• Screening Mammography: Does Overdiagnosis Overshadow Prevention of
Advanced Breast Cancer?
• Periodic Health Exams in General Population Don't Reduce Mortality Risk
• Cardiovascular Effects of Sulfonylureas and Metformin in Patients with Type 2 Diabetes
• Fecal Immunochemical Testing for Colorectal Cancer Screening
• More Evidence That Exercise Is Beneficial in Parkinson Disease
• Alcohol is a Major Contributor of Empty Calories to the American Diet
• FDA Posts Adverse Event Reports Related to Energy Drinks
• Testosterone Doesn't Improve Erectile Function When Added to Sildenafil
• Zolpidem Use Among Inpatients Associated with Higher Rate of Falls
• Do Friendly Bugs Fight Fat?
MM: Screening in general is a touchy subject and questionable in its universal need. How much good does it do in general? We see that there does not appear to be a significant improvement in mortality relative to mammography and mammography may actually be an induction to increased morbidity and anxiety associated with inaccurate diagnostic projection. Colonoscopy screenings may harbor similar statistics. As an example, if only 15% of colonoscopies have significant problems that are discovered, then 85% of screenings are unjustified. Does this mean that we should stop performing these tests? Is the risk of the test and a possible bowel perforation lessor greater than the risk of an undiscovered colon disease that may be discovered in time to treat it? Should we stop performing mammographies in the general public and reserve it only for those women who have either a familial or other predisposition for breast cancer?
N Engl J Med 2012 Nov 22; 367:1998
Screening Mammography: Does Overdiagnosis Overshadow Prevention of Advanced Breast Cancer?
Analysis of U.S. data spanning 30 years suggests many mammographically detected tumors are destined to be harmless.
Screening to lower cancer mortality should enable earlier detection of malignancies destined to be fatal while also facilitating early treatment of screen-detected cancers. U.S. investigators analyzed three decades of federal data to assess the long-term effects of screening mammography. Breast cancer rates from 1976 through 1978 (when mammography was uncommon) were used to estimate baseline incidence; data from 2006 through 2008 were used to estimate current incidence. To minimize confounding effects of menopausal hormone therapy, the transitory increase in incident breast cancers from 1990 through 2005 was not included. Models for determining the excess in screen-detected early-stage breast cancer as well as the reduction in diagnoses of late-stage cancer included the "best-guess" estimate, in which the underlying incidence of breast cancer was assumed to rise by 0.25% annually (the known percent change in women who were younger than 40).
Incidence of early-stage breast cancer rose from 112 (baseline) to 234 (current) cases per 100,000 women. During the same 30-year interval, incidence of late-stage disease declined by 8 cases per 100,000. Overdiagnosis (i.e., identification of tumors destined not to progress to advanced disease) attributable to screening mammography affected an estimated 1.3 million women (including >70,000 women in 2008 alone, when overdiagnosis accounted for 31% of tumors identified in women 40 and older). During the study period, breast cancer mortality fell by 28% among women 40 and older and by 42% in women younger than 40, a group in which screening was not prevalent.
Comment: By promoting early diagnosis of breast cancer, screening mammography can save lives. However — and consistent with other reports (JW Womens Health Sep 22 2010and JW Womens Health Aug 11 2011) — this study suggests that screening's contribution to the decline in breast cancer mortality is surpassed by improvements in treatment, and that the benefits of screening mammography are smaller and the harms associated with overdiagnosis greater than have been previously appreciated. This viewpoint supports the 2009 USPSTF recommendation that women begin biennial mammograms at age 50 (JW Womens Health Nov 16 2009). In the future, comprehensive genetic analysis of breast tumors could allow cancers to be distinguished according to their potential to cause advanced disease (JW Oncol Hematol Oct 9 2012). Until then, the pros and cons of mammography should be incorporated into the counseling that women receive as they decide whether and when to be screened.
— Andrew M. Kaunitz, MD Published in Journal Watch Women's Health November 21, 2012
CITATION(S): Bleyer A and Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012 Nov 22; 367:1998.
(http://dx.doi.org/10.1056/NEJMoa1206809)
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Periodic Health Exams in General Population Don't Reduce Mortality Risk
General wellness checks to identify disease risk factors and symptoms in healthy people appear to have no effect on mortality, according to a Cochrane meta-analysis in BMJ.
Researchers analyzed the results of 14 randomized trials comprising some 180,000 adults (geriatric trials were excluded). Patients were randomized either to health checks conducted in a primary care or community setting or to no health checks. The exams were not associated with a reduction in all-cause, cardiovascular, or cancer-related mortality.
