• Inflammatory Bowel Disease Is Increasing
• PPIs Associated with Hip Fractures in Women, Particularly Smokers
• PPIs Don't Ease Asthma Symptoms in Children with Severe Asthma and Asymptomatic GERD
• Predicting Thyroid Dysfunction When Baseline TSH Is "Normal"
• Thigh-Length vs. Below-Knee Compression Stockings
• Nosocomial Measles Outbreak
• What's Really Important in a Woman's Lipid Profile?
• Selective and Nonselective NSAIDs Are Associated with Excess Cardiovascular Risk
• New Insights into the Biology of Metastasis
• Younger Breast Cancer Survivors Have Unique Concerns
• Breast Cancer Prognosis and Management: Role of Gene Expression Profiling
MM: Is it possible that the Standard American Diet (SAD) has pervaded so much of the world to the point that those of us in North America are sharing the maladies that seen to accompany our lifestyle along with the benefits. It would seem that, like everything else in life, one must balance the benefits with the risks. I think that nothing is more pronounced than the effects of food sensitivities on the GI tract and their subsequent effects on the immune and inflammatiry systems. It will be interesting to see if the effects of Genetically Modified Foods (GMO’s) show an even greater effect on worldwide maladies that seem to historically only have an effect on more western cultures.
Gastroenterology 2012 Jan; 142:46
Inflammatory Bowel Disease Is Increasing
A review of published research worldwide showed increasing incidence of both Crohn disease and ulcerative colitis but lacked data from developing countries.
To summarize worldwide data on the incidence and prevalence of inflammatory bowel disease (IBD) — which comprises ulcerative colitis (UC) and Crohn disease (CD) — researchers systematically reviewed 238 incidence and 122 prevalence studies. The highest percentage of studies came from Europe, the second highest from Asia and the Middle East, and the third highest from North America.
Incidence rates of IBD were highest in Europe and North America, with lower rates in Asia and the Middle East. Incidence did not differ by sex but did differ by age, with the highest rates among 20- to 29-year-olds. Among studies with at least 10 years of data that tracked incidence over time, 75% showed increasing incidence of CD, and 60% showed increasing incidence of UC. Conversely, no studies of CD and only 6% of UC studies demonstrated decreasing incidence of these conditions. In studies conducted after 1980, 56% showed increasing incidence of CD and 29% showed increasing incidence of UC. Among studies demonstrating increasing incidence of IBD, the average annual percentage change ranged from 1.2% to 23.3% for CD and from 2.4% to 18.1% for UC.
Comment: These data are consistent with the theory that increasing rates of inflammatory bowel disease are associated with industrialization and urbanization and that IBD is becoming increasingly more common on a worldwide basis.
— Douglas K. Rex, MD Published in Journal Watch Gastroenterology February 3, 2012
Citation(s):Molodecky NA et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012 Jan; 142:46.
http://www.ncbi.nlm.nih.gov/pubmed/22001864?dopt=Abstract
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PPIs Associated with Hip Fractures in Women, Particularly Smokers
Regular use of proton-pump inhibitors carries increased risk for hip fracture among postmenopausal women, especially those with a history of smoking, according to a study in BMJ.
Using data on 80,000 women from the Nurses' Health Study, researchers noted a 35% increased risk for hip fracture among regular users of PPIs. Risk increased with longer duration of use and returned to normal after stopping use for more than 2 years. However, the PPI-fracture link appeared to be limited to current or previous smokers, among whom PPI use was associated with a 50% increased risk relative to nonuse.
The authors point to previous research linking smoking to impaired calcium absorption. Since PPIs may also inhibit calcium absorption, the authors theorize that the two factors may work synergistically to increase fracture risk.
http://www.bmj.com/content/344/bmj.e372
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MM: As a pharmacist it has been alarming to see the increased use of PPI’s in children starting as neonates and progressing through adolescence. The mis-conception that these drugs are safe and even inocuous is disturbing. This attitude has been demonstrated by their ready availability as OTC products. Using a “quick fix” for a relatively minor perceived discomfort is rarely the appropriate approach to take. This is a prime example of that caveat. To think that we are causing increased upper respiratory infections and increased bone fractures in the short run; increased bacterial resistance and potentially decreased immune function in the long run makes the indiscriminate use of PPI’s in children inconscionable.
