SAN DIEGO, Sept. 30-Women who have had a wrist fracture on the threshold of menopause or later are more likely to have a future osteoporotic fracture, a researcher reported here Thursday.

Analysis of data from the National Osteoporosis Risk Assessment (NORA) indicates that women with a history of wrist fractures have a doubling of risk for future breaks, said Ya-Ting Chen, Ph.D. Furthermore, these findings identify an at-risk anatomic site that can easily fall under the radar, according to Dr. Chen and colleagues who analyzed data from nearly 160,000 women.

Dr. Chen, who is director of outcomes research and management at Merck Pharmaceutical in West Point, Pennsylvania, reported results of the analysis at the annual meeting of the North American Menopause Society.

Dr. Chen said that in clinical practice, doctors tend to focus on spine and hip fractures.

“This practice is consistent with the National Osteoporosis Foundation recommendations, which state that you should consider treatment in women with fractures in these locations,” Dr. Chen said.

“The implication of our study is that you should also pay attention to women who fracture wrists, because they have high risks down the road,” said Dr. Chen.

The NORA trial included 158,940 postmenopausal women. The team analyzed prior wrist fractures by their association with future fractures at the hip, spine, rib, wrist, and forearm. The investigators also analyzed the women’s fracture risk by age, and divided the women into two groups, those 50 to 64 years old and those at least 65 years old. The data included three years of follow-up.

At baseline, no women had a diagnosis of osteoporosis and did not use any bone-specific medication. They had responded to a follow-up survey and had reported their wrist-fracture status since they were 45 years old at the time of enrollment. The investigators excluded women who reported fractures at other anatomic sites.

The investigators then calculated the participants’ absolute risk, based on a per 1,000 person-year basis, by summing up new fractures divided by person-years of follow-up. They calculated the relative risk of future fractures for the 8,665 women with prior wrist fractures and compared their rate to that of 150,275 women without wrist fractures.

Within this group, 4,316 women reported 4,728 new fractures. Those who were 50 to 64 years old had a rate of 24.2 new fractures per 1,000 person-years, compared with a rate of 7.7 for those without a prior wrist fracture. In women 65 or older, the rates were 36.4 for those with wrist fractures and 13.9 for women with no wrist fracture.

Among the women 50 to 64 years old, the adjusted relative risk showed that those with a history of wrist fracture were 2.4 times more likely to have a subsequent fracture. Those older than 65 with such fractures were 2.1 times more likely to have a later fracture.

On the basis of these findings, the investigators concluded that women with a history of wrist fractures should be evaluated for preventive treatment.

“We know from just about everything regarding osteoporosis research that one of the best predictors of a fracture is a previous fracture. What this study shows us is that we should include wrist fractures,” said Wulf H. Utian, M.D., Ph.D., the executive director of the North American Menopause Society and a consultant gynecologist at The Cleveland Clinic. Dr. Utian was not involved in the study.

“We used to say that a vertebral fracture was the key risk factor, but these findings show us that the wrist is also an important predictor,” he added. “Anyone with a previous fracture should have a bone evaluation and may well need to be on anti-osteoporosis therapy.”

Primary source: North American Menopause Society. 16th annual meeting. September 28-30, 2005. Abstract #S-1.

PITTSBURGH, May 8 — Teenagers who believe that wealthy, successful people smoke are more likely to become smokers, researchers here reported.

Those who believe that their parents disapprove of smoking are less likely to smoke, and the stronger the disapproval they sense, the less likely they are do it, Brian A. Primack, M.D., of the University of Pittsburgh, and colleagues reported in the May issue of the Archives of Adolescent and Pediatric Medicine.

In a cross-sectional survey of current smoking and susceptibility to smoking, the researchers studied 1,138 high school students. Of these, 216 (19.0%) reported current smoking, and 342 (38.3%) of 893 nonsmoking students were at risk for future smoking.

The students were recruited from a public high school outside Pittsburgh. Their mean age was 15.9; 47.2% were male, and 90.2% were white.

Factor analysis for the study identified three normative beliefs, labeled “perceived prevalence of smoking,” “perceived popularity of smoking among elite and successful elements of society,” and “disapproval of smoking by parents and peers.”