An editorialist concludes: "The history of health promotion through routine health checks has been one of glorious failure, but generations of well meaning clinicians and public health physicians struggle to allow themselves to believe it. We need to reinforce the message lest some enthusiast reinvent the health check in another guise."
http://www.bmj.com/content/345/bmj.e7191
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Ann Intern Med 2012 Nov 6; 157:601
Cardiovascular Effects of Sulfonylureas and Metformin in Patients with Type 2 Diabetes
Compared with metformin, sulfonylurea was associated with a higher rate of cardiovascular events or death in a large retrospective study.
Cardiovascular disease (CVD) is the primary cause of death in patients with diabetes. Two common classes of drugs used in treating type 2 diabetes are sulfonylureas and metformin. Their impact on cardiovascular outcomes is not well known. Using a database from the national Veterans Health Administration, researchers conducted a retrospective cohort study comparing the effects of sulfonylureas and metformin on the composite endpoint of acute myocardial infarction, stroke, or death.
Among 253,690 patients (97% men; 75% white), metformin was prescribed in 61% and sulfonylureas in 39% (55% glyburide; 45% glipizide). Those who used both medications, rosiglitazone, or pioglitazone were excluded. Differences between the metformin and sulfonylurea groups were median follow-up (0.80 years vs. 0.61 years), median age (62 vs. 67), and hemoglobin A1c levels (7.0 vs. 7.3). Characteristics of the two groups were similar after propensity score matching of 80,648 patients in each treatment group. Unadjusted rates of the composite endpoint were 18.2 per 1000 person-years for sulfonylurea users and 10.4 per 1000 person-years among metformin users. The adjusted hazard ratio was 1.21 and was similar with glyburide and with glipizide. The authors estimated 2.2 more CVD events or deaths and 1.2 more CVD events per 1000 person-years in sulfonylurea versus metformin recipients. Results were similar in analyses stratifying patients by CVD history, age, body-mass index, and proteinuria.
Comment: Sulfonylureas appear inferior to metformin with respect to cardiovascular outcomes. As an editorialist points out, both of these drugs were approved prior to the use of cardiovascular endpoints for diabetic drug trials. The mechanism by which sulfonylureas might increase cardiovascular mortality is unclear. This retrospective cohort study indicates the need for a well-designed, evidence-based study to compare the cardiovascular safety of diabetic drugs.
— Joel M. Gore, MD Published in Journal Watch Cardiology November 21, 2012
CITATION(S): Roumie CL et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: A cohort study. Ann Intern Med 2012 Nov 6; 157:601.
http://www.ncbi.nlm.nih.gov/pubmed/23128859?dopt=Abstract
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Am J Gastroenterol 2012 Oct; 107:1570
Fecal Immunochemical Testing for Colorectal Cancer Screening
FIT detected most cancers, but only a minority of advanced adenomas.
Fecal immunochemical testing (FIT) might be more accurate than guaiac-based fecal occult blood testing (gFOBT) in screening for colorectal cancer. In this Dutch study, 1256 average-risk patients submitted single specimens for FIT (OC-Sensor) just before undergoing screening colonoscopy.
Colonoscopy identified 8 patients (0.6%) with colorectal cancer and 113 (9%) with advanced adenomas. At a cutoff of 50 ng/mL, FIT was positive in 10% of patients. Sensitivity and specificity of FIT for detecting advanced adenomas were 38% and 93%, respectively. For colorectal carcinoma, sensitivity was 88% (i.e., FIT was positive in 7 of 8 patients with cancer), and specificity was 91%. Five of the seven FIT-positive cancers were localized (Dukes stage A). FIT detected proximal and distal advanced neoplasia with equal sensitivity.
The Journal Watch General Medicine Perspective
According to these findings, if patients were screened initially with a single FIT, most localized cancers and about one third of advanced adenomas would be detected, and 90% of patients (those who were FIT-negative) would avoid colonoscopy. Failure to detect most advanced adenomas is not necessarily a fatal flaw, if additional research shows that repeated FIT screening (i.e., at 1- or 2-year intervals) detects many of these lesions before they progress to unresectable cancers. One of our Journal Watch Gastroenterologyeditors, an expert in colorectal cancer screening, comments below on FIT.
— Allan S. Brett, MD The Journal Watch Gastroenterology Perspective
Current colorectal cancer screening guidelines recommend that clinicians who use fecal blood testing switch from gFOBT to FIT (Am J Gastroenterol 2009; 104:739). Consistent results from several types of studies, including randomized, controlled trials, indicate that patient adherence (i.e., completion of the test) and test sensitivity strongly favor FIT over gFOBT. Several national screening programs outside the U.S. now are based on FIT, and cost-effectiveness analyses suggest that annual FIT is at least as cost-effective as is colonoscopy every 10 years. Several randomized, controlled trials, including one in U.S. Veterans Administration hospitals) have been organized to compare FIT and colonoscopy.
