BETHESDA, Md., Aug. 19-Two genetic mutations that appear to put people at increased risk for developing bladder cancer could account for about 31% of bladder cancers, say Spanish and American researchers.

In a large study conducted among patients with bladder cancer in Spain, those found to be missing both copies of a gene that helps to neutralize carcinogens had nearly double the risk of developing bladder cancer as those with two intact copies, reported Montserrat Garcia-Closas, M.D., and colleagues of the National Cancer Institute here and centers in Spain and the U.S.

Patients with only one copy of the gene had about a 20% greater risk for bladder cancer, according to results of the study published in the Aug. 20 issue of The Lancet.

Patients who had a variant form of a second carcinogen-detoxifying gene had about a 40% greater risk for developing transitional cell carcinoma (TCC) of the bladder, and this elevated risk was especially great among cigarette smokers, reported Dr. Garcia-Closas and colleagues.

“These findings provide compelling evidence for the role of common polymorphisms in the etiology of cancer,” Dr. Garcia-Closas and colleagues wrote. “Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.”

The American Cancer Society estimates that there were 60,240 new cases of bladder cancer in the United States in 2004, occurring nearly three times more frequently in men than in women. Bladder cancer accounted for an estimated 12,710 deaths in the U.S. last year.

Both cigarette smoking and workplace exposure to the class of chemicals known as aromatic amines have been linked to increased bladder cancer risk. These chemicals, which are also found in tobacco smoke, are widely used in the manufacture of paints, pharmaceuticals, plastics and agricultural chemicals.

The association between amine exposure and bladder cancer points to genes that encode for proteins that lie along pathways for amine metabolism, noted Emanuela Taioli, M.D., Ph.D., and Sara Raimondi, Ph.D., of the Fondazione Policlinico IRCCS in Milan, Italy, in an accompanying commentary.

“The issue is whether patients carrying unfavorable polymorphisms in these genes are at a higher risk of bladder cancer than patients with more favorable combinations of genetic polymorphism, given the same level of environmental exposure,” they wrote.

To determine whether this was so, Dr. Garcia-Closas and colleagues looked for mutations in genes that normally detoxify carcinogens: glutathione S-transferase M1, or GSTM1, and N-acetyltransferase-2, or NAT2.

They did this by looking for polymorphisms among 1,150 Spanish patients with TCC, and 1,149 controls, all of whom were white. They also performed meta-analyses on various studies looking at links between NAT2 and GSTM1 and bladder cancer.

They found that the odds ratio for bladder cancer for people with deletion of one GSTM1 allele was 1.2 (95% CI 0.8-1.7); for people with deletion of both alleles (GSTM1 null) the odds ratio was 1.9 (1.4-2.7, p for trend

BALTIMORE — Percutaneous alcohol septal ablation appears to be as safe as isolated septal myectomy for patients with hypertrophic obstructive cardiomyopathy, across clinical settings and regardless of patient volume, a database study showed.

Despite the older age in the ablation patients, they had lower rates of in-hospital mortality (0% versus 5.4%) and new-onset hemodialysis (0% versus 2.5%), with no significant difference in rates of stroke (0.6% versus 0.8%) or placement of permanent pacemakers and implantable cardioverter-defibrillators (18.4% versus 13.6%), according to Srihari Naidu, MD, of Winthrop University Hospital in Mineola, N.Y.

In addition, length of stay (three versus six days) and inflation-adjusted median patient cost ($11,739 versus $30,499) favored the alcohol ablation group (P<0.0001 for both), he reported at the Society for Cardiovascular Angiography and Interventions meeting here.

“Real-world in-hospital data appear to strongly favor alcohol ablation, regardless of whether the comparator group is myectomy without CABG or myectomy without CABG or mitral valve replacement,” he said.

“These results … should better inform clinical decision making, including resource utilization for drug-refractory [hypertrophic obstructive cardiomyopathy] patients in need of invasive therapy.”

Steven Bailey, MD, a cardiologist at the University of Texas Health Science Center in San Antonio, commented that “in the cardiology community in general, there really is a lot of uncertainty about what the best therapies for these patients are.”