On average, students believed that 56% of people in the U.S. smoke cigarettes at least once a month, and that 48% of high school seniors do so. Actually, 22.3% of the U.S. population smokes at least once a month, and 21.9% of high school seniors do, the researchers reported.

In the fully adjusted regression model, the perceived prevalence of smoking was independently associated with current smoking, but not with susceptibility to smoking.

Popularity among successful, elite members of society was independently associated with an increased likelihood of current smoking and a susceptibility to smoking among those who did not smoke. Of the students, 27.7% believed that wealthy people smoke more than poor people.

Multiple logistic regression showed that each of the three constructs was independently associated with current smoking (adjusted odds ratios, 1.05 [95% confidence interval, 1.02-1.08], 1.12 [CI, 1.02-1.23], and 0.66 [CI, 0.59-0.75], respectively), even after controlling for covariates.

Each one-point increase in the elite-smoker scale was associated with a 12% increase in the odds of being a current smoker and a 20% increase in the odds of being susceptible to future smoking, the researchers reported.

By contrast, after adjusting for peer and family smoking, adolescents were less likely to be current smokers or to start smoking if they perceived a higher prevalence of parental and/or peer disapproval, the researchers said.

The students’ perceptions of smoking among the successful, elite and disapproval by parents and peers were independently associated with susceptibility to future smoking (OR ratios, 1.20 [CI, 1.11- 1.29] and OR 0.87 [CI, 0.79-0.96], respectively).

In the fully adjusted model, disapproval by family and friends was also significantly associated with both current smoking and susceptibility to smoking. A one-point increase in response to disapproval was associated with a 34% decrease in the odds of being a current smoker and a 13% decrease in the odds of being susceptible to future smoking, the researcher reported.

Teenagers may be influenced by the perception of how others will feel about their smoking and whether people they admire smoke, rather than simply the notion that many people smoke, the researchers said.

In this study, 24.2% of students incorrectly believed that most successful business people smoke at least once a month, and 27.7% incorrectly believed that wealthy people smoke more than poor people.

It is likely, the researchers said, that media portrayals of smoking, which often show smoking in a glamorous light, contribute to a false impression of high smoking prevalence among the elite.

This finding, the researchers said, suggests that smoking beliefs can be improved by more accurate information about the true prevalence of smoking, but also by emphasizing more accurate information about the types of individuals who smoke.

It may also be valuable, Dr. Primack’s team said, to implement media restrictions and also media-literacy programming, the researchers said.

Because the study population was drawn from a single large high school and was fairly homogeneous in terms of ethnic and racial makeup, generalizability of these finding may be limited, the researchers noted.

Furthermore, they said, because this was a cross-sectional study, only association, but not causation, could be determined. Longitudinal studies and randomized intervention trials are needed to determine directional and causal nature of these associations. For example, teens who start smoking may develop different beliefs later on.

Finally, the researchers underscored the negative role of the perceived popularity of smoking among elite subgroups, and, by contrast, the positive part played by peer and family disapproval in keeping nonsmokers smoke-free.

No financial conflicts were reported. This study was supported by the Maurice Falk Foundation and Tobacco Free Allegheny.

In addition, Dr. Primack is supported in part by a Physician Faculty Scholar Award from the Robert Wood Johnson Foundation and by a grant from the National Cancer Institute.

Primary source: Archives of Pediatric and Adolescent Medicine

Source reference:

Primack BA, et al “Improving Measurement of Normative Beliefs Involving Smoking Among Adolescents” Arch Pediatr Adoles Med 2007; 161:434-439.

SAN FRANCISCO, Oct. 29 — Two biologics tried off-label for systemic lupus erythematosus failed to meet any endpoints in randomized trials, researchers reported here.

Neither rituximab (Rituxan) nor abatacept (Orencia) improved any primary or secondary endpoint, reported Joan T. Merrill, M.D., of the University of Oklahoma in Oklahoma City, and colleagues at the American College of Rheumatology meeting.

Only aspirin, antimalarial drugs, and prednisone (Deltasone) have won FDA approval for lupus, which is notoriously difficult to treat. Given the lack of options, “the standard of care in lupus is continuously off-label,” Dr. Merrill said. “People have no choice.”

Indeed, an informal survey she took of the audience at the late-breaking trials session revealed that a fair number of rheumatologists have tried rituximab for their lupus patients, and none was willing to stop on the basis of the data she presented.