A practical problem that clinicians encounter when they try to switch to FIT is the lack of comparative performance data on the several commercial FIT assays available in the U.S. Several years ago, in a study of six commercial FITs available in Germany, researchers found that several had awful performance characteristics, including very poor specificity. However, the laboratory-based assay used in the current study (OC-Sensor) has been evaluated in many studies and is believed to perform best.
This Dutch study suggests that FIT is equally effective in both the proximal and distal colon, whereas some previous evidence had suggested better performance in the distal colon. This result is encouraging, but the endpoint for the study was advanced conventional (i.e., tubular, tubulovillous, or villous) adenomas. The study ignores (as do all FIT studies) the 30% of colorectal cancers that arise through a genetic pathway characterized by hypermethylation; the precursors of these cancers are not conventional adenomas but rather serrated lesions (sessile serrated polyps, also known as sessile serrated adenomas). Further, these serrated lesions are located primarily in the proximal colon. Endoscopically, these premalignant serrated lesions have no vessels on their surface, and some evidence shows that they don't bleed at all. The future of sensitive fecal testing that can identify both conventional and serrated precancerous lesions in the proximal colon is more likely to lie in fecal DNA testing than in FIT.
— Douglas K. Rex, MD de Wijkerslooth TR et al. Immunochemical fecal occult blood testing is equally sensitive for proximal and distal advanced neoplasia. Am J Gastroenterol 2012 Oct; 107:1570. (http://dx.doi.org/10.1038/ajg.2012.249)
http://www.ncbi.nlm.nih.gov/pubmed/22850431?dopt=Abstract
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Arch Neurol 2012 Nov 5
More Evidence That Exercise Is Beneficial in Parkinson Disease
Treadmill exercise — especially lower-intensity, longer-duration exercise — improved gait, and stretching and resistance training improved strength.
To examine the effects of various forms of exercise on gait speed, strength, and fitness in patients with Parkinson disease (PD), researchers performed a prospective, single-blind trial. They randomized 67 patients to one of three exercise treatment arms, performed three times a week for 3 months: lower-intensity treadmill training, higher-intensity treadmill training, or stretching plus resistance exercises. Higher-intensity training sessions lasted 30 minutes, and patients had to achieve 70% to 80% of their heart-rate reserve. Lower-intensity training sessions lasted 50 minutes, but patients only had to reach 40% to 50% of their heart-rate reserve. The stretching and resistance exercises were low intensity and included use of three resistance machines in a gym setting. The primary outcome was improvement in gait speed (on the 6-minute walk); secondary outcomes were cardiovascular fitness (peak oxygen consumption per unit time) and muscle strength (1-repetition maximum strength).
All three interventions significantly improved gait speed. However, lower-intensity training improved gait speed to the greatest degree (by 12%, vs. 9% with stretching/resistance training and 6% with higher-intensity exercise). Both treadmill groups had improved cardiovascular fitness variables, whereas the stretching and resistance training group had improved muscle strength and improved scores on the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale.
Comment: These findings add to an expanding literature revealing the benefits of exercise for patients with Parkinson disease. Experiments in animals previously revealed that exercise upregulates chemicals that may be important to the Parkinson brain, although the mechanisms underpinning these positive effects remain unknown.
These results may need to be reproduced in a larger clinical trial. The benefits in the stretching and resistance arm might have been greater with a more intensive intervention. Also, it is unclear how much gait speed and fitness measures will translate into quality-of-life improvements. The UPDRS motor scores did not improve for treadmill training, as they did in other studies, calling into question whether the benefits of exercise occur more in nonmotor domains, or whether this lack of improvement was specific to that intervention.
All patients improved in this study, but the results revealed important differences between the therapies that may be helpful in tailoring regimens in clinical practice.
Aerobic exercise, stretching, and resistance training may all be used and may all be potentially useful in a single patient. How to administer exercise, in what dose, and what types of exercise to use remain to be clarified by future studies.
— Michael S. Okun, MD Published in Journal Watch Neurology November 20, 2012
CITATION(S): Shulman LM et al. Randomized clinical trial of 3 types of physical exercise for patients with Parkinson disease. Arch Neurol 2012 Nov 5; [e-pub ahead of print].
(http://dx.doi.org/10.1001/jamaneurol.2013.646)
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Alcohol is a Major Contributor of Empty Calories to the American Diet
Adults in the U.S. consume an average of 100 calories from alcohol per day, according to a data brief from the CDC's National Center for Health Statistics.