There are not enough robust databases from single centers to help clarify the issue and randomized trials are unlikely because of a variety of confounding variables, Bailey told MedPage Today.

Naidu’s study “was important because it did look at national trends in terms of therapy,” said Bailey, who moderated the SCAI session.

“In the case of percutaneous procedures, there does not seem to be a major morbidity or mortality associated with doing them,” he said.

Recent data from larger centers indicating a surgical mortality rate of less than 1% have raised questions about whether there is any advantage to alcohol septal ablation, which carries risks of complete heart block and procedural complication, over the more established myectomy, according to Naidu.

To look at the two procedures using national data, Naidu turned to the PREMIER Perspective database that includes information on about one-sixth of U.S. hospitals.

He searched for patients who underwent either alcohol septal ablation or isolated septal myectomy (without concomitant CABG) from Jan. 1, 2000, to June 30, 2010, identifying 242 who underwent myectomy at 97 hospitals and 163 who underwent ablation at 37 hospitals.

On average, patients who underwent alcohol septal ablation were older (60 versus 54, P<0.01), although other baseline characteristics were similar.

Despite the age difference, ablation was associated with a lower rate of mortality and new-onset hemodialysis, a shorter hospital stay, and lower costs.

There was a higher rate of mitral valve replacement in the myectomy group (27.7% versus 0%, P<0.0001), but after excluding patients who had valve replacement, there was still an advantage for mortality, length of stay, and cost in the ablation group.

Bailey said that the study raises some questions that need to be investigated including how patients were selected for one treatment or the other. This would provide a true comparison of the relative safety of alcohol septal ablation and isolated septal myectomy, he said.

Naidu reported that he had no conflicts of interest. His co-author is an employee of The Medicines Company.

A steady-state pattern electroretinogram known as PERGLA was able to detect destruction of retinal ganglion cells early enough to allow vision correcting surgery, a prospective study found.
In a cohort of patients with glaucoma undergoing PERGLA, intraocular pressure was significantly lessened after trabeculectomy or drainage implant surgery to 10.4 mm Hg from a baseline measurement of 19.7 mm Hg (P<0.001), according to Mitra Sehi, PhD, and colleagues from the University of Miami in Palm Beach Gardens, Fla.
This reduction in intraocular pressure resulted in electrophysiologic improvements in the responses of dysfunctional or damaged ganglion cells to 0.46 μV from 0.37 μV (P=0.001), they reported online in Ophthalmology.

This increase in postoperative amplitude as measured on the glaucoma-specific electroretinogram, the researchers explained, “implies that viable [retinal ganglion cells] were able to generate a stronger electrical signal after surgery.”

Glaucoma is characterized by a progressive loss of retinal ganglion cells and axons, even before changes in vision occur, a process that appears to be reversible to a certain extent.

An earlier retrospective study suggested that the dysfunction of these retinal cells could be detected and measured using PERGLA, which utilizes a stimulus of contrast-reversed gratings rather than simple flashes of light to evaluate changes in waveforms in damaged retinal ganglion cells.

The test is noninvasive: Electrodes are placed on the patient’s forehead, temples, and lower eyelids, and the system measures various parameters including pressure, amplitude, and phase lag.

To assess the utility of PERGLA for the early detection of retinal damage, Sehi and colleagues recruited 47 patients with glaucoma that could not be controlled medically, testing various clinical variables before and after surgery on one eye for each patient.

As measured by standard automated perimetry, 34% of the eyes were classified as having early disease, 30% had moderate disease, and 36% were advanced.

Patients’ mean age was about 70, and most were white women.

Their most common diagnoses were primary open-angle glaucoma and low-tension glaucoma.

A total of 72% had trabeculectomy with antifibrosis therapy and the remainder had drainage implant surgery.

The researchers found that in the operated eyes, mean ocular perfusion pressure improved, from 45.8 mm Hg to 53.1 mm Hg (P<0.001), as did PERGLA phase (P=0.01), which suggested recovery in retinal ganglion cell function.

