• Fat Returns After Liposuction, but to Unexpected Places
• Conventional Wisdom on Salt Questioned
• Abbott Laboratories gets FDA approval for Androgel 1.62% Formula
• 1,000 More Lawsuits Over Avandia to be Settled
• New Hair Growth Option
• Rejection Really Hurts
• Antidepressants and Risks for Breast and Ovarian Cancer
• Use of Proton-Pump Inhibitors in Infants and Children
• Long-Term Proton-Pump Inhibitor Therapy in Children
• Do Topical Antibiotics Promote Wound Healing in the Absence of Infection?
• Off-Label Use of Azathioprine in Dermatology
• Do Analgesics Interfere with Efficacy of Selective Serotonin Reuptake Inhibitors?
• Treatment of Painful Diabetic Neuropathy
• Bisphosphonates and Atypical Fractures: New Data from Sweden
• In Early-Stage Prostate Cancer, Long-Term Data Favor Prostatectomy
• Surgery vs. Observation for Early-Stage Prostate Cancer
• Etiology of Chronic Pancreatitis
• Lengthened WHI Follow-Up: Postmenopausal Estrogen Therapy
• Infant-Strength Acetaminophen to Be Discontinued, Just One Children's Concentration
Will Be Available
• Tai Chi Exercise in Heart Failure Patients
• Long-Term Proton-Pump Inhibitor Therapy in Children
• Preventing Phenytoin-Induced Gingival Hyperplasia in Children
• FDA Alert: Topiramate Increases Risk for Birth Defects
• Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis
• Low vitamin D levels in women with breast cancer are linked to more
aggressive tumors and poorer prognosis by Craig Weatherby
http://www.nature.com/oby/journal/vaop/ncurrent/pdf/oby201164a.pdf
Fat Returns After Liposuction, but to Unexpected Places
Patients may ask about a small study from the journal Obesity showing that fat lost during liposuction returns within a year, but to different places on the body.
Researchers randomized 30 nonobese patients with areas of disproportionate adipose tissue deposits (in the lower abdomen, hips, or thighs) to either small-volume liposuction or to a no-liposuction control group. Measurements of body fat placement were taken at baseline. By 1 year, the percentage of body fat did not differ between groups, and the fat had, according to the study's abstract, "reaccumulated differently across various sites." For example, liposuctioned thighs remained reduced, but regained fat went to the upper abdomen.
As to why the adipose doesn't return to the place from which it was taken, one expert (not involved with the study) told the New York Times that the procedure may "violently [destroy] the fishnet structure under the skin where fat cells live."
http://www.nytimes.com/2011/05/01/weekinreview/01kolata.html?adxnnl=1&adxnnlx=
1304524808-tL/nrGRmz3RXz3jZTACBVA
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Conventional Wisdom on Salt Questioned
A JAMA study calls into question the current dogma on limiting the population's salt intake and on salt's health effects. Initial reaction to the study, as reported in the New York Times, is skeptical.
Researchers followed a European cohort comprising roughly 3700 subjects without cardiovascular disease at baseline. All had 24-hour urine sodium excretion measured at enrollment.
After a median follow-up of almost 8 years, cardiovascular mortality was highest among participants in the lowest tertile of sodium excretion, and the inverse-association trend retained statistical significance after multivariable adjustment. Sodium excretion was not associated with all-cause mortality.
The incidence of hypertension did not rise with increasing tertiles of sodium excretion. Each 100-mmol increase in excretion was associated with a 1.7-mm Hg increase in systolic pressure, but diastolic pressure did not correlate with excretion.
The authors note that their findings "do not negate the blood pressure-lowering effects of a dietary salt reduction in hypertensive patients." Critics echo the authors' own list of their study's limitations, including the relative youthfulness of the cohort (averaging about age 40), and the inclusion of only white Europeans.
http://jama.ama-assn.org/content/305/17/1777.short
http://www.nytimes.com/2011/05/04/health/research/04salt.html
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Abbott Laboratories gets FDA approval for Androgel 1.62% Formula
Abbott Laboratories has received approval for a new, more potent formulation of its testosterone gel. The approval is for treating men with hypogonadism or low testosterone, a condition associated with fatigue, depression and various sexual dysfunctions.
This new formula, Androgel 1.62 percent, delivers 40.5 milligrams of gel in two pumps of the canister. The older, Androgel 1% formulation included 50 milligrams in four pumps. The company says the two formulations are not interchangeable and both require a prescription.
The FDA approval is based on a study showing 78 percent of men using the gel had normal testosterone levels after one year of use. More and more, drug companies are targeting low testosterone as a new market opportunity. It is estimated that about 14 million American men are believed to have irregularly low testosterone levels, though only 1.3 million are being treated. The estimated U.S. market for testosterone therapies is $1.1 billion.
http://finance.yahoo.com/news/Abbott-gets-FDA-clearance-for-apf-1957904740.html?x=0
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1,000 More Lawsuits Over Avandia to be Settled
$700 million to resolve about 12,000 suits has been agreed upon by Glaxo, alleging the drugmaker failed to warn consumers that Avandia could cause heart attacks and strokes. There are a total of about 5,300 state-court cases pending around the country. The company said last September it would stop promoting Avandia worldwide after regulators said the treatment would be withdrawn from the market in Europe and sales would be limited in the U.S. because of studies linking the drug to increased risks of heart attacks. Avandia sales fell 43 percent due to the restrictions, the company said. Avandia was once the world's best-selling diabetes medication and generated $3 billion in annual sales. A court in Los Angeles has already seen 2,400 former Avandia users settling their claims.
http://www.bloomberg.com/news/2011-05-04/glaxo-is-poised-to-settle-about-1-000-suits-over-avandia-drug-lawyer-says.html
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New Hair Growth Option
Latisse, the prescription eyelash-enhancing solution, is now being used on the scalp.
Three or four drops daily and the Allergan drug that has already won a following among women for helping them grow long, fluttery eyelashes, is now being used by men to treat baldness.