Using data from NHANES 24-hour dietary recall interviews of adults from 2007 to 2010, researchers found that a third of men and 18% of women consume alcohol on a given day. Among the other findings:
- People who regularly drink alcoholic beverages obtain about 16% of their total calories from alcohol. Dietary guidelines recommend that so-called empty calories (i.e., discretionary solid fats and added sugars) should comprise no more than 5 to 15% of a healthy diet.
- People in the highest income categories consumed, on average, the most calories per day from alcohol.
- Of all the demographic groups, men aged 20 to 39 years consumed the most calories (174) from alcoholic beverages.
http://www.cdc.gov/nchs/data/databriefs/db110.htm#ref2
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FDA Posts Adverse Event Reports Related to Energy Drinks
The FDA publicly released the adverse event reports for four energy drinks — 5-Hour Energy, Monster Energy, Rockstar Energy, and Red Bull. Thus far, 18 fatalities have been linked to the highly caffeinated energy drinks (5 to Monster Energy, 13 to 5-Hour).
Some of the symptoms mentioned in the reports include increased heart rate, fatigue, vomiting, loss of consciousness, and cardiac and respiratory arrest. A federal report also found that an energy drink was listed as a possible cause for over 13,000 emergency room visits in 2009, theNew York Times reports.
The FDA says that important information may be missing from the adverse event reports, making it "difficult ... to fully evaluate" whether the energy drinks caused the injuries reported. Nevertheless, the agency advises consumers to consult a healthcare provider before using the products.
http://www.fda.gov/Food/NewsEvents/ucm328536.htm
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Testosterone Doesn't Improve Erectile Function When Added to Sildenafil
The addition of testosterone to sildenafil does not appear to improve erectile function in men with low testosterone, according to an Annals of Internal Medicine study.
During a 3- to 7-week run-in phase, 140 men with erectile dysfunction (ED) and low testosterone levels were given dose-optimized sildenafil. They were then randomized to either transdermal testosterone or placebo gel for 14 weeks.
After sildenafil treatment, both groups experienced an improvement in erectile function. But after the addition of testosterone, there were no significant differences between the groups in any measure of sexual function. The authors speculate that sildenafil may have raised men's testosterone levels enough so that additional testosterone would not have an effect. The authors note that they did not test the effect of testosterone alone.
They conclude that the findings "do not support the routine addition of testosterone therapy for improving erectile response to selective PDE5 inhibitors in men with ED who have low testosterone levels, which has become commonplace in clinical practice."
http://annals.org/article.aspx?articleid=1391696
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Zolpidem Use Among Inpatients Associated with Higher Rate of Falls
Inpatients who were given zolpidem were six times more likely to fall than patients who were prescribed the drug but didn't take it, according to a cohort study in the Journal of Hospital Medicine.
Researchers assessed zolpidem prescriptions among all non-ICU, non-pregnant inpatients at the Mayo Clinic in 2010. After adjusting for factors such as delirium and insomnia, patients who were administered zolpidem had a higher rate of falls than those who did not take zolpidem (3.04 vs. 0.71 falls per 100 patients). The authors estimate for every 55 patients treated with zolpidem, one additional fall could be expected to occur.
They note that at their institution, order sets have been changed to discourage use of zolpidem, and they recommend that other hospitals follow suit.
http://onlinelibrary.wiley.com/doi/10.1002/jhm.1985/abstract
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http://www.vitalchoice.com/shop/pc/articlesView.asp?id=1958
Do Friendly Bugs Fight Fat?
Clinical trial hints that certain probiotic bacteria help cut body fat; other friendly
bugs may fatten us
by Craig Weatherby
The October 22 issue of The New Yorker magazine featured a startling article on research into the friendly bacteria known as “probiotics”. In his article – titled “Germs Are Us: Bacteria make us sick. Do they also keep us alive?” – Michael Specter reported on some truly astonishing findings.
For example, Barry J. Marshall and J. Robin Warren earned a Nobel Prize in medicine for discovering that a bacterium called Helicobacter pylori is the leading cause of ulcers. But there’s now good evidence that body levels of the hormones that send hunger or satiety signals to the brain (i.e., ghrelin and leptin) become disordered in people who lack H. pylori.
Thanks to heavy use of antibiotics, an increasing number people have grown up without H. pylori bacteria. Consequently, these folks tend to overeat and become overweight or obese. And in 2006, researchers from Washington University in St. Louis found that microbial populations (microflora) in the gut differ between obese and lean people … and that when obese people lose weight their microflora reverts back to that observed in lean people. Last year, the same team reported that probiotic bacteria produced a change in many metabolic pathways in mice … particularly those related to carbohydrate (sugar/starch) metabolism.