In contrast, unoperated eyes tested three months later in 25 patients showed no difference in mean intraocular pressure, which was 15 mm Hg at baseline and 14.6 mm Hg subsequently (P=0.57).

There also were no significant changes in amplitude or phase in the unoperated eyes, the researchers reported.

PERGLA measurement has limitations, they acknowledged, such as a small dynamic range and the possibility of bias when central vision is poor or cataracts are present.

Further studies are needed with larger numbers of patients to explore other factors that may enhance the electrophysiologic responses of retinal cells to reductions in intraoperative pressure, the researchers concluded.

The study was supported by the Maltz Family Endowment for Glaucoma Research, Barney Donnelley, the Kessel Foundation, Research to Prevent Blindness, the National Institutes of Health, and Allergan.

One author is a consultant to Allergan and receives financial support from Carl Zeiss Meditec.

The authors declared that they have no financial interest in any device or technique discussed in this study.

Treatment of eustachian tube dysfunction with a nasal steroid spray did not significantly improve otitis media with effusion or negative middle ear pressure, a randomized trial found.

Complete tympanometric normalization was seen at six weeks in 18.9% of patients treated with intranasal aqueous triamcinolone acetonide and in 32.4% of those who received placebo, according to Laura J. Orvidas, MD, of the Mayo Clinic in Rochester, Minn., and colleagues.

This represented a nonsignificant difference in proportions of −13.5% (95% CI −33.2 to 6.2, P=0.18), the investigators reported in the May issue of Archives of Otolaryngology-Head and Neck Surgery.

Because inflammation in the nasopharyngeal area could contribute to the development of acute eustachian tube dysfunction, treatment with intranasal corticosteroids has been advocated, although the drugs are not currently recommended for this.

Spontaneous remission occurs in some patients with a watchful waiting approach, but the rate of resolution of the ear symptoms is uncertain.

To clarify a potential role for intranasal steroids in both children and adults, the investigators prospectively enrolled 91 patients with otitis media with effusion and/or negative middle ear pressure. They were between ages 6 and 95, with 37% younger than 18.

At baseline, all patients had a tympanogram for objective assessment.

They also completed a questionnaire, on which 22% reported problems with balance, 30% had tinnitus, and 26% had symptoms characteristic of a common cold. Parents filled out the questionnaire for children younger than 12 and helped older children fill it out.

Those ages 12 years and older received two sprays of the steroid or placebo in each nostril once daily; younger children were given one spray in each nostril daily.

As with the overall study population, a subgroup of pediatric patients also showed no significant benefit with the steroid treatment.

Among patients ages 6 to 17, 7% in the treatment arm had normalization on a follow-up tympanogram, as did 27% of those in the placebo group, for a difference in proportions of 20% (95% CI −45.7 to 5.7, P=0.14).

When the investigators analyzed outcomes according to individual ears, they found that 21.8% of ears in patients treated with the steroid had normalization, as did 35.1% of those in patients given placebo (P=0.15).

On a follow-up questionnaire, more patients who had been treated with the steroid reported persistent fullness or pressure in the ears.

Symptom scores that reflected both severity and frequency tended to be higher in treated patients (P=0.07), but after adjustment for baseline symptom score, no significant benefit was seen for the treatment (P=0.27).

Adverse events such as nosebleeds and cough occurred in both groups, but were not severe and none of the patients withdrew because of these events.

The investigators concluded that treatment with triamcinolone acetonide was ineffective for normalization of tympanometry findings associated with eustachian tube dysfunction, and also failed to show symptomatic improvements.

Analysis of data from the placebo arm of the study determined that the rate of spontaneous resolution was low, at about one-third, but there were no serious problems associated with watchful waiting.

“This new information about natural disease history in adults should prove valuable for patient counseling,” the investigators wrote.

Limitations of the study included a lower number of participants than originally was planned and the use of a nonvalidated questionnaire to evaluate symptoms.

The study also did not formally differentiate between patients with and without allergic rhinitis.

“Given the inflammatory nature of allergic rhinitis and the established potential negative effect on eustachian tube function, it is certainly possible that nasal steroids may have a role in treating patients with [eustachian tube dysfunction] who fall within this specific subcategory,” Orvidas and colleagues wrote.