Although Latisse does not appear to be a silver bullet for hair loss, it does appear to work in much the same way as Rogaine or Propecia. That is, all three can strengthen and darken hair that grows from a dying follicle, but none can bring a dead one back to life. This results in an enhanced, refortified hairline rather than a brand new head of hair.
http://www.nytimes.com/2011/05/05/fashion/05SKIN.html?_r=1&partner=rss&emc=rss
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Proc Natl Acad Sci U S A 2011 Apr 12; 108:6270.
Rejection Really Hurts
The same brain areas are involved in physical pain and romantic rejection.
How similar is the "hurt" of rejection to physical pain? To examine whether both types of pain activate the same brain regions, these investigators used functional magnetic resonance imaging in 40 subjects recruited because they felt "intensely rejected" after "experiencing an unwanted romantic relationship break-up." They viewed pictures of a friend (and were told to think about positive experiences) or the ex-partner (and thought about the rejection). In other trials, the participants were exposed to two levels of thermal stimulation on the forearm so that researchers could examine brain activations with mild warmth or physical pain.
Participants rated their social rejection and physical pain at comparable levels of distress on 5-point scales. Compared with a control activity, social rejection and physical pain individually increased activity in the dorsal anterior cingulate cortex and the anterior insula. In further analyses, social rejection (and physical pain) activated two operculo-insular secondary somatosensory areas that have been strongly associated with physical pain, but not with emotion, in other studies.
Comment: This study demonstrates that intense emotional pain activates brain regions that represent physical pain in the secondary somatosensory system. Interestingly, dread of impending pain also involves these areas. Many psychiatric disorders (e.g., depression, anxiety, post-traumatic stress disorder) present with somatic symptoms (e.g., postconcussion syndrome and fibromyalgia). Thus, it is intriguing to speculate that such interactions may occur through involvement of these brain areas. Conceivably, improvement of somatic symptoms with treatment actually results from modulation of activity in this region.
— Jonathan Silver, MD Published in Journal Watch Psychiatry May 2, 2011
Citation(s): Kross E et al. Social rejection shares somatosensory representations with physical pain. Proc Natl Acad Sci U S A 2011 Apr 12; 108:6270.
http://www.ncbi.nlm.nih.gov/pubmed/21444827?dopt=Abstract
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PLoS ONE 2011 Apr 6; 4:e18210
Antidepressants and Risks for Breast and Ovarian Cancer
A meta-analysis found a modest association, but studies associated with industry ties produced different results from those without such ties.
In the U.S., most of the 27 million individuals taking antidepressant medications are women. In this review of 35 preclinical and 26 epidemiologic studies, investigators examined possible associations of antidepressant use with breast and ovarian cancers. The researchers also looked at the effect of industry sponsorship and performed a random-effects meta-analysis of the epidemiologic studies.
In the meta-analysis, a modest association was found between antidepressants and risk for breast or ovarian cancer (pooled odds ratio, 1.11); the effects seemed slightly stronger for selective serotonin reuptake inhibitors than for tricyclics. In the studies overall, 33% reported some association between antidepressants and cancer, and 67% reported either no association or an antiproliferative effect. Notably, none of the 15 industry-funded studies reported increased risk, whereas 20 of the 46 without industry ties found increased risk.
Comment: When relative risks, even when statistically significant, are this close to 1.0, any inferences about causality should be viewed with caution. Depression, anxiety, or other underlying conditions might account for at least part of the risk association. Some experimental research has suggested a biphasic association between antidepressants and cancer cell growth — with short-term use, low dose, or both increasing cancer risk, and with higher doses inhibiting growth. Large-scale, prospective, epidemiologic studies are needed to tease apart these possibilities. The results also underscore how important it is for systematic reviews and meta-analyses to attend to the sources of funding. Overall, the findings suggest that although the added risks appear to be modest, physicians treating women who are taking antidepressants, particularly women with other risk factors, need to be especially vigilant about cancer surveillance.
— Joel Yager, MD
Published in Journal Watch Psychiatry May 2, 2011
Citation(s): Cosgrove L et al. Antidepressants and breast and ovarian cancer risk: A review of the literature and researchers' financial associations with industry. PLoS ONE 2011 Apr 6; 4:e18210. (http://dx.doi.org/10.1371/journal.pone.0018210)
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Pediatrics 2011 May; 127:925
Use of Proton-Pump Inhibitors in Infants and Children
PPIs are not effective in infants, but this analysis suggests that a trial of PPIs might be warranted in children and adolescents with gastroesophageal reflux.
The use of proton-pump inhibitors (PPIs) in infants and children has increased substantially during recent years. Investigators aimed to conduct a systematic review of 12 studies involving 895 children (age range, 0–17 years) to examine the efficacy and safety of PPIs when used to treat symptoms of gastroesophageal reflux disease (GERD) and gastric acidity. Heterogeneity among the studies prevented a formal meta-analysis, so the investigators reviewed results by age groups as follows:
- Efficacy in infants: PPIs were no more effective than placebo in reducing irritability and spilling (4 studies) and were more effective than hydrolyzed formula (1 study).
- Efficacy in children: PPIs were equally effective in reducing GERD symptoms as a control (higher dose of same PPI, ranitidine, or alginate) in five studies.
- Efficacy in adolescents: Esomeprazole and pantoprazole were equally effective in reducing GERD symptoms compared with a different PPI dose and significantly reduced GERD symptoms from baseline (2 studies).
- PPIs were more effective in reducing gastric acidity than placebo, alginates, or ranitidine in infants and children (4 studies).
Comment: Many clinicians avoid extensive evaluation of infants with signs consistent with gastroesophageal reflux and treat such patients empirically. Given concerns about side effects of PPIs and lack of efficacy in infants, perhaps trying some old-fashioned approaches such as thickened formula is appropriate (JW Pediatr Adolesc Med Dec 24 2008). The data in children suggest that various approaches are effective. Although the data in adolescents are limited, extrapolation from adult studies suggests that PPIs are effective in older adolescents. However, long-term use of PPIs in children might cause enterochromaffin cell-like hyperplasia in the stomach, the clinical consequences of which are unclear (JW Gastroenterol Apr 29 2011).