Jeffrey Lawson, M.D., of the Piedmont Arthritis Clinic in Greenville, S.C., said in an interview afterward that he was not at all convinced by the data.

Despite the lack of evidence and expense of biologics, frustration makes these treatments attractive, said Dr. Lawson, who was not involved in the studies.

Rituximab has a feasible mechanism in lupus by depleting B-cells, which have been posited as playing a central role in the condition, Dr. Merrill noted.

So her group conducted a randomized, blinded phase II/III study comparing rituximab (two 1,000-mg infusions on weeks one, two, 24 and 25) and placebo over 52 weeks among patients with moderately to severely active extrarenal systemic lupus erythematous.

All 257 participants were on a stable dose of one immunosuppressive drug — methotrexate, mycophenolate mofetil (CellCept), or azathioprine (Azasan, Imuran).

Most were already chronic prednisone users but all were randomized to a dose of 0.5, 0.75, or 1.0 mg prednisone, which was tapered off during the study.

For the primary endpoint, the proportion of patients who had a major clinical response defined as no severe flare up to week 24 and no moderate or severe flare to week 52 was similar between groups (12.4% rituximab versus 15.9% placebo) as was the proportion who had a partial clinical response (17.2% versus 12.5%).

None of the secondary endpoints for British Isles Lupus Assessment (BILAG) scores or SF-36 physical component scores or reduction in steroid doses was significant either.

But an exploratory endpoint — mean BILAG global score — offered a possible explanation. For this endpoint, an identical improvement was seen in the first weeks of treatment for both groups that remained fairly stable thereafter.

“This confirms what we have all hypothesized for a very long time,” Dr. Merrill noted. “Steroids work.”

Maintenance of background medications plus prednisone was apparently sufficient to keep that improvement stable over the course of the trial and “really not giving any other treatment a chance,” she said.

In the subgroup analyses, African Americans and Hispanics did significantly better on rituximab than placebo with a higher proportion meeting the high bar for major or partial clinical response.

Methotrexate-treated patients also did significantly better with rituximab (P=0.007).

Serious adverse event rates were similar between groups, although rituximab was associated with a small trend for more neutropenia and more frequent non-serious infections and infusion reactions on the second course.

The researchers found a similar lack of benefit in the first trial of abatacept for SLE.

This one-year, phase II trial included 175 patients with lupus and active polyarthritis, serositis, or discoid lesions who were randomized to infusions of abatacept (about 10 mg/kg) or placebo on days one, 15, 29, then every four weeks.

Again, patients were given prednisone tapered off after one month at 30 mg per day.

For the primary endpoint, abatacept-treated patients were no less likely to have a new flare adjudicated as meeting BILAG A or B criteria after the start of the steroid taper (79.7% versus 82.5%, difference -3.5, 95% confidence interval -15.3 to 8.3).

Likewise, secondary endpoints using less stringent cutpoints for flares were not significantly different between groups.

In the exploratory analyses, though, abatacept improved quality of life related to physical health (difference 3.92, 95% CI 1.22 to 6.52) and fatigue and sleeping problems significantly more than placebo (difference -9.45, 95% CI -17.65 to -1.25).

Notably, new flares as assessed by the treating physician without use of BILAG scale scoring were significantly reduced as well, which highlighted concerns about trial design.

“I think the accuracy of the measurements is a problem,” Dr. Lawson said.

Dr. Merrill defended BILAG as a sensitive tool that would have picked up a difference if there had been one, but she agreed with audience comments during the question-and-answer session that the best cutoffs to use in trials needs further work.

Dr. Merrill reported receiving consulting fees from Genentech, Bristol-Myers Squibb, and Biogen-Idec. Co-authors reported conflicts of interest for Genentech, Schering Plough, Abbott, and Roche.

Dr. Lawson reported a wide range of financial relationships with companies involved in this area of medicine.

Primary source: American College of Rheumatology Meeting

Source reference:
Merrill JT, et al “The Efficacy and Safety of Abatacept in SLE: Results of a 12-month Exploratory Study” ACR 2008; Abstract L15.

Additional source: American College of Rheumatology Meeting

Source reference:
Merrill JT, et al “Efficacy and Safety of Rituximab in Patients with Moderately to Severely Active Systemic Lupus Erythematosus (SLE): Results from the Randomized, Double-blind Phase II/III Study EXPLORER” ACR 2008; Abstract L12.