JAMA 2012 Jan 25; 307:373
PPIs Don't Ease Asthma Symptoms in Children with Severe Asthma and Asymptomatic GERD
In addition, lansoprazole raised the incidence of adverse events.
Gastroesophageal reflux disease (GERD) is more common in children with asthma than in children without asthma, but whether the association is causal is uncertain. Nonetheless, patients with uncontrolled asthma and no reflux symptoms are often given proton-pump inhibitors (PPIs) despite unproven benefit. To examine the effect of PPIs on asthma control in children, researchers randomized 306 children (age range, 6–17 years) with poorly controlled asthma and no reflux symptoms to receive lansoprazole or placebo in addi
tion to inhaled corticosteroid treatment for 24 weeks; of 115 children who underwent esophageal pH monitoring, 43% had asymptomatic GERD.
The mean change in Asthma Control Questionnaire score (the primary outcome) and secondary measures of asthma control did not differ significantly between the lansoprazole and placebo groups in the entire sample or in the subgroup of patients who had reflux on pH monitoring. Patients treated with lansoprazole were 1.3 times more likely than placebo recipients to experience upper respiratory infections (a significant difference) and had 6 times more fractures (6 vs. 1 fracture, a nonsignificant difference; P=0.06).
Comment: These results are consistent with those of a similar study in adults (JW Gen Med Apr 16 2009). Unnecessary PPI use raises asthma-related healthcare costs and risk for upper respiratory infection and possibly fracture in children. An editorialist notes that although PPIs have little or no proven benefit in children with reflux, PPIs continue to be prescribed on the basis of experience in adults and because they are perceived as safe. The available studies indicate there is no role for empirical treatment of asymptomatic GERD in patients of any age with asthma.
— David J. Amrol, MD Dr. Amrol is an Associate Professor of Clinical Internal Medicine and Director of the Division of Allergy and Immunology at the University of South Carolina School of Medicine in Columbia.
Published in Journal Watch General Medicine February 2, 2012
Citation(s):Holbrook JT et al. Lansoprazole for children with poorly controlled asthma: A randomized controlled trial. JAMA 2012 Jan 25; 307:373.
(http://dx.doi.org/10.1001/jama.2011.2035)
http://www.ncbi.nlm.nih.gov/pubmed/22274684?dopt=Abstract
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MM: I have long felt that the medical acronym “WNL” (Within Normal Limits) is one of the most offensive acronyms commonly used by medical professionals. This article demonstrates how true that is. For a long time a TSH has been considered normal if it was between 0.5 and 5.0. When these numbers arise, even if a person demonstrates symptoms, many practitioners discount what they see before them because they are looking at the numbers instead. Hopefully this study will get the appropriate attention that it should and will help the countless number of patients who have been otherwise neglected because their lab tests failed to elicit a response since they were WNL. We must recpgnize that ranges are ranges of an entire population, not a healthy population and those ranges include those who are not in an optimal place. We should reconsider our approach to look at “optimal or appropriate” ranges and not only “normal” ranges.
J Clin Endocrinol Metab 2012 Jan; 97:93
Predicting Thyroid Dysfunction When Baseline TSH Is "Normal"
In women, risk for hypothyroidism increases substantially when TSH level is 2.5 to 4.5 mIU/L.
Thyroid-stimulating hormone (TSH) levels near the upper and lower limits of the designated normal range may predict above-average risk for hypothyroidism and hyperthyroidism, respectively. In a population-based Norwegian study, researchers identified 15,000 euthyroid adults (age range of most, 40–70) who had serum TSH levels between 0.2 and 4.5 mIU/L. During a mean follow-up of 11 years, these findings emerged:
- In women, the eventual incidence of overt hypothyroidism was low (1%–3%) when baseline TSH was <2.5 mIU/L. Above this threshold, hypothyroidism eventually developed in 8%, 14%, and 32% of those with baseline TSH levels of 2.5–2.9, 3.0–3.9, and 4.0–4.5 mIU/L, respectively.
- In men, the eventual incidence of overt hypothyroidism was <2% when baseline TSH was <3.0 mIU/L. However, hypothyroidism eventually developed in 9% and 15% of those with baseline TSH levels of 3.0–3.9 and 4.0–4.5 mIU/L, respectively.