— Howard Bauchner, MD Published in Journal Watch Pediatrics and Adolescent Medicine May 4, 2011
Citation(s): van der Pol RJ et al. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: A systematic review. Pediatrics 2011 May; 127:925.
http://www.ncbi.nlm.nih.gov/pubmed/21464183?dopt=Abstract
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Aliment Pharmacol Ther 2011 Apr; 33:829
Long-Term Proton-Pump Inhibitor Therapy in Children
A high percentage of children developed low-grade enterochromaffin cell-like hyperplasia.
The hypergastrinemia associated with long-term proton-pump inhibitor (PPI) therapy is suspected of causing enterochromaffin cell-like (ECL) hyperplasia or even carcinoid tumors in the developing stomachs of children.
To address this issue, investigators in Canada retrospectively reviewed sequential gastric biopsies from 65 children who received PPI therapy for >9 months (median, 2.29 years). The median age of patients at the time of first biopsy was 8.2 years (range, <1–17 years). Biopsy tissue was stained to identify ECL cells and was read by a pathologist who was blinded to the timing of the biopsies.
ECL hyperplasia was found in 40 of 65 patients (9 patients had ECL hyperplasia prior to PPI therapy) and in 82 of 458 biopsies (67 biopsies had grade 1 hyperplasia, and 15 had grade 2 hyperplasia). The median duration of PPI use was nonsignificantly longer in patients with ECL hyperplasia than in those without (3.17 years and 2.20 years). No patients developed chronic atrophic gastritis or carcinoid tumors. The authors concluded that a high percentage of children who receive chronic PPI therapy develop ECL hyperplasia, but that it is low grade and has no known clinical implications.
Comment: This small study suggests that the hypergastrinemia produced by PPI therapy has similar effects in children similar to those in adults. The absence of high-grade hyperplasia, neoplasia, or carcinoid tumors is reassuring, but larger long-term studies are required to verify these results.
— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) Published in Journal Watch Gastroenterology April 29, 2011
Citation(s): Hassall E et al. Gastric histology in children treated with proton pump inhibitors long term, with emphasis on enterochromaffin cell-like hyperplasia. Aliment Pharmacol Ther 2011 Apr; 33:829. http://www.ncbi.nlm.nih.gov/pubmed/21320136?dopt=Abstract
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J Am Acad Dermatol 2011 Mar; 64:S30.
Do Topical Antibiotics Promote Wound Healing in the Absence of Infection?
Three small studies found that a petrolatum-based ointment advanced wound healing as well as topical antibiotics.
Dermatologists frequently use topical antibiotics for minor surgical wounds, even those that have very low risks for infection. Recently, three industry-sponsored studies examined whether topical antibiotics were beneficial in promoting wound healing compared with a petrolatum-based ointment (Aquaphor) in procedures with low probability of infection. The petrolatum-based ointment was compared with:
- Polymyxin B-bacitracin (P/B) in 30 patients who had shave excisions of two seborrheic keratoses from opposite sides of the trunk;
- P/B in 20 African-American patients with dermatosis papulosa nigra who underwent scissor removal of two papules from opposite sides of the face; and
- P/B or polymyxin B/bacitracin/neomycin in 20 patients with laser-produced wounds on the forearm.
Wound healing was not improved by the use of topical antibiotics in any of the studies.
Comment: Two previous studies (J Amer Acad Dermatol 1985; 13:207; Ann Pharmacother 1997; 31:559) indicated that topical antibiotic ointment reduced the frequency of infection of minor scratches and insect bites in children. Whether those findings are relevant for adults is uncertain. Topical antibiotics have also been found useful for minor wounds sutured in the ER (Acad Emerg Med 1995; 2:4; Am J Emerg Med 2004; 22:1).
Nevertheless, topical antibiotics have few uses in dermatology; the primary exception is in the treatment of impetigo, for which mupirocin and retapamulin are as effective as oral agents. Topical antibiotics, however, have no proven benefit in treating infections of pressure ulcers or venous or diabetic wounds, and have proved no better than petrolatum for preventing wound infections after dermatologic surgery. These three latest trials, though small, show that they don't improve wound healing, either. Dermatologists should stop using topical antibiotics following surgical procedures: They are more expensive than petrolatum; can produce contact dermatitis; and can, rarely, cause anaphylaxis.
— Jan V. Hirschmann, MD Published in Journal Watch Dermatology March 11, 2011
Citation(s): Taylor SC et al. Postprocedural wound-healing efficacy following removal of dermatosis papulosa nigra lesions in an African American population: A comparison of a skin protectant ointment and a topical antibiotic. J Am Acad Dermatol 2011 Mar; 64:S30. (http://dx.doi.org/10.1016/j.jaad.2010.11.009)
http://www.ncbi.nlm.nih.gov/pubmed/21247663?dopt=Abstract
http://www.ncbi.nlm.nih.gov/pubmed/21247662?dopt=Abstract
http://www.ncbi.nlm.nih.gov/pubmed/21247665?dopt=Abstract
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MM: Clinical experience is a very valuable tool and if properly analyzed and documented should be held in higher regard to guide other practitioners. After all, we have seen enough falsified studies in the peer-reviewed journals to realize that all the literature needs to be viewed with a grain of salt. This approach tends to level the playing field in how we should view data.
Arch Dermatol 2011 Apr; 147:474
Off-Label Use of Azathioprine in Dermatology
A systematic review points to the need for long-term registries to ensure evidence-based healthcare decision making in dermatology.
Since the early days of my practice, I have used azathioprine in patients with recalcitrant dermatoses, including blistering diseases, lupus erythematosus, atopic dermatitis, and vasculitis, and have often noted a steroid-sparing effect.
These authors performed a systematic review of the literature for trials of off-label azathioprine use for different dermatologic indications. From 3870 citations, they selected for analysis 43 randomized trials and case series involving six or more patients. They found high-level evidence to support the use of azathioprine in atopic dermatitis; moderate-level evidence for use in bullous pemphigoid, type 1 leprosy reactions, airborne contact dermatitis, and chronic actinic dermatitis; and low-level evidence for other conditions, including cutaneous lupus erythematosus, lichen planus, erythema multiforme, vasculitis, and pityriasis rubra pilaris. The authors point out that further research and the creation of registries might lead to improved recommendations for these diseases.