Children develop a sense of fairness and altruism, or selflessness, earlier than previously thought, according to a new study.

Researchers from the University of Washington found that 15-month-old babies could tell the difference between equal and unequal portions of food. This perception, the study authors noted, affected the babies’ willingness to share.

“Our findings show that these norms of fairness and altruism are more rapidly acquired than we thought,” study leader Jessica Sommerville, a University of Washington associate professor of psychology, said in a university news release. “These results also show a connection between fairness and altruism in infants, such that babies who were more sensitive to the fair distribution of food were also more likely to share their preferred toy.”

In conducting the study, the researchers had 15-month-olds sit with one of their parents while watching two short videos of people sharing.

In one video, someone distributed crackers either equally or not equally between two people. The second movie was similar, but the people were given milk instead of crackers.

Since babies pay more attention when they are surprised, the researchers noted those participating in the study spent more time looking at the video when one recipient got more food than the other.

“The infants expected an equal and fair distribution of food, and they were surprised to see one person given more crackers or milk than the other,” explained Sommerville.

The study, published Oct. 7 in the online journal PLoS ONE, also found there were differences in altruism among the 47 babies studied. The researchers had them choose between two toys: a simple LEGO block or a more elaborate LEGO doll. The researchers found one-third of the babies shared the toy they chose or preferred, while another third shared the toy they didn’t choose. The final third group of children didn’t share at all, which may have been because they were simply nervous around a stranger.

Comparing the two experiments, the researchers found that 92 percent of the babies who shared their preferred toy — labeled “altruistic sharers” — had spent more time looking at the unequal division of food. Meanwhile, 86 percent of the babies who shared the toy they did not choose — called “selfish sharers” — had paid more attention when the food was divided equally.

“The altruistic sharers were really sensitive to the violation of fairness in the food task,” noted Sommerville. In contrast, the selfish sharers showed an almost opposite reaction.

The findings could be used to help foster sharing and cooperation among children, the research team suggested. They pointed out, however, that more research is needed to determine if fairness and altruism are innate qualities or ones that can be nurtured.

“It’s likely that infants pick up on these norms in a nonverbal way, by observing how people treat each other,” added Sommerville.

More information

The American Academy of Pediatrics has more about toddler growth and development.

Screening asymptomatic, average-risk women for ovarian cancer with currently-available technologies may yield only modest reductions in mortality, researchers suggested.

Computer simulations, using real-world data on the frequencies of aggressive versus relatively indolent tumors, indicated that a broad-based screening program would reduce ovarian cancer deaths by 10.9%, according to Laura J. Havrilesky, MD, MHSc, of Duke University, and colleagues.

Writing online in Cancer, Havrilesky and co-authors said the benefit was less than might be expected because most of the tumors detected in their early stages — when they could be more effectively treated — were of an indolent phenotype.

Such tumors are less likely to kill patients within a given time frame. As a result, detecting and treating these lesions early would not have as much effect on five- or 10-year survival rates, they suggested.

However, a National Cancer Institute researcher noted in an accompanying editorial that more targeted screening could be worthwhile.

“For women who are at higher risk for developing ovarian cancer because of known mutations in the breast cancer 1 (BRCA1) or BRCA2 genes or a significant family history, screening presents a more hopeful picture,” wrote Patricia Hartge, MA, ScD.

“A higher background risk means that a positive screen will be accurate more often, resulting in fewer ultrasound studies and surgeries that yield no cancer,” she added.

The American Cancer Society (ACS) estimates that around 21,880 U.S. women will be diagnosed with ovarian cancer in 2010, and 13,850 will die of the disease.

In recent randomized controlled trials, screening strategies incorporating cancer antigen 125 (CA 125) and transvaginal ultrasound imaging of the ovaries have demonstrated high specificities and acceptable positive predictive values, but produced no measurable improvement in ovarian cancer-related mortality, according to background provided by Havrilesky and colleagues.

They noted that follow-up data from two large trials of postmenopausal screening for ovarian cancer to assess the impact of screening on mortality will not be complete until 2014.

In their current study, Havrilesky and colleagues analyzed data from the CDC’s Surveillance, Epidemiology, and End Results (SEER) registry and interim results from the U.K. Collaborative Trial of Ovarian Cancer Screening.