The study was funded by sanofi-aventis.

The authors reported no financial conflicts.

WASHINGTON — Although the healthcare reform law forbids it, using cost factors in comparative effectiveness research could save billions of dollars and put Medicare on a more secure financial footing, researchers argued.

Writing in the single-topic October issue of Health Affairs, they criticized the current payment model, in which Medicare covers any treatment that is deemed “reasonable and necessary,” regardless of how it stacks up in cost or efficacy against other comparable treatments.

“The time is ripe for Medicare to use comparative effectiveness research to reach a new paradigm, which would include equal payments for services that provide equivalent results,” wrote authors Steven Pearson, MD, MPH, and Peter Bach, MD.

Pearson is president of the Institute for Clinical and Economic Review at Massachusetts General Hospital’s Institute for Technology Assessment. Bach is an attending physician at Memorial Sloan-Kettering Cancer Center in New York City and former adviser to the CMS Administrator.

The 2009 economic stimulus bill included $1.1 billion to fund comparative effectiveness research, and the Affordable Care Act (ACA), the healthcare reform law passed six months ago, established the Patient-Centered Outcomes Research Institute to identify priorities and conduct research to compare the clinical effectiveness of different medical treatments.

But the ACA explicitly forbids the new institute from considering costs of things like drugs, devices, treatments, services, or diagnostic tools in its comparative analyses. That language was added after discussions over using cost in comparative effectiveness research turned into a debate about “rationing.”

“Medicare’s processes for determining coverage and setting reimbursement rates are like computer programs that date all the way back to the 1960s,” Pearson and Bach wrote. “They demonstrate the arcane complexity of decades of ad-hoc updates with no fundamental redesign.”

The reimbursement-plus-profit model currently used by Medicare is often criticized by policy experts who argue that the doctors who stand to gain the most under Medicare are the ones who provide the most expensive procedures.

Under the model proposed by Pearson and Bach, Medicare would still use its “reasonable and necessary” standard, but would also use comparative effectiveness research to assign each treatment to one of three categories — “evidence of superior comparative clinical effectiveness; evidence of comparable comparative clinical effectiveness; or insufficient evidence to determine comparative clinical effectiveness.”

Payment for treatments in the “superior” bucket would be set according to current Medicare formulas. For treatments in the “comparable” bucket, Medicare would examine the rates paid for those comparable alternatives and pay at the lowest price.

If a new service or treatment lacked evidence of comparative effectiveness, Medicare would set up a temporary payment schedule while comparative research is conducted. If, over time, evidence fails to show a new modality is superior to an existing one, Medicare would evaluate whether it should reimburse for the new service, and likely drop reimbursement rates for the service in the meantime.

The authors list a number of barriers to using costs to set payment policies, and partisan politics is near the top of the list.

But they argue that “the straightforward idea of paying equally for comparable results would make sense to most Americans,” and said if patients and others banded together to support the idea, it could perhaps start in private health plans or state Medicaid programs and eventually influence how Medicare pays for care.

Two other papers published in the same issue help bolster that view. They reported on national opinion polls that found that people generally see the value of comparative effectiveness research, but fear that it may be used to ration care, and they do not want their medical treatment choices restricted.

Meanwhile, two other researchers, writing in still another paper in Health Affairs argue that the Patient-Centered Outcomes Research Institute should not use cost in its comparative analyses.

“Including cost-effectiveness analyses in the research sponsored by the institute may be unnecessary as well as politically and legally questionable,” wrote Alan M. Garber, MD, of Stanford University’s Center for Health Policy, and Harold Sox, MD, of Dartmouth Medical School. Sox co-chaired the Institute of Medicine (IOM) Committee on Comparative Effectiveness Research Priorities in 2009.

However, cost-conscious insurance companies, physician groups, hospitals, and savvy patients should compare costs of various treatments, they wrote.

Pearson and Bach also acknowledged the politically sensitive issue of using cost in comparative effectiveness.