Comment: This is a call to action. Without great cost, we could develop registries that might allow us, after a few years of observation, to make firm recommendations about the use, efficacy, and potential toxicity of azathioprine in dermatology. We should also create similar registries to evaluate the off-label use of various drugs for other diseases, including but not limited to the use of rituximab for pemphigus, mycophenolate for multiple indications, and anti–tumor necrosis factor agents for inflammatory dermatoses.
— Jeffrey P. Callen, MD Published in Journal Watch Dermatology May 6, 2011
Citation(s): Schram ME et al. Off-label use of azathioprine in dermatology: A systematic review. Arch Dermatol 2011 Apr; 147:474
http://www.ncbi.nlm.nih.gov/pubmed/21482898?dopt=Abstract
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Proc Natl Acad Sci U S A 2011 Apr 25
Do Analgesics Interfere with Efficacy of Selective Serotonin Reuptake Inhibitors?
Results from an animal study and from reanalyzed STAR*D data suggest so, although unexamined confounders may exist.
Cytokines may be important in depression. These immunomodulators are produced by glial cells, regulate brain serotonin and noradrenergic systems, and activate the hypothalamic-pituitary-adrenal axis. Antidepressants increase levels of p11, a specific protein that regulates depression in rodent models and interacts with the serotonin receptor. To learn about possible interactions of antidepressants, cytokines, p11, and anti-inflammatory drugs (NSAIDs), researchers conducted experiments in mice and reanalyzed data from the large STAR*D study.
The selective serotonin reuptake inhibitors citalopram and fluoxetine increased p11 levels in mouse frontal cortex, but coadministered ibuprofen (IBU) or acetylsalicylic acid (ASA) blocked this increase. IBU lowered plasma citalopram levels. The tricyclic desipramine produced a small p11 increase, which was not affected by IBU or ASA. Antidepressant-related p11 increases were dependent on signaling by two cytokines (interferon-gamma and tumor necrosis factor-alpha). In a mouse model of depression, IBU, ASA, and acetaminophen prevented the behavioral response to SSRIs but not to antidepressants of other types.
Of STAR*D patients who took citalopram for 12 weeks, significantly fewer achieved remission if taking NSAIDs than if not taking NSAIDs (45% vs. 55%). Findings were similar in a comparison of other analgesic use with nonuse (37% vs. 54%).
Comment: This elegant translational study connects the observations in a rodent depression model with possible clinical response to antidepressants. SSRIs (but not noradrenergic antidepressants) increase cytokines, which increase p11, resulting in the antidepressant response. NSAIDs (and acetaminophen) inhibit the step-activating cytokines. Clinically, worse antidepressant response is associated with analgesic use. Further research is needed, including prospective studies of various antidepressant types and studies of other possible etiologies – e.g., putatively NSAID-lowered plasma levels of SSRIs or a greater likelihood that depression will be refractory to treatment in patients with pain. Meanwhile, clinicians should carefully evaluate their depressed patients' analgesic use; it may be one reason for poor response. For patients requiring analgesics, clinicians may wish to consider non-SSRIs.
— Jonathan Silver, MD Published in Journal Watch Psychiatry May 2, 2011
Citation(s): Warner-Schmidt JL et al. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A 2011 Apr 25; [e-pub ahead of print]. (http://dx.doi.org/10.1073/pnas.1104836108)
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Diabetes Care 2011 Apr; 34:818.
Treatment of Painful Diabetic Neuropathy
A new guideline and results of a new randomized trial might be helpful for clinicians.
A new guideline from the American Academy of Neurology addresses treatment of patients with painful diabetic neuropathy. Based on a comprehensive literature review, the authors conclude that only one drug, the anticonvulsant pregabalin (Lyrica), merits "Level A" support (i.e., support based on at least 2 high-quality randomized trials). However, the highest-quality pregabalin trials demonstrated only small benefits over placebo (effect sizes of 10%–15%). Numerous drugs — particularly antidepressants, other anticonvulsants, and opioids — have "Level B" (i.e., less rigorous) ratings; effect sizes were larger for some of these drugs than for pregabalin, but studies were methodologically inferior.
The guideline authors call for head-to-head drug comparisons, and one has just been published. In a double-blind, randomized, crossover trial, researchers compared 6-week courses of amitriptyline and duloxetine (Cymbalta) in 58 adults with painful diabetic neuropathy. Amitriptyline was titrated from 10 to 50 mg (if tolerated), and duloxetine was titrated from 20 to 60 mg. Pain relief provided by the two drugs was similar; for example, with both drugs, 60% of patients improved by >30% on visual analog pain scales. Dry mouth was more common with amitriptyline, constipation was more common with duloxetine, and somnolence was common with both.
Comment: This guideline reminds us that more effective and better-tolerated therapies are needed for painful diabetic neuropathy. The only FDA-approved treatments are pregabalin and duloxetine; other drugs are prescribed off-label. The guideline lists pregabalin as the only Level A treatment, but that's partly because large industry-sponsored studies exist for brand-name pregabalin but not for many of the other drugs. For cost reasons, many patients will prefer initial trials of inexpensive generic amitriptyline and gabapentin, rather than expensive brand-name drugs (duloxetine and pregabalin).
— Allan S. Brett, MD Published in Journal Watch General Medicine May 5, 2011
Citation(s): Bril V et al. Evidence-based guideline: Treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011 Apr 11; [e-pub ahead of print].
(http://dx.doi.org/10.1212/WNL.0b013e3182166ebe)
Kaur H et al. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: A randomized, double-blind, cross-over clinical trial. Diabetes Care 2011 Apr; 34:818. (http://dx.doi.org/10.2337/dc10-1793)
http://www.ncbi.nlm.nih.gov/pubmed/21355098?dopt=Abstract
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N Engl J Med 2011 May 5; 364:1728
Bisphosphonates and Atypical Fractures: New Data from Sweden
Relative risk was higher among bisphosphonate users, but absolute risk was small; risk fell rapidly after drug discontinuation.