- In women, the eventual incidence of overt hyperthyroidism was roughly 1% at baseline TSH levels between 0.5 and 4.5 mIU/L. However, hyperthyroidism eventually developed in 4% of women whose baseline TSH was 0.2 to 0.49 mIU/L.
- In men, the eventual incidence of overt hyperthyroidism remained <1% regardless of baseline TSH.
Comment: Progressively higher TSH levels across the upper half of the published normal range predict progressively higher risk for developing overt hypothyroidism, especially in women. These data could help clinicians decide when to repeat TSH testing (if at all) in patients with normal thyroid function tests.
— Allan S. Brett, MD Published in Journal Watch General Medicine January 31, 2012
Citation(s): Åsvold BO et al. Serum TSH within the reference range as a predictor of future hypothyroidism and hyperthyroidism: 11-year follow-up of the HUNT study in Norway. J Clin Endocrinol Metab 2012 Jan; 97:93. (http://dx.doi.org/10.1210/jc.2011-1724)
http://www.ncbi.nlm.nih.gov/pubmed/22049180?dopt=Abstract
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MM: It should make many of those who need to wear compression hosiery happy that they may use a below the knee (BK) product with more confidence. These are typicqally less expensive and typically more comfortable than their longer counter-part. Unfortunately the issue of graduated vs anti-embolism style hosiery was not addressed in this article. The former is appropriate for ambulatory patients whereas the latter should be reserved for those who are confined to a bed. Having been a certified fitter for more than a decade I have seen many clinicians fail to recognize the difference between these very different product genres and their appropriate use. This could be due to the general use of anti-embolism hosiery in the hospital setting where most clinicians are first exposed to compression hosiery and the relative lack of information provided during clinical rotations on the differences and different uses of the two types. The fitters at Mark Drugs are trained and educated in the proper fitting and use of these products. They are happy to answer questions and assess the appropriate product to meet your needs.
Blood 2011 Dec 16;
Thigh-Length vs. Below-Knee Compression Stockings
Prevention of postthrombotic syndrome was similar with both types of stockings in patients with venous thrombosis, but adverse effects were less common with below-knee stockings.
The postthrombotic syndrome (PTS) is a serious complication of lower-extremity venous thrombosis (VT). It occurs in nearly 50% of patients with VT, despite treatment with anticoagulants, and is associated with persistent leg swelling, pain, and skin discoloration. The use of compression elastic stockings (CES) can decrease the frequency of PTS, but whether thigh-length (TL) CES are superior to below-knee (BK) CES is uncertain.
To compare the effectiveness of the two types of stockings, an international team of investigators conducted an open-label, randomized trial involving 267 patients with a first episode of VT. Of these, 135 were fitted with TL CES and 132 with BK CES. After an initial course of low-molecular-weight heparin, oral anticoagulants were administered for 6 months in 162 patients with an unprovoked VT (80 in the TL group and 82 in the BK group), and for 3 months in the 105 patients with a transient risk factor (55 in the TL CES group and 50 in the BK CES group). Patients were followed up for 3 years and, at predefined times, were assessed for PTS using the Villalta scale (JW Oncol Hematol Dec 9 2008).
PTS developed in similar percentages of patients using TL or BK CES (33.9% and 36.7%, respectively), and severe PTS occurred in three patients in each group. The hazard ratio for TL CES compared with BK CES was 0.92 and was unaffected by baseline characteristics, location of the VT (popliteal vs. more proximal vein), or duration and intensity of anticoagulant therapy. Stocking-related adverse effects such as erythema and pruritus occurred more often with TL CES than BK CES (40.7% vs. 27.3%; P=0.017) and resulted in a trend toward more-frequent discontinuation of TL CES than BK CES (21.5% vs. 13.6%; P=0.11).
Comment: Prevention of PTS has proved elusive, despite considerable study. Shortening the interval between VT diagnosis and achievement of therapeutic anticoagulation could be beneficial, as could prolonging anticoagulation in persons at risk for VT recurrence. All patients should be fitted with CES, and this study clearly shows that BK CES are preferable to TL CES.