“Just mentioning Medicare and comparative effectiveness research in the same sentence is enough to raise temperatures in Washington health policy circles,” they wrote.

No one knows that better than Donald Berwick, MD, administrator of CMS. Berwick’s appointment was held up by Republicans who accused the longtime healthcare improvement advocate of favoring a system in which cost considerations would be used to deny medical care for some Americans.

Berwick defended his mission of lowering healthcare costs during a Health and Human Services summit on Monday dedicated to improving healthcare quality.

Berwick told attendees at the summit that he has a threefold aim as head of CMS: to improve care, to improve the nation’s health, and to “lower per capita costs of healthcare without harming a single hair on any person’s head.”

The October issue of Health Affairs is funded by the National Pharmaceutical Council, WellPoint Foundation, and Association of American Medical Colleges.

Americans should drastically reduce the amount of dietary sugar that’s added at the table, during cooking, and in processing, the American Heart Association said in new guidelines aimed at the rise of obesity in America.

Added sweeteners — sugars that aren’t naturally part of the food we eat — shouldn’t account for more than 100 calories a day for women or 150 calories for men, the AHA said in a scientific statement.

For the average adult, that’s roughly five to nine teaspoons of sugar per day, Rachel K. Johnson, PhD, MPH, RD, of the University of Vermont in Burlington, and colleagues wrote.

Americans’ current intake averages 22 teaspoons, or 355 calories, per day — largely from soft drinks and other sweetened beverages — according to the 2001–2004 National Health and Nutrition Examination Survey (NHANES). A single can of cola contains about eight teaspoons of sugar.

And sugar consumption has been on the rise, up 19% (about 76 calories per day) since 1970, according to one U.S. Department of Agriculture report.

The AHA has recommended limiting intake of food and drinks with added sugars since 2006, but the new statement marks the first time the association has proposed a specific upper limit.

Its recommendations drew generally favorable responses from nutrition and heart experts contacted by MedPage Today and ABC News, but general skepticism about whether consumers will be willing, or able, to follow the advice.

“I think that these are good recommendations,particularly for a society where obesity and metabolic syndrome are increasing in epidemic proportions,” said Carl Lavie, MD, medical director of cardiac rehabilitation and prevention at Ochsner Heart and Vascular Institute in New Orleans.

“However, the at-risk population will generally not be walking around counting their calories or grams of sugar. Therefore, for this to really be effective, the food industry will have to make changes that substantially reduce the sugar content of common foods such as fruit drinks, cereals, etc.”

Just determining how much sugar has been added to a food may be challenging, though, the AHA statement acknowledges, since since food labels don’t distinguish it from naturally-occurring sugars.

But the body can tell the difference, according to an experiment that pitted highly-processed, sugar-rich foods, such as a chocolate-coated candy bar and soda with chips, to snacks such as raisins or bananas and peanuts.

It revealed higher glucose and insulin levels with the sugary, refined-grain snacks, “which suggests that the glycemic response to food is influenced by the carbohydrate content and physical state of the food, such as processed or whole, liquid, or solid,” Johnson’s group noted.

Indeed, many nutrition experts believe that sugared sodas are major villains in the obesity epidemic.

“Liquid sugar in soft drinks is the worst culprit because besides rapidly elevating blood sugar, liquid calories are not sensed as well as calories that we eat,” wrote Jana Klauer, MD, of St. Lukes-Roosevelt Hospital in New York City. “In other words, if we drink a 350 calorie soda with our burger and fries, we don’t necessarily eat less to compensate for the extra calories in the soda.”

Emerging evidence from other studies, though not conclusive, has suggested that added sugars may also raise blood pressure more than naturally-occurring sugars and may have a different impact on lipids, inflammation, and oxidative stress.

And while trial data are likewise limited, “evidence from observational studies indicates that a higher intake of soft drinks is associated with greater energy intake, higher body weight, and lower intake of essential nutrients,” Johnson and colleagues said.

Added sugar also accounts for a large degree of overspending on discretionary calories — the fudge factor between what’s needed nutritionally and what would maintain current weight — in the American diet, they added.