Friendly bugs and weight: Species matters
Most recently, a review of the clinical and animal evidence affirms the idea that – when it comes to weight control – probiotic bugs are not created equal (Million M et al. 2012). The authors of that review found that Lactobacillus acidophilus – the bacterial strain commonly used to ferment yogurt, and put in probiotic supplements – resulted in significant weight gain in humans and in animals.In contrast, ingestion of Lactobacillus plantarum was associated with weight loss in animals and Lactobacillus gasseri was associated with weight loss both in obese humans and in animals.
As they concluded, “Different Lactobacillus species are associated different effects on weight change that are host-specific. Further studies are needed to clarify the role of Lactobacillus species in the human energy harvest and weight regulation. Attention should be drawn to the potential effects of commonly marketed lactobacillus-containing probiotics on weight gain.” (Million M et al. 2012) Now, the results of a clinical trial seem to identify two probiotic bugs that help keep body fat in check.
Probiotics may help cut body fat levels
The results of the new clinical trial, performed at the University of Winnipeg, Manitoba indicate that two probiotics help to reduce body fat … and suppress a dangerous pathogenic bug (Omar JM et al. 2012). The randomized, double-blind crossover trial was conducted by scientists from the University of Manitoba, McGill University, and Micropharma Limited. The researchers fed 28 healthy but overweight people one of three kinds of meals for 43 days, and their diets contained just enough calories to maintain their current body weights.
- Control Meal containing no probiotics.
- Test Meal containing FAE-active Lactobacillus fermentum
- Test Meal containing BSH-active Lactobacillus amylovorus
Participants ate their assigned meal regimen over six weeks, followed by a “wash-out” period to clear the subjects' systems before proceeding to the next treatment. The participants consumed the probiotics in yogurt and were not allowed to eat any other food other than the meals provided them. Each participant's fecal matter was tested to measure their gut flora before and after each treatment, and body fat was measured using a special x-ray scanner. The results showed that the probiotic meal regimens lowered body fat by three to four percent over six weeks. Co-author Dr. Peter Jones commented on the seemingly small change: “Four percent over six weeks doesn't sound like a deal maker but just do the math. Take it out for a year or a decade and you're talking about ... a pretty sizable change”. Why would probiotic bacteria affect deposition of body fat? As Dr Jones said, “If you change the types of bugs in your gut, those bugs actually metabolize energy which would otherwise be absorbed and laid down as new fat”.
In their published paper, the authors expressed this hypothesis in scientific terms
(Omar JM et al. 2012):
- “Consumption of Lactobacillus amylovorus or Lactobacillus fermentum bacteria as probiotics may assist in reducing the development of obesity, since these bacteria may confer modifications to energy handling within the host.”
- “This creates a microbiome which favors fat oxidation over fat storage, by populating the gut with protective bacteria and preventing the proliferation of pathogenic bacteria, which may ultimately lead to a reduction in body adiposity and transformation of body composition.”
Also, the group taking BSH-active Lactobacillus amylovorus showed a significant cut in their levels of clostridial cluster IV … an unhealthy bacteria related to C. difficile, a bug that often makes hospital patients very sick. Clearly, more research is needed to pinpoint the bacteria that help with weight control and those that hurt. It may be that bacteria have much more to do with weight control than ever thought ... and possibly much more than the factors usually cited, such as corn syrup.
Sources: McNulty NP, Yatsunenko T, Hsiao A, Faith JJ, Muegge BD, Goodman AL, Henrissat B, Oozeer R, Cools-Portier S, Gobert G, Chervaux C, Knights D, Lozupone CA, Knight R, Duncan AE, Bain JR, Muehlbauer MJ, Newgard CB, Heath AC, Gordon JI. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med. 2011 Oct 26;3(106):106ra106. doi: 10.1126/scitranslmed.3002701. Million M, Angelakis E, Paul M, Armougom F, Leibovici L, Raoult D. Comparative meta-analysis of the effect of Lactobacillus species on weight gain in humans and animals. Microb Pathog. 2012 Aug;53(2):100-8. Epub 2012 May 24. Omar JM, Chan YM, Jones ML, Prakash S, Jones PJH. Lactobacillus fermentum and Lactobacillus amylovorus as probiotics alter body adiposity and gut microflora in healthy persons. Journal of Functional Foods. Published online ahead of print, doi: 10.1016/j.jff.2012.09.001. Sonnenburg JL, Chen CT, Gordon JI. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol. 2006 Nov;4(12):e413.
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