A recent population-based study suggested that long-term bisphosphonate use raised risk for atypical femoral fractures involving the subtrochanteric region or shaft (JW Gen Med Mar 3 2011). Now, investigators have reviewed fractures that occurred during 2008 among all older Swedish women (age, ≥55). Of 1271 subtrochanteric or femoral shaft fractures, 59 were atypical according to strict radiological criteria.
The relative risk for atypical fracture associated with bisphosphonate use, compared with no use, was 47.3; this corresponded to 5 additional cases per 10,000 patient-years of bisphosphonate use. In a comparison between the 59 atypical cases and 263 controls with typical subtrochanteric or shaft fractures, 78% of cases and 10% of controls had used bisphosphonates (adjusted odds ratio, 33.3). This elevated risk was similar with use of alendronate and risedronate, and was not further increased with concomitant use of corticosteroids or proton-pump inhibitors. Likelihood of atypical fracture rose with duration of bisphosphonate use (risk was elevated 10-fold within the first 2 years of use and 50-fold with longer use), but fell after discontinuation: A 70% reduction in risk was observed for each year after last use, regardless of duration of prior use.
Comment: These findings clarify that, although prevalence of bisphosphonate use is high among women who experience atypical fractures, absolute risk for such fractures is small. Given the well-documented ability of bisphosphonates to prevent osteoporotic fractures, the benefits of this drug class substantially outweigh its risks — provided that use is limited to those patients who meet criteria for prescription therapy. The rapid decline in risk for atypical fractures after bisphosphonate discontinuation supports recommendations for intermittent use (JW Womens Health Aug 12 2010).
— Andrew M. Kaunitz, MD Published in Journal Watch Women's Health May 4, 2011
Citation(s): Schilcher J et al. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011 May 5; 364:1728.
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http://www.nejm.org/doi/full/10.1056/NEJMoa1011967
In Early-Stage Prostate Cancer, Long-Term Data Favor Prostatectomy
Estimates of 15-year survival in early prostate cancer favor use of prostatectomy over watchful waiting, according to a New England Journal of Medicine report. An editorialist cautions, however, that the results may not be directly applicable to U.S. patients.
Researchers randomized 700 men from Sweden, Finland, and Iceland diagnosed with early prostate cancer either to radical prostatectomy or watchful waiting. After a median 13-years' follow-up, the prostatectomy group showed lower risks for metastases, death from prostate cancer (14.6% vs. 20.7%), and all-cause mortality.
An editorialist points out that the results "may not be relevant for men with low-risk early-stage prostate cancers identified by PSA screening." He says that in the U.S., fewer than half of such patients have palpable tumors, while almost 90% of the study's cohort did.
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N Engl J Med 2011 May 5; 364:1708.
Surgery vs. Observation for Early-Stage Prostate Cancer
During median follow-up of 12.8 years, fewer deaths occurred among men who underwent radical prostatectomy than among those assigned to watchful waiting.
In a prior trial of 695 men with localized prostate cancer, investigators from the Scandinavian Prostate Cancer Group Study Number 4 showed that, during median follow-up of 10.8 years, patients randomized to radical prostatectomy had lower risk for mortality and metastases than those assigned to observation (JW Oncol Hematol Sep 16 2008). In that study, patients in the surgery group with local recurrence (palpable or histologically confirmed) received hormonal therapy. Those in the observation group with obstructive voiding disorders received transurethral resection, and those with metastases detected by bone scan received hormonal therapy.
Now, these investigators report that, after a median follow-up of 12.8 years, mortality was lower in the surgery group than in the observation group (47.8% vs. 57.8%; P=0.007). Also, disease-specific mortality was lower in the surgery group (cumulative incidence of death from prostate cancer at 15 years, 14.6% vs. 20.7%; relative risk, 0.62; P=0.01). The survival benefit noted in the original report was maintained and was confined to patients aged <65. The number needed to treat to avert one death was 15. Of note, among men who underwent radical prostatectomy, those with extracapsular tumor growth had a sevenfold higher risk for death from prostate cancer than those without extracapsular tumor growth.
Comment: In this well-executed study, additional follow-up continues to demonstrate a survival benefit for men aged <65 who undergo radical prostatectomy for localized prostate cancer. However, as noted by an editorialist, the newly appreciated survival benefit provided by radical prostatectomy in Scandinavian men with low-risk prostate cancer might not apply to men in the U.S. with low-risk, early-stage disease. In the current trial, 88% of the Scandinavian men had palpable tumors, and cancers were detected by screening in only 5.2% of patients. In contrast, <50% of U.S. men with newly diagnosed prostate cancer have palpable tumors, and most cancers are identified by screening.
— Robert Dreicer, MD, MS, FACP Published in Journal Watch Oncology and Hematology May 4, 2011
Citation(s):Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011 May 5; 364:1708.
Smith MR. Effective treatment for early-stage prostate cancer — Possible, necessary, or both? N Engl J Med 2011 May 5; 364:1770
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Clin Gastroenterol Hepatol 2011 Mar; 9:266
Etiology of Chronic Pancreatitis
Heavy alcohol use has been overestimated, and smoking underestimated, for their roles in causing CP.
Chronic pancreatitis (CP) has historically been attributed to heavy alcohol consumption in up to 90% of patients. Many patients with CP report that they are automatically but inaccurately assumed to abuse alcohol at the time of hospital admission. However, recent discoveries of genetic mutations associated with CP and the recognition of smoking as a risk factor might counter this long-standing belief.
To further investigate the etiology of CP, researchers analyzed data on 539 patients and 695 controls (first-degree relatives, spouses, and friends of patients) from 19 academic referral and community centers across the U.S. that contributed to a large cohort study on CP (North American Pancreatitis Study 2). Information collected included a working diagnosis from each patient's physician, which was used to assign etiologic categories (alcohol, nonalcohol, or idiopathic) and patient characteristics, including demographics and self-reported alcohol and tobacco use.