NHANES data suggested that these calories take up 30% to 42% of total energy intake, much higher than recommended.

The AHA scientific statement suggested splitting discretionary calories between fats and sugars, which led to the recommendation to limit added sugar to 100 to 150 calories for the average adult.

But this still needs to be in the context of an overall healthy diet “to achieve and maintain healthy weights and decrease cardiovascular risk while at the same time meeting essential nutrient needs,” the statement concluded.

From a practical standpoint, outside nutrition experts noted that turning the AHA recommendations into action by consumers may not be easy. And some said the AHA concentrated too much on added sugar instead of total sugar and total carbohydrate intake.

“Replacing [sugared sodas] with fruit juice is not helpful, as the sugar content, although naturally present, is just as high,” noted Walter Willett, MD, MPH, DrPH, chairman of the Department of Nutrition at the Harvard School of Public Health.

“Also, it is important to keep in mind that refined starches like white bread, white rice, and potatoes have adverse metabolic effects similar to sugar because they are rapidly converted to glucose in the body.”

Johnson reported conflicts of interest or funding from the U.S. Department of Agriculture Hatch, Dairy Management Inc.-National Dairy Council, and International Dairy Foods Association.

Coauthors reported conflicts of interest or funding from the National Heart, Lung, and Blood Institute, National Institutes of Health, Schering-Plough, Egg Nutrition Council, Merck, Hershey, Kraft, Mars, Canadian Pediatric Endocrine Group, Children’s Hospital of Orange County, Columbia University, Endocrine Society Science Writers Conference, AHA, Dr. Robert C. and Veronica Atkins Foundation, National Institute of Diabetes and Digestive and Kidney Diseases, Unilever, American Diabetes Association, New York City Department of Health, D’Life, Veterans Administration, Sensicorp, and the Mt. Sinai School of Medicine.

BOSTON, Feb. 4 — Comforting data about the safety of the second major drug aimed at blocking HIV entry to target cells were revealed here today.

Vicriviroc, which blocks the CCR5 co-receptor on the surface of immune cells, had been associated with an increase in malignancies in early studies. (See: IAS: Cancers Worry Vicriviroc HIV Researchers)

But there were no malignancies after 48 weeks of the VICTOR E-1 study and no differences in adverse events between either of two doses of vicriviroc and placebo, said Barry Zingman, M.D., of Montefiore Medical Center in New York.

It now seems likely that the malignancies that had been reported at the Toronto World AIDS Conference were part of the “natural history of the disease in a very sick population,” he said at the 15th Conference on Retroviruses and Opportunistic Infections here.

Dr. Zingman said the current phase II study shows the drug is a “very potent oral CCR5 inhibitor and holds a lot of potential” for HIV treatment, if it succeeds in phase III studies.

In the VICTOR trial, 116 volunteers on an optimized background regimen were randomized to placebo, 20 mg a day of vicriviroc, or 30 mg a day.

To be eligible for the trial, volunteers had to have a strain of virus that was predisposed to use the CCR5 co-receptor, to have been treated with drugs from the three major classes of HIV therapeutics, and to have resistance mutations to protease inhibitors and nucleoside reverse transcriptase inhibitors.

The primary endpoint of the study was the change in HIV RNA copies at the end of 48 weeks, Dr. Zingman said, and both doses of vicriviroc outperformed placebo.

On average, volunteers getting the high dose of vicriviroc had a drop of 1.77 log10 copies/mL of blood, compared with 1.75 for the low dose and 0.79 for placebo.

The researchers also measured the proportion of volunteers achieving blood HIV levels of fewer than 50 copies per mL.

On placebo, only 14% of patients reached that level, compared with 56% for the high dose of vicriviroc and 52% for the lower dose. The differences from placebo were significant at P=0.0002 and P=0.0004, respectively.

Interestingly, the reduction in viral load appeared to be independent of the number of active drugs in the background regimen, Dr. Zingman said.

There were no apparent dose-related or drug-related toxicities, Dr. Zingman said, and grade 3 and 4 adverse events were evenly distributed, with 20% in the placebo arm, 20% in the low-dose vicriviroc arm. and 21% in the high-dose arm.