The SEER data indicated that more than 80% of tumors with an aggressive histology type are detected at stage III or IV, whereas half of indolent cancers are diagnosed at stage I and another 13% at stage II.

The researchers developed a computer model based on these data that also incorporated information on survival rates associated with different tumor stages and grades. For comparison, Havrilesky and colleagues also developed a one-phenotype model based on averages of the SEER data on aggressive and indolent tumor types.

The model was validated against results from the U.K. screening trial, in which 101,000 postmenopausal women from the general population were tested with either CA-125 or transvaginal ultrasound.

The two-phenotype model indicated that aggressive tumors would constitute 62% of detected cancers and 68% of deaths.

In the one-phenotype model, assuming an annual screening interval for a population ages 50 to 85, the mortality reduction was predicted to be 14.7%, relative to no screening. The reduction was 10.9% in the two-phenotype model.

The difference was attributable to the lower death rate associated with indolent tumors — about 50% at 10 years, compared with 80% for the aggressive phenotype, according to the model.

“Our findings support the commonly held clinical impression that many early stage ovarian cancers are destined to remain in the early stages for some time, whereas advanced stage cancers likely have spread rapidly,” Havrilesky and colleagues wrote.

In her editorial, Hartge said randomized trials now ongoing — including the U.K. study, which has yet to report survival data — “will provide the strongest evidence about the potential for reducing ovarian cancer death through screening.”

She added that the current study “remind[s] us that a fundamental breakthrough in understanding the early biology of ovarian cancer could radically change the opportunities to save lives through screening.”

Hartge also noted that the study did not directly address harms of screening, such as the unnecessary surgeries that result from false-positive findings from screening.

The base model in the study predicted a lifetime false-positive rate of five per 100 women in the population with annual screening.

The study was funded by the American Board of Obstetrics and Gynecology/American Association of Obstetricians and Gynecologists Foundation.

Havrilesky reported research funding from Precision Therapeutics and B.D. Tripath Oncology. One co-author also received research funding from Precision. Another co-author reported consulting fees from Medtronic.

Hartge, a U.S. government employee, reported no financial conflicts.

ATLANTA, June 29 ??” A vaccine against cervical cancer should be added to the list of recommended routine shots for girls ages 11 and 12, a federal public health panel has urged.

The CDC’s Advisory Committee on Immunization Practices (ACIP) agreed today that the Gardasil vaccine against human papillomavirus (HPV)??”the sexually transmitted organism that causes most cervical cancers??”should be part of growing up for American girls.

“This is a big breakthrough for women’s health and for cancer prevention,” said Anne Schuchat, M.D., director of the National Center for Immunizations and Respiratory Diseases at the CDC. She called the ACIP decision an “historic vote.”

“It’s a very exciting day,” Dr. Schuchat told reporters after the ACIP voted unanimously to recommend:

That the vaccine be part of routine care for girls 11 and 12.
The girls as young as nine could be vaccinated, if parents and health-care providers agree.
That women and girls between the ages of 13 and 26 should have access to the vaccine as a “catch-up.”
And that the vaccine should be part of the federal Vaccines for Children program, which provides free vaccines for children who are uninsured, Medicaid recipients, Native Americans, or Alaska Natives.

The vaccine, manufactured by Merck, targets four strains of HPV, including two that are thought to be responsible for 70% of all cervical cancer.

A second vaccine, made by GlaxoSmithKline, is under development and will target a wider variety of HPV strains, but Dr. Schuchat said today’s recommendations only apply to Gardasil, which is the only HPV vaccine licensed in the U.S.

The vaccine’s initial target??”the sexually transmitted HPV??”raised controversy in some circles, on the basis of fears that immunizing young girls would send a dangerous message, but Dr. Schuchat said today’s decision was based on two factors:

That a large majority of young women acquire HPV infections soon after the onset of sexual activity, so that targeting girls 11 and 12 would prevent most such infections.
Younger people have more active immune systems, so that the vaccine is likely to be most effective in girls.

The committee recommended a three-shot regimen. At $120 for each shot, the total cost would be $360 for each immunization.

Dr. Schuchat said the committee considered several cost-effectiveness scenarios, based on the stated prices and a range of other assumptions, but all agreed that the three-shot program would be a valuable addition to public health.