Etiology was determined to be alcohol use in less than half of patients with CP (44.5%), followed by idiopathic (28.6%) and nonalcohol (but known) causes (26.9%). Nonalcohol and idiopathic etiologies were more common in women than in men. Current smoking and smoking >1 pack per day were strong independent risk factors for those with idiopathic CP (odds ratio, 1.8 and 1.9, respectively) compared with controls without CP.
Comment: This study represents the largest epidemiologic investigation of CP performed in the U.S. The results demonstrate that alcohol is less commonly implicated as the cause of CP than previously believed and that idiopathic disease is surprisingly common. This finding will be welcomed by patients who are erroneously assumed to be alcoholics. Also, the potent effects of smoking merit our attention. A growing body of data is showing that the combination of smoking with a second risk factor (alcohol or genetic mutations) is particularly toxic to the pancreas. We need to be especially vigorous in our efforts to convince patients with CP to stop smoking.
— Chris E. Forsmark, MD Dr. Forsmark contributed patients to this study.
Published in Journal Watch Gastroenterology May 6, 2011
Citation(s): Coté GA et al. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011 Mar; 9:266. http://www.ncbi.nlm.nih.gov/pubmed/21029787?dopt=Abstract
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JAMA 2011 Apr 6; 305:1305
Lengthened WHI Follow-Up: Postmenopausal Estrogen Therapy
Women's Health Initiative follow-up of postintervention phase showed estrogen had no substantial adverse effects on most health outcomes; reduction in relative risk for breast cancer persisted.
In the Women's Health Initiative (WHI) Estrogen-Alone Trial, 11,000 postmenopausal women with hysterectomies (age range at baseline, 50–79) received conjugated equine estrogen or placebo for a median of 5.9 years; the trial was stopped at mean follow-up of 7.1 years when initial findings showed excess risk for stroke in the estrogen group. Subsequent analysis showed that, in younger WHI participants (age range at baseline, 50–59), estrogen use was associated with lower risk for coronary heart disease (CHD) and overall mortality during the intervention period. Now, investigators have assessed postintervention health outcomes in 7645 WHI participants.
Overall, at a mean 10.7 years after baseline, estrogen use was not associated with excess risk for stroke or other adverse outcomes (CHD, deep venous thrombosis, hip fracture, colorectal cancer, and mortality during follow-up). As had been noted in previous WHI analyses of the intervention phase, risk for invasive breast cancer was lower in the estrogen group than in the placebo group (hazard ratio, 0.77; 95% confidence interval, 0.62–0.95); moreover, among younger women, estrogen use was associated with lower risk for CHD (HR, 0.59; 95% CI, 0.38–0.90) and marginally lower risk for mortality during follow-up (HR, 0.73; 95% CI, 0.53–1.00).
Comment: Although these new findings from the WHI are intriguing, they do not imply that estrogen-only therapy should be recommended at this time for cardioprotection or breast cancer chemoprophylaxis. What these results do provide is reassurance to young menopausal women who are posthysterectomy and who present with bothersome vasomotor symptoms that use of estrogen therapy for as long as 6 years is safe.
— Andrew M. Kaunitz, MD Published in Journal Watch Women's Health April 5, 2011
Citation(s): LaCroix AZ et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA 2011 Apr 6; 305:1305.(http://dx.doi.org/10.1001/jama.2011.382)
http://www.ncbi.nlm.nih.gov/pubmed/21467283?dopt=Abstract
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Infant-Strength Acetaminophen to Be Discontinued, Just One Children's Concentration Will Be Available
Infant-strength drops of acetaminophen, sold at a concentration of 80 mg/0.8 mL, will be pulled from the market by the middle of this year in an effort to have just one concentration (160 mg/5 mL) of liquid acetaminophen available to children under 12 years of age, according to a midweek announcement from the Consumer Healthcare Products Association.
The association's president and CEO said the change should "make it easier for parents and caregivers to appropriately use single-ingredient liquid acetaminophen."
When marketed for infants, the 160-mg/5-mL acetaminophen will come with syringes and flow restrictors; for older children, the drug will continue to come with dosing cups.
http://www.chpa-info.org/05_05_11_PedAceConv.aspx
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Arch Intern Med 2011 Apr 25; 171:750
Tai Chi Exercise in Heart Failure Patients
No change in cardiorespiratory fitness but better quality of life
Growing interest in the value of exercise training in patients with heart failure has led to studies of various adjunctive mind-body techniques, one of which is tai chi. Tai chi focuses on gentle meditative exercise, relaxation, balance training, breathing techniques, and visualization.
Boston investigators randomized 100 patients (mean age, 67) with heart failure (median New York Heart Association class, II) to twice-weekly sessions of tai chi (with encouragement to practice tai chi at home) or general education. Patients were assessed with standard cardiorespiratory fitness tests as well as disease-specific quality-of-life measures. At 12 weeks, no between-group differences in cardiac fitness or work capacity were noted, but the tai chi group had substantial improvements in quality of life, overall mood, and cardiac exercise self-efficacy.
Comment: The lack of improvement in cardiorespiratory fitness is not surprising given the low intensity of tai chi and the short duration of treatment. Participants on average performed only about 10 hours of home tai chi during the entire 12-week trial. An editorialist notes that improving quality of life is a worthy goal, but that larger, longer, and more rigorous trials are needed before clinical recommendations can be made.
— Thomas L. Schwenk, MD Published in Journal Watch General Medicine May 3, 2011
Citation(s): Yeh GY et al. Tai chi exercise in patients with chronic heart failure: A randomized clinical trial. Arch Intern Med 2011 Apr 25; 171:750.
(http://dx.doi.org/10.1001/archinternmed.2011.150)
http://www.ncbi.nlm.nih.gov/pubmed/21518942?dopt=Abstract
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Aliment Pharmacol Ther 2011 Apr; 33:829
Long-Term Proton-Pump Inhibitor Therapy in Children
A high percentage of children developed low-grade enterochromaffin cell-like hyperplasia.
The hypergastrinemia associated with long-term proton-pump inhibitor (PPI) therapy is suspected of causing enterochromaffin cell-like (ECL) hyperplasia or even carcinoid tumors in the developing stomachs of children.