One of the effects of treatment with the CCR5 inhibitor also appears to be a change in tropism, with CXCR4-tropic virus appearing within a short time after treatment with the drug.

Dr. Zingman said it appears that the CXCR4-tropic virus is present at the beginning, and emerges once the dominant CCR5 strain is suppressed by vicriviroc.

Despite that change, he said, the combination of vicriviroc and the optimized background regimen results in lowered HIV viral loads and increases in CD4 counts.

The study shows that vicriviroc is a “viable drug,” commented John Mellors, M.D., of the University of Pittsburgh, co-chairman of the conference’s scientific program.

He said it is reassuring that the “initial blip or signal or noise” of malignancies hasn’t been observed since the early studies, but added it had to be examined. “It wasn’t Chicken Little,” he said. “It was important to look at.”

The study was supported by Schering-Plough, which is developing vicriviroc.

Dr. Zingman did not report any potential conflicts.

Primary source: Conference on Retroviruses and Opportunistic Infections

Source reference:
Zingman B, et al “Vicriviroc, a next generation CCR5 antagonist, exhibits potent, sustained suppression of viral replication in treatment-experienced adults: VICTOR-E1 48-week results” CROI 2008; Abstract 39LB.

Treatment with adalimumab (Humira) was effective for both joint and skin manifestations of psoriatic arthritis in patients whose disease had not responded adequately to prior therapy, a multicenter, open-label study found.

After 12 weeks of therapy, 78% of such patients had experienced at least a 20% improvement in symptoms as defined by the American College of Rheumatology (ACR20), according to Dafna D. Gladman, MD, of the University of Toronto, and colleagues.

And ACR20 response rates did not differ significantly between patients who had previously received a biologic drug (70.3%) and those who were biologic-naive (81.1%), the researchers reported online in the Journal of Rheumatology.

Adalimumab, a fully human monoclonal antibody that inhibits the effects of tumor necrosis factor-alpha, has been shown in randomized trials to be effective in psoriatic arthritis, but in randomized studies patients with active disease that has not previously responded to biologic therapy may be excluded.

So to assess the efficacy and safety of the drug as used in routine clinical care, Gladman and colleagues enrolled 127 adults with at least three tender joints and three swollen joints despite treatment with disease-modifying anti-rheumatic or biologic drugs.

Patients’ mean age was 48.8, and mean duration of psoriatic arthritis was 11.1 years. More than half were men.

In the study, known as ACCLAIM, patients self-administered 40 mg of adalimumab subcutaneously every other week in addition to their other ongoing therapies.

A total of 64.6% had previously received methotrexate, and 42.5% had already used a biologic agent, most commonly etanercept.

Overall, 55.9% of patients improved by 50% according to ACR criteria and 21.3% improved by 75%.

These levels of response were reached by 60% and 25.6% respectively of those who were biologic-naive and by 45.9% and 10.3% of those who had previous biologic treatment.

Although responses were somewhat greater for patients who were biologic-naive, the differences were not statistically significant, according to the investigators.

Among patients who had psoriatic involvement of at least 3% of their body surface area at baseline, 64.7% had improved by 50%, and 47.1 had improved by 75% at week 12.

Other clinical changes compared with baseline included: Active dactylitis in four or more digits, 11% versus 33.9% (P<0.001) Enthesitis in the Achilles tendon, 14.2% versus 29.9% (P=0.004) Enthesitis at the plantar fascia, 11% versus 24.4% (P=0.008)

Physical function and health-related quality of life, as measured on the Health Assessment Questionnaire-Disability Index (HAQ-DI), also showed a statistically and clinically significant improvement by week 12 (−0.44, P<0.001).

In addition, about half of the patients had a change in their HAQ-DI that exceeded the minimum clinically important difference of −0.3.

On a work productivity questionnaire, significant improvements were seen in the domains of output (P=0.003), time (P<0.001), and physical impairment (P<0.001).

During the study, 63.8% of patients experienced at least one adverse event, most of which were mild.

