behaviors are lacking for younger adolescents. A survey was conducted with 1,728 tenth-grade students to assess their attitudes about eating, dieting, weight control, and frequency of purging. Height, weight, and skin-fold thicknesses were also measured. Thirteen percent reported purging behavior. Female purgers outnumbered male purgers 2 to 1. Male purgers were significantly heavier than male nonpurgers and had significantly greater skin-fold thicknesses and weight/height2 ratios. Both male and female purgers felt guiltier after eating large amounts of food, counted calories more often, dieted more frequently, and exercised less than nonpurgers. Our findings suggest that an alarming number of young adolescents may employ unhealthy weight regulation strategies. Physicians who see adolescents should look for the presence of the attitudes and behaviors that characterize bulimia; this will enhance the likelihood of detection of the disorder and prevention of its complications.