To address this issue, investigators in Canada retrospectively reviewed sequential gastric biopsies from 65 children who received PPI therapy for >9 months (median, 2.29 years). The median age of patients at the time of first biopsy was 8.2 years (range, <1–17 years). Biopsy tissue was stained to identify ECL cells and was read by a pathologist who was blinded to the timing of the biopsies.
ECL hyperplasia was found in 40 of 65 patients (9 patients had ECL hyperplasia prior to PPI therapy) and in 82 of 458 biopsies (67 biopsies had grade 1 hyperplasia, and 15 had grade 2 hyperplasia). The median duration of PPI use was nonsignificantly longer in patients with ECL hyperplasia than in those without (3.17 years and 2.20 years). No patients developed chronic atrophic gastritis or carcinoid tumors. The authors concluded that a high percentage of children who receive chronic PPI therapy develop ECL hyperplasia, but that it is low grade and has no known clinical implications.
Comment: This small study suggests that the hypergastrinemia produced by PPI therapy has similar effects in children similar to those in adults. The absence of high-grade hyperplasia, neoplasia, or carcinoid tumors is reassuring, but larger long-term studies are required to verify these results.
— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) Published in Journal Watch Gastroenterology April 29, 2011
Citation(s): Hassall E et al. Gastric histology in children treated with proton pump inhibitors long term, with emphasis on enterochromaffin cell-like hyperplasia. Aliment Pharmacol Ther 2011 Apr; 33:829 http://www.ncbi.nlm.nih.gov/pubmed/21320136?dopt=Abstract
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Neurology 2011 Apr 12; 76:1338
Preventing Phenytoin-Induced Gingival Hyperplasia in Children
Folic acid supplementation prevents gingival hyperplasia in most children started on phenytoin monotherapy.
Phenytoin is an excellent and cost-effective antiepileptic drug (AED) that is especially useful in developing countries with limited access to newer AEDs. However, phenytoin-induced gingival overgrowth (PIGO), along with related cosmetic problems, is a common adverse effect that often restricts chronic use of phenytoin. Previous, small, uncontrolled studies have suggested that folic acid (FA) has a role in preventing PIGO. To assess whether FA supplementation (0.5 mg/day) could prevent this adverse event, researchers in India conducted a large, randomized, placebo-controlled study in 120 children with new diagnoses of epilepsy who recently started phenytoin monotherapy (age range, 6–15 years).
The primary outcome was the incidence of PIGO at 6 months after starting phenytoin. Gingival depth was measured bimonthly, and all patients received oral hygiene education. At 6 months, there was an absolute risk reduction of 67%, with only 21% of those on FA developing PIGO compared with 88% receiving placebo. Most placebo recipients (67%) developed PIGO in the first 2 months. Mean phenytoin doses and serum levels did not differ between the two study arms. However, the mean serum phenytoin level in placebo recipients who developed PIGO was higher than in placebo recipients without PIGO, but was similar to the level in FA recipients without PIGO, further supporting the potential of FA to blunt the development of PIGO at similar phenytoin levels.
Comment: This well-conducted and valuable study demonstrates the efficacy of folic acid supplementation for the prevention of phenytoin-induced gingival overgrowth in children. Routine prescription of FA supplementation may allow for more widespread use of phenytoin in places with inadequate access to antiepileptic medications with more attractive adverse effect profiles. Longer follow-up of this cohort would be required to determine whether FA supplementation is truly preventive or simply slows the development of PIGO.
— Joseph Sullivan, MD Dr. Sullivan is Assistant Professor, Clinical Neurology and Pediatrics, and Director, Pediatric Epilepsy Center, University of California, San Francisco.
Published in Journal Watch Neurology May 3, 2011
Citation(s): Arya R et al. Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurology 2011 Apr 12; 76:1338.
http://www.ncbi.nlm.nih.gov/pubmed/21482950?dopt=Abstract
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FDA Alert: Topiramate Increases Risk for Birth Defects
Because of a topiramate-associated risk for oral clefts, the FDA has now designated topiramate as a pregnancy category D drug.
On March 4, 2011, the FDA reported an increased risk for oral clefts in infants born to women taking topiramate during pregnancy.
Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry revealed that mothers taking topiramate during the first trimester of pregnancy had an increased risk for infants born with oral cleft palate or lip. According to the registry data, 1.4% of infants exposed to topiramate in utero were born with a cleft lip or palate, compared with a range of 0.38% to 0.55% of infants born to mothers taking other antiepileptic medications during pregnancy and with 0.07% of infants born to mothers who neither had epilepsy nor took antiepileptic medications.
Topiramate has now been designated as a category D drug ("positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks").
Comment: Oral clefts form in the first trimester, during the earliest phases of development, often before many women even know they are pregnant. Clinicians treating women of childbearing potential should carefully weigh the risks and benefits of topiramate and must inform their patients of the increased risk for oral clefts in a baby gestated while they are on this medication. As topiramate can also reduce the efficacy of estrogen-containing contraceptives, physicians should discuss with these patients reliable options for contraception while on topiramate to avoid unplanned pregnancies.
These findings underscore the importance of prenatal counseling for all women of childbearing potential who are considering treatment with medications that have an unknown effect in pregnancy. Most frequently-used medications in migraine have an unknown risk in pregnancy (FDA pregnancy category C). Clinicians prescribing drugs classified by the FDA as anything other than category A or B to women of childbearing potential should counsel them regarding the use of safe and effective forms of birth control.
— Ana Recober, MD, and Rashmi Halker, MD Dr. Recober is Assistant Professor, Department of Neurology, University of Iowa Hospitals and Clinic, Iowa City. Dr. Halker is Assistant Professor of Neurology, Mayo Clinic, Phoenix.
Published in Journal Watch Neurology May 3, 2011
Citation(s): Food and Drug Administration. FDA drug safety communication: Risk of oral clefts in children born to mothers taking Topamax (topiramate). Mar 4 , 2011.