“The bottom line was that almost every way this was assessed, it was a cost-effective intervention,” she said.

The ACIP, Dr. Schuchat said, looks at three factors when it makes recommendations: efficacy, safety, and cost-effectiveness. “On all three fronts, this vaccine looks very good,” she said.

The recommendations now go to the CDC director and to the Department of Health and Human Services and should be approved within a few months, Dr. Schuchat said, adding the committee does not expect any alterations.

Once the recommendations are final, it will be up to physicians and health-care payers to provide the shots. Historically, pediatricians have followed CDC guidelines and health-care payers have agreed to cover costs.

Lowering cholesterol with statins may help cut the risk of developing gallstones that require surgery, researchers found.
In a large U.K. database, patients who were taking statins had a 22% lower risk of gallstone disease followed by cholecystectomy than those who weren’t on the cholesterol drugs (OR 0.78, 95% CI 0.73 to 0.83), according to Michael Bodmer, MD, of University Hospital in Basel, Switzerland, and colleagues.
But to enjoy the benefit, patients had to be on statins for about a year to a year and a half, the researchers reported in the Nov. 11 issue of the Journal of the American Medical Association.
Patients who had filled fewer than five prescriptions saw no benefit, those who had filled five to 19 prescriptions had a 15% reduced risk (OR 0.85, 95% CI 0.77 to 0.93), and those who had filled 20 or more had a 36% reduced risk (OR 0.64, 95% CI 0.59 to 0.70).

“Our findings may be of clinical relevance given that gallstone disease represents a major burden for healthcare systems,” Bodmer and his colleagues said.

Anywhere from 10% to 20% of white adults in industrial nations develop gallstones, which are a major cause of gastrointestinal tract illness and inpatient admission, they said.

In the U.S. alone, more than 700,000 cholecystectomies are performed each year.

Most gallstones (80% to 90%) are formed from cholesterol-saturated bile, with the rest consisting mainly of polymerized calcium bilirubinate.

Thus, it has been proposed that lowering cholesterol may lessen the chances of forming gallstones, but studies looking at the association have yielded mixed results.

Bodmer’s group examined data from the U.K.-based General Practice Research Database, which included 27,035 patients who had had a cholecystectomy and 106,531 controls matched by age, sex, general practice, calendar time, and years in the database. Of these, 2,396 patients and 8,868 controls had a history of statin use.

About three-quarters of the patients and controls were female, and their mean age was 53.4.

Current statin use was present in 1% of patients and 0.8% of controls who had filled one to four prescriptions, in 2.6% of patients and 2.4% of controls with five to 19 prescriptions, and 3.2% of patients and 3.7% of controls for 20 or more prescriptions.

After adjustment for several confounders, current statin use was associated with a lower risk of gallstone disease requiring removal of the gall bladder in those who had filled at least five prescriptions.

The findings were consistent across age, gender, and BMI categories, as well as across statin class.

In addition, the association remained significant regardless of whether the comparison was made with patients with normal cholesterol levels or those with hypercholesterolemia, “suggesting that a possible effect of statins on gallstone formation may be largely independent of the presence of hypercholesterolemia,” the researchers said.

They listed some limitations of the study, including the possibility of some outcome misclassification because original medical records were not reviewed and the lack of adjustment for potentially relevant lifestyle factors or socioeconomic status.

Also, they noted that the observational study design precluded any proof of a causal relationship.

This study did not receive any outside funding.

The Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel Pharmacoepidemiology Unit, University of Basel, and the Boston Collaborative Drug Surveillance Program reported having a research collaboration with various companies in the pharmaceutical industry. Regarding drug companies producing and selling statins, the Basel Pharmacoepidemiology Unit as well as the Boston Collaborative Drug Surveillance Program had or currently have a research collaboration with AstraZeneca and Novartis. The Division of Clinical Pharmacology and Toxicology at the University Hospital Basel currently receives an unconditional grant from AstraZeneca. All of these funded research collaborations are unrelated to this article. The authors reported conducting numerous studies using the U.K.-based General Practice Research Database in the past, and currently working on several projects. Some, but not all, of the studies are industry-sponsored. The authors reported conducting research for the pharmaceutical industry for many years, including collaborations involving Pfizer, Novartis, Bristol-Myers Squibb, AstraZeneca, and Merck Sharp & Dohme. Meier and two of his co-authors reported conducting research related to psoriasis in the past for MerckSerono.