— David Green, MD, PhD Published in Journal Watch Oncology and Hematology January 31, 2012
Citation(s):Prandoni P et al. Thigh-length versus below-knee compression elastic stockings for prevention of the post-thrombotic syndrome in patients with proximal-venous thrombosis: A randomized trial. Blood 2011 Dec 16; [e-pub ahead of print].
(http://dx.doi.org/10.1182/blood-2011-11-391961)
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MMWR Morb Mortal Wkly Rep 2012 Jan 20; 61:30
Nosocomial Measles Outbreak
Measles, contracted in a hospital emergency department, affected both unimmunized and previously vaccinated individuals.
In the U.S., most cases of measles are imported from endemic areas where immunization rates are low. On March 28, 2009, a physician reported a measles case involving an unvaccinated 23-month-old boy in Pennsylvania. Subsequently, five additional individuals with measles — including the source patient — were identified. All six individuals had been in the same hospital emergency department (ED) on March 10.
The source patient was a 10-year-old boy with unknown vaccination history who had moved to the U.S. from India 2 days before being evaluated in the ED for a rash. The infection was transmitted to the examining physician in the ED (who had a history of measles vaccination), to the index patient and family members who had accompanied him to the ED (his brother and father) for treatment of an unrelated problem, and to an 11-month-old infant who had been examined in the same ED. The index patient and his brother were unvaccinated by parental choice; the 11-month-old was too young for vaccination. All cases manifested within 18 days of the ED exposure. Diagnosis was established by detection of antimeasles IgM antibodies in the patients' serum.
Comment: In the U.S., measles vaccination is almost ubiquitous; coverage is sufficient to provide herd immunity, and endogenous cases are very rare. Unfortunately, some parents — because of religious beliefs or, more often, because of the now-rampant antivaccination propaganda — refuse to immunize their children, thereby exposing themselves and others to preventable illness. Transmission to the previously vaccinated physician raises several issues. Certainly, hospitals should maintain immunity records for all staff. However, to judge by his history, this physician should have been immune. Given the huge expense engendered by this tiny outbreak, requiring serologic proof of immunity in healthcare workers would seem to be cost-effective.
— Stephen G. Baum, MD Published in Journal Watch Infectious Diseases February 1, 2012
Citation(s): Centers for Disease Control and Prevention (CDC). Hospital-associated measles outbreak — Pennsylvania, March–April 2009. MMWR Morb Mortal Wkly Rep 2012 Jan 20; 61:30. http://www.ncbi.nlm.nih.gov/pubmed/22258416?dopt=Abstract
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Ann Intern Med 2011 Dec 6; 155:742.
What's Really Important in a Woman's Lipid Profile?
Prospective data from the Women's Health Initiative suggest that HDL level is a significant inverse predictor of coronary events, regardless of LDL level.
An inverse association exists between HDL level and cardiovascular disease. In men, this association has been found to be independent of LDL level. To find out if the association is consistent across the spectrum of LDL or apolipoprotein (apoA-I and apoB100) levels in women, researchers conducted an industry-sponsored analysis of data involving 26,861 participants in the Women's Health Study. All were aged 
45 and healthy at baseline.
During approximately 11 years of follow-up, 929 cardiovascular events occurred, including 602 coronary events and 319 strokes. In multivariate analysis, HDL and apoA-I levels were inversely associated with risk for coronary events (but not for stroke). This association was consistent in subgroups stratified by age, race, hypertension, smoking status, diabetes, hormone therapy, and body-mass index. After risk-factor adjustment, the inverse association of HDL level with coronary events remained statistically significant across the range of LDL levels. In women with low apoB100 levels, however, neither HDL nor apoA-I level was associated with coronary risk.
Comment: These observational data suggest that in healthy women, HDL level is the most useful lipid-panel predictor of incident coronary events, and that the association holds for a broad range of LDL levels. When assessing global coronary risk in women, clinicians should focus especially on HDL level. However, no outcomes studies have demonstrated an association of targeted HDL-raising therapy with improved outcomes. For now, LDL remains the prime target of lipid modification in women with hypercholesterolemia.