(http://www.fda.gov/Drugs/DrugSafety/ucm245085.htm)
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Lancet Neurol 2011 May; 10:436
Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis
Among children with acute demyelination, low vitamin D levels, past infection with the Epstein-Barr virus, and the HLA-DRB1*15 allele were associated with development of MS.
Researchers sought to identify risk factors for multiple sclerosis (MS) among children with incident central nervous system demyelination. They prospectively studied 302 children (aged <16 years) who presented within 90 days after demyelination-symptom onset to one of 23 centers in Canada.
During a median follow-up of 3 years, 63 children (21%) developed MS. Older age at onset of demyelination symptoms (12 vs. 9 years) was associated with significantly increased risk for MS. Among children who presented with multifocal deficits, those with encephalopathy were significantly less likely than those without encephalopathy to develop MS. Oligoclonal bands in cerebrospinal fluid were more common among children who developed MS than among those who did not (60% vs. 15%).
Development of MS was associated with lower vitamin D serum concentration, previous Epstein-Barr virus infection and anti-EBNA1 titers, and the presence of one or more HLA-DRB1*15 alleles. MS was diagnosed in significantly more children with all three of these risk factors than in children with none of these risk factors (57% vs. 5%).
Comment: One goal of this study was to evaluate very early demyelination, when environmental factors are linked closely in time with disease development. The findings provide useful prognostic information to help clinicians distinguish between the pediatric demyelinating diseases of MS and acute disseminated encephalomyelitis. The authors offer a helpful risk-stratification algorithm to guide counseling and follow-up in clinical practice.
— Robert T. Naismith, MD Published in Journal Watch Neurology May 3, 2011
Citation(s): Banwell B et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: A prospective national cohort study. Lancet Neurol 2011 May; 10:436.
http://www.ncbi.nlm.nih.gov/pubmed/21459044?dopt=Abstract
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May 5, 2011 Vitamin D Lack Linked to Toughest Breast Tumors
Low vitamin D levels in women with breast cancer are linked to more aggressive tumors and poorer prognosis
by Craig Weatherby
Low blood levels of vitamin D may promote riskier breast tumors and worsen women’s chances of survival, judging by a new study.
Prior research has looked for and found links between low vitamin D levels and higher risk of developing breast cancer … as well as reduced survival rates among women lacking adequate intake or blood levels. (To learn about the debate over intake and blood levels, see our sidebar, “Vitamin D RDAs still deemed inadequate”.)
This epidemiological study – by a team at the University of Rochester Medical Center (URMC) – is one of the first to look for links between vitamin D blood levels and the risk for aggressive tumors in women already diagnosed with breast cancer. The URMC study, reported this week at the American Society of Breast Surgeons, associates low, “sub-optimal” vitamin D levels with poor scores on every major biological marker proven to help predict a breast cancer patient’s prognosis. “The magnitude of the findings was quite surprising,” said lead researcher Luke J. Peppone, Ph.D., M.P.H. “Based on these results, doctors should strongly consider monitoring vitamin D levels among breast cancer patients and correcting them as needed.” (URMC 2011)
Analysis links low vitamin D levels to risk for aggressive breast cancer
The study’s authors examined various key factors related to breast cancer prognosis among 155 women who underwent surgery for breast cancer between January 2009 and September 2010. They also obtained blood samples for all the patients within the one-year period before and after surgery, to get accurate vitamin D levels. Meanwhile, the researchers collected relevant breast cancer data on each patient including age, race, menopause status, stage of cancer at diagnosis, estrogen and progesterone status, HER2 expression, gene expression, and Oncotype Dx score.
Oncotype Dx is a newer diagnostic test for early-stage breast cancer that looks at a group of 21 genes within a woman’s tumor sample and issues a score between 0 and 100 that predicts the likelihood of a recurrence. A higher risk of recurrence is usually reflected in scores greater than 30. Finally, the women were separated into two groups, based on whether their vitamin D levels were deemed “optimal” or “sub-optimal” – that is, greater or less than 32 ng/ml (nanograms per milliliter) – a demarcation point that can also be expressed as greater or less than 80 nmol/L (nanomoles per liter).
The URMC team’s statistical analysis showed that cancers known to be more aggressive – such as triple-negative tumors – correlated with low vitamin D levels. (The term “triple-negative” refers to breast tumors that do not depend on estrogen, progesterone, or HER2 human epidermal growth factor receptor 2, and cannot bet reated with the drugs used for those hormone-dependent forms. These cancers don't usually respond to treatments for hormone-dependent tumors. But some chemotherapy drugs can yield positive outcomes, and drugs now in clinical trials show promise.)
Lower vitamin D levels were also strongly linked to increasing (i.e., riskier) Oncotype scores. Finally, patients with invasive cancer – versus women with in-situ or stage 0 disease – were also more likely to have sub-optimal vitamin D levels.
The authors arrived at two key conclusions, which led them to recommend vitamin D blood tests for cancer patients, and vitamin D injections or supplements as needed:
- “Breast cancer patients with suboptimal vitamin D levels were more likely to have tumors with more aggressive tumor profiles and worse prognostic markers, lending support to previous research that found decreased breast cancer survival among vitamin D deficient individuals.”
- “In addition, this study found that suboptimal vitamin D levels were not only associated with poor prognostic markers of survival (ER- and triple negative tumors) but also increased risk of recurrence (Oncotype scores).”
It’s worth noting that the premenopausal and black women in this study were more likely to have sub-optimal vitamin D levels, compared to postmenopausal white women.
Sources: Rickles A, Peppone L, Huston A, Piazza K, Skinner K. Poster Presentation #1701 - Serum 25-Hydroxyvitamin D and Prognostic Tumor Characteristics in Breast Cancer Patients. Scientific Session Abstracts Official Proceedings Volume 18. The American Society of Breast Surgeons 12th Annual Meeting, April 27 - May 1, 2011, Washington, DC. Accessed at http://www.breastsurgeons.org/annual/documents/2011_ASBrS_official_proceedings.pdf. University of Rochester Medical Center (URMC). Aggressive Breast Tumors Linked to Vitamin D Deficiency. April 29, 2011. Accessed at
http://www.urmc.rochester.edu/news/story/index.cfm?id=3182
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