Patients who had a “complete” remission of myelodysplastic syndrome (MDS) after treatment with lenalidomide (Revlimid) still had circulating drug-resistant malignant stem cells — and the disease resumed its progression in most patients despite continued treatment, a small study found.
The study, published in the Sept. 9 issue of the New England Journal of Medicine, tracked seven patients with MDS marked by the so-called 5q genomic deletion who had obtained complete clinical responses to lenalidomide — two of whom also had complete cytogenetic responses — along with an eighth patient with similar disease who failed lenalidomide therapy.
Researchers led by Sten Eirik W. Jacobsen, MD, PhD, of the University of Oxford in England, found that all seven patients who achieved remission, including those with complete cytogenetic responses, had MDS-associated stem cells with the 5q deletion still in circulation — though these were knocked down considerably during treatment.

Not surprisingly, the surviving malignant stem cells tended to be “distinctly resistant” to lenalidomide, Jacobsen and colleagues reported.

The drug was eventually stopped in five of the patients following renewed disease progression, including the two who had obtained complete cytogenetic responses.

New cytogenetic aberrations were detected in all of the patients tested during treatment (or, in one case, following treatment interruption).

These findings are “direct in vivo evidence of the persistence of a phenotypically and functionally distinct minor del(5q)-bearing stem-cell population in patients with myelodysplastic syndrome; these stem cells are selectively resistant to an otherwise effective therapy,” Jacobsen and colleagues wrote.

The researchers suggested that the results may help explain why lenalidomide eventually loses effectiveness in many MDS cases.

But the study also offers an opportunity. It “may facilitate delineation of specific cellular targets apart from those in the bulk of the clone,” potentially leading to new treatments to kill off the minority of malignant cells that survive initial therapy, they wrote.

There may also be immediate clinical implications, Jacobsen and colleagues indicated, in that the ability to detect and characterize stem-cell subtypes in patient samples could help in monitoring clonal evolution — a potential prognostic indicator.

“In that regard, we observed an upregulation of cell-surface IL3RA” on MDS stem cells during remission as well as progression, the researchers noted. Such cells “might from the outset be the most resistant to lenalidomide treatment.”

Jacobsen and colleagues acknowledged that the cancer stem cell hypothesis — in which rare and distinct populations of malignant cells escape otherwise effective treatments and can cause the cancer to recur — is controversial.

Also fueling the debate have been findings that so-called cancer stem cells are not rare or distinct after all.

To overcome that objection, Jacobsen and colleagues focused on cells that not only had the 5q deletion but also were positive for CD34 and CD90 markers with low or undetectable CD38. These were analyzed in patients’ bone marrow samples taken before and during lenalidomide therapy.

As opposed to other MDS-related progenitors and stem cells, those with these characteristics were more likely to be resistant to lenalidomide, the researchers found.

The study also included an eighth patient with MDS who was generally similar to the other cases, but who failed to respond to lenalidomide. Clonal analysis of marrow samples from this patient both before and during treatment showed a “complex karyotype” similar to what was seen in the other patients after lenalidomide treatment.

Jacobsen and colleagues suggested that this finding supported the idea that lenalidomide resistance is “associated with acquisition of new cytogenetic aberrations.”

Funding for the study came from the EuroCancerStemCell Consortium, the Swedish Cancer Society, the Swedish Research Council, Avtal om Läkerutbildning och Forskning, Region Skåne, the Göran Gustafsson Foundation, Hemato-Linné, the Torsten and Ragnar Söderbergs Foundation, the Cluster of Excellence in the Area of Regenerative Biology and Reconstructive Therapies, the Medical Research Council, the Oxford Partnership Comprehensive Biomedical Research Centre, the Leukemia and Lymphoma Society, and the Astellas Foundation for Research on Metabolic Disorders.

Two authors reported receiving payments from Celgene for consulting and development of educational presentations. Other authors declared they had no relevant conflicts of interest.

ROCKVILLE, Md., Jan. 14 — The FDA today approved natalizumab (Tysabri), the star-crossed multiple sclerosis agent, for refractory moderate-to-severe Crohn’s disease showing evidence of inflammation.