— Joel M. Gore, MD Published in Journal Watch Cardiology February 1, 2012
Citation(s): Mora S et al. Association of high-density lipoprotein cholesterol with incident cardiovascular events in women, by low-density lipoprotein cholesterol and apolipoprotein B100 levels: A cohort study. Ann Intern Med 2011 Dec 6; 155:742.
http://www.ncbi.nlm.nih.gov/pubmed/22147713?dopt=Abstract
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Selective and Nonselective NSAIDs Are Associated with
Excess Cardiovascular Risk
These drugs were risky in myocardial infarction patients and were associated with new-onset atrial fibrillation.
The cardiovascular risks of selective cyclooxygenase (COX)-2–blocking nonsteroidal anti-inflammatory drugs (NSAIDs) are well recognized (JW Gen Med Feb 25 2005). Current guidelines also discourage use of nonselective NSAIDs in patients with known cardiovascular disease (CVD), but some clinicians still prescribe these medications, because they believe that short-term use is unlikely to raise risk significantly. To address this issue, Danish investigators took advantage of that country's highly integrated and digitized medical databases, which accurately capture discharge diagnoses and pharmaceutical prescriptions for the entire country.
In a prospective observational study that involved 84,000 patients with first myocardial infarctions (MIs) between 1997 and 2006, 40% of patients suffered recurrent MIs or death, and 42% received NSAIDs at some time. NSAID use was associated with a significant excess risk for recurrent MI or death (hazard ratio, 1.5–1.7, depending on timing and duration of NSAID use after MI). Not surprisingly, risk was high for two COX-2 blockers, rofecoxib (HR, 1.4–2.3) and celecoxib (HR, 1.3–1.9). But, unexpectedly, risk was even higher for the nonselective NSAID diclofenac (HR, 1.7–3.3). Ibuprofen and other nonselective NSAIDs (except naproxen) also were associated with excess risk. This risk became apparent immediately after use for some NSAIDs and within several weeks for most (JW Cardiol Jun 8 2011).
In a case-control study, more than 32,000 patients with initial diagnoses of atrial fibrillation (AF) or flutter between 1999 and 2008 were compared with nearly 326,000 age- and sex-matched controls without AF or flutter. After adjustment for several confounders, risk for AF or flutter was clearly higher with current use of COX-2 blockers (incidence rate ratio, 1.27) and nonselective NSAIDs (IRR, 1.17). Those rates were even higher for NSAID users who had started the medications within 60 days of AF or flutter onset (JW Gen Med Jul 26 2011).
In neither of these studies were investigators able to capture fully and control for all risk factors that could confound the analyses. Nevertheless, the large size of the studies, the inclusion of essentially all cases in the country (i.e., no selection bias), and the quality of the data provide confidence that the results are accurate. The first study did not include patients with known CVD who had not experienced MIs. Nevertheless, the data seem to support current guidelines that discourage NSAID use in patients with CVD. In particular, the data indicate that even short-term use (e.g., for transient musculoskeletal ailments) leads to excess cardiovascular risk.
— Anthony L. Komaroff, MD Published in Journal Watch General Medicine December 29, 2011
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Nature 2012 Jan 5; 481:85.
New Insights into the Biology of Metastasis
Cancer stem cells and endothelial signaling might point to novel therapies.
Relatively few malignant cells shed by primary tumors metastasize successfully: Either the cells do not enter distant organs, or they enter but fail to multiply. Understanding the molecular biology of successful metastatic colonization could open a route to novel targeted treatments. Now, two studies in mouse models of breast cancer address this approach.
An international team found that only some of the cells shed into the circulation by a primary tumor — cancer stem cells — can establish metastases (JW Gen Med Aug 27 2009). These cells attach to endothelial cells in the target organ's microcirculation, and then invade the stroma. Next, the stem cells induce fibroblasts in the stroma to produce a molecule called periostin. Blocking periostin can prevent metastatic colonization.
A team from Rockefeller University showed that silencing a particular microRNA (miR-126) in breast cancer cells encourages attachment of the cancer cells to endothelial cells, invasion of stromal tissue at metastatic sites, and growth of n
ew blood vessels to feed the cancer cells as they colonize the sites. Signals from endothelial cells seem important in silencing miR-126.