The agency’s action followed an advisory committee’s recommendation for approval subject to “strict post-marketing surveillance.”

Natalizumab was approved for relapsing MS in November 2004. But in February 2005 it was withdrawn by its maker, Biogen Idec, and distributor, Elan, after three patients in clinical trials developed progressive multifocal leukoencephalopathy, a rare viral infection of the brain. Two of the cases were fatal. At the same time, the FDA stopped clinical trials of the drug.

The drug was returned to the market in June 2006 under a strict risk management program. There were no cases of multifocal leukoencephalopathy reported in the Crohn’s trials.

The approval requires that everyone involved in using natalizumab in Crohn’s disease — patients, prescribing physicians, pharmacies, and infusion centers — participate in a special educational program called TOUCH. MS patients must also participate in their own TOUCH program.

For Crohn’s, the program involves strict monitoring guidelines, including an extensive education program on natalizumab’s risks.

The drug’s prescribing information includes a boxed warning about the risk of progressive multifocal leukoencephalopathy. Natalizumab is a humanized monoclonal antibody that targets alpha-4 integrin, an adhesion molecule involved in inflammatory processes.

Other adverse effects in clinical trials include headache, fatigue, infusion reactions, urinary tract infections, joint and limb pain, rash, respiratory tract infections, and nausea.

The drug’s manufacturers, Elan Corp. and Biogen Idec, have also reported cases of clinically significant liver injury in the post-marketing setting.

Concerns about progressive multifocal leukoencephalopathy have so far kept the drug off the European market for Crohn’s. In July and again in November of last year, medical advisory panels in the European Union recommended against approval for Crohn’s.

The companies said the European Commission is still considering their application. They expect a decision by the end of March.

Conventional therapies for Crohn’s disease include corticosteroids and tumor necrosis factor inhibitors such as infliximab (Remicade) and adalimumab (Humira).

The FDA’s approval was based primarily on two clinical studies, ENCORE and ENACT-2.

In the former, 12 weeks of natalizumab led to responses in 60% of patients, compared with 44% of placebo-treated patients. Forty-eight percent of natalizumab patients sustained responses through week 12, compared with 32% of placebo-treated patients (P

ROCKVILLE, Md., June 30 — As the number of confirmed cases of Salmonella Saintpaul continues to climb — 810 cases in 36 states and the District of Columbia — the CDC and FDA hinted that tomatoes may not be the only culprit in the outbreak.

The case reported most recently was a person who became sick on June 15, even though the fields where tomatoes were harvested in late April and early May have already been plowed under, David Acheson, M.D., associate commissioner for foods at the FDA, said at press briefing.

The fact that the FDA and CDC have not been able to pinpoint an exact source of the infected tomatoes despite weeks of trace-back investigations had been fueling speculation about other sources.

And Patricia Griffin, M.D., chief of the CDC’s Enteric Diseases Epidemiology Branch, seemed to confirm that when she characterized the outbreak as a “produce outbreak” rather than a tomato outbreak.

Dr. Acheson tried to put that genie back in the bottle with repeated assurances that neither the CDC nor the FDA has evidence that points to another source.

That said, Dr. Acheson conceded that it was “possible” that there were other sources of infection.

On June 20, Dr. Acheson said the FDA had traced the suspect tomatoes to two distribution chains — one originating at farms in central and southern Florida and the other in Mexico. For more than a week, FDA and CDC experts have been conducting investigations at every point along those supply chains.

Those investigations have come up empty so far, but Dr. Acheson said they have discovered that as many as 90% of tomatoes are likely to be re-packaged, a process that makes trace-back efforts difficult if not impossible.

Tomatoes, he said, are packaged to fill specific orders from stores and restaurants. So if a store requests a crate of small, ripe tomatoes, the packaging house will open crates from several different sources — farms in several different states and Mexico, for instance — to locate small ripe tomatoes and pack them into a single crate.

The repacking process is so complicated that just as tomatoes from Mexico are sent to Florida for packing and repacking, tomatoes from Florida are sent to packagers in Mexico to undergo the same repacking process.

According to the CDC, the greatest number of Salmonella Saintpaul cases is in Texas — 342 — followed by New Mexico with 85 cases and Illinois with 78.

At least 95 people — from under a year old to 99 — have been hospitalized. Fifty-one percent of cases have occurred in women.