Comment: Both of these studies identify different molecular mechanisms that seem to play roles in encouraging breast cancer metastasis. Blocking a molecule produced by cancer stem cells prevented metastases; targeting the second mechanism also should be possible. These results are intriguing, but whether they will apply to human breast cancer is uncertain.
— Anthony L. Komaroff, MD Published in Journal Watch General Medicine January 31, 2012
Citation(s):Malanchi I et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 2012 Jan 5; 481:85.
Png KJ et al. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 2012 Jan 12; 481:190.
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J Natl Cancer Inst. 2012 Jan 23
Younger Breast Cancer Survivors Have Unique Concerns
A systematic review focuses on quality of life, emotional health, and menopause- and fertility-related issues in survivors age 50 or younger.
Therapeutic advances have prolonged survival among both younger and older women with breast cancer. However, concerns about early menopause, infertility, and emotional health are more likely in younger survivors. Investigators performed a systematic review of studies concerning quality of life (QOL), menopausal or fertility-related symptoms, and behavioral outcomes in younger breast cancer survivors (age 
50 years or premenopausal at diagnosis).
Depressive symptoms were more common and more severe in younger survivors than in older survivors or in age-matched women without cancer. QOL scores were lower in younger survivors than the national reference score for similar-age women without cancer. Women with chemotherapy-induced menopause had more concerns about sexuality and more-prevalent and severe vasomotor symptoms than women who did not experience iatrogenic early menopause. Half of younger breast cancer survivors believed that their clinicians did not adequately address their concerns about fertility.
Comment: These findings should remind clinicians who provide primary care to women with breast cancer that extra attention must be paid to the emotional and reproductive health needs of younger survivors, including proactive use of antidepressants, referral to mental health specialists, and guidance on contraception for those women who want or need to avoid pregnancy. Nonhormonal management of menopausal issues (e.g., vasomotor and atrophic genital symptoms) is particularly relevant; moreover, addressing quality-of-life concerns is likely to improve adherence to adjuvant therapy. Finally, referring these women to fertility specialists before chemotherapy is initiated will help address their concerns about future reproductive options.
— Andrew M. Kaunitz, MD Published in Journal Watch Women's Health February 2, 2012
Citation(s):Howard-Anderson J et al. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 2012 Jan 23; [e-pub ahead of print]. (http://dx.doi.org/10.1093/jnci/djr541)
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Lancet 2011 Nov 19; 378:1812.
Breast Cancer Prognosis and Management: Role of Gene Expression Profiling
Molecular signatures are increasingly important for guiding treatment recommendations.
Gene expression profiling has shown that molecular heterogeneity is a hallmark of breast cancer. Authors of a recent review present a comprehensive update of the molecular subtypes of breast cancer and their clinical ramifications. Microarray-based analyses first allowed identification of seven intrinsic subgroups of breast cancer (luminal A, luminal B, basal like, human epidermal growth factor receptor 2 [HER2] enriched, normal breast like, claudin low, and molecular apocrine). These subtypes differ in expression of estrogen receptors (ERs), progesterone receptor (PRs), proliferation-related genes, HER2, and other markers — and each responds differently to chemotherapy and endocrine therapy. Other microarray platforms (e.g., MammaPrint, Oncotype DX) can be used to provide more-refined prognostic information and to predict overall benefit from chemotherapy. However, no platform can yet foretell responses to specific chemotherapeutic agents.
Comment: That there is more to breast cancer than estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 is now well recognized. Tumors that are ER and PR positive can have distinct responses to chemotherapy and endocrine therapy (e.g., luminal A tumors are more likely to respond to endocrine therapy, and luminal B tumors are more likely to respond to chemotherapy). Molecular predictors are becoming standard tools to help clinicians guide patients through treatment recommendations. Prospective studies are under way to validate the predictive abilities of these tests.
— Virginia Kaklamani, MD, DSc Dr. Kaklamani is an Assistant Professor in the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine in Chicago.
Published in Journal Watch Oncology and Hematology January 10, 2012
Citation(s):Reis-Filho JS and Pusztai L. Gene expression profiling in breast cancer: Classification, prognostication, and prediction. Lancet 2011 Nov 19; 378:1812.
http://www.ncbi.nlm.nih.gov/pubmed/22098854?dopt=Abstract
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