Three serious adverse events occurred (cerebrovascular accident, venous thrombosis, psoriatic arthropathy) that were considered unlikely to be related to treatment.

The authors acknowledged that the study had limitations, including its open-label design, short duration, and small numbers.

The study was supported by funding from Abbott Laboratories, including assistance with medical writing.

Two of the investigators were Abbott employees.

The earliest known case of coronary artery disease has been found in the 3,550-year-old mummy of an Egyptian princess. She lived between 1580 and 1550 B.C., and died in her early 40s, say researchers.

Their investigation with whole-body CT scans found that this wasn’t a unique case. About 45 percent of 43 other mummies also had evidence of atherosclerosis, an accumulation of plaque in arteries.

The findings suggest that atherosclerosis has afflicted humans for a long time and isn’t just a modern disease. The study was scheduled for presentation Sunday at the annual scientific session of the American College of Cardiology (ACC), held in New Orleans.

“Commonly, we think of coronary artery or heart disease as a consequence of modern lifestyles, mainly because it has increased in developing countries as they become more westernized,” co-principal investigator Dr. Gregory S. Thomas, a clinical professor and director of Nuclear Cardiology Education, University of California, Irvine, said in an ACC news release.

“These data point to a missing link in our understanding of heart disease, and we may not be so different from our ancient ancestors,” he suggested.

Genetic factors associated with atherosclerosis may play a more important role in the disease than previously thought, said Thomas and his colleagues.

Most of the atherosclerosis in the mummies was located in large arteries, including the aorta in the abdomen. But atherosclerosis was also found in important small arteries. About 7 percent of the mummies had obstructions in heart arteries, which can cause a heart attack, and 14 percent had blockages in arteries to the brain, which can cause a stroke.

The researchers noted that studying the mummies didn’t allow them to determine the exact cause of death, but they pointed out that ancient Egyptian scrolls describe symptoms consistent with cardiac chest pain.

The study is published online and in the April print issue of the Journal of the American College of Cardiology: Cardiovascular Imaging.

More information

The U.S. National Heart, Lung, and Blood Institute has more about atherosclerosis.

SAN DIEGO, April 21 — In patients with advanced rectal carcinoma, adding bevacizumab (Avastin) to neoadjuvant chemotherapy and radiation led to 100% local control at four years, investigators in a small clinical study reported here.
Therapy that included bevacizumab, which binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF), led to tumor downstaging in 12 of 22 evaluable patients, and four-year disease-free survival was 88%, Rakesh Jain, Ph.D., of Harvard, reported at the American Association for Cancer Research meeting.
“I know of no other therapy in this patient population where we can even get close to 100% tumor control,” Dr. Jain said. “Although this needs to be confirmed in a randomized trial against a placebo group, these are very impressive numbers.”

The findings provide support for the concept of tumor vascular normalization. Tumor vasculature involves not only the formation of new vessels to feed the tumor but also disordered structure that impedes the therapeutic activity of cancer drugs and radiation, said Dr. Jain.

Bevacizumab destroys some of the tumor vasculature and helps normalize function in remaining blood vessels to make the tumor more susceptible to other forms of therapy, he said.

“Restoring order to blood vessels inside a tumor opens up a window of opportunity for treatment,” said Dr. Jain.

The current study involved 24 patients with late-stage (T3/T4) nonmetastatic rectal cancer. They received four cycles of neoadjuvant therapy, consisting of:

bevacizumab 5 or 10 mg/kg on day one
5-fluorouracil 225 mg/m2/24 hours weekly during cycles two through four
external beam radiation at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks

Each patient had surgery seven to nine weeks after completion of neoadjuvant therapy.

Follow-up evaluation included serial tumor biopsies, FDG-PET scans, and examination of blood and urine samples for potential biomarkers.

Five of the 24 patients had no evidence of residual primary tumor after completion of neoadjuvant therapy.

In the remaining 19 patients residual microscopic disease usually occurred as malignant glands embedded in fibrosis (ypT1 to ypT4).

Bevacizumab-induced blockade of vascular endothelial growth factor led to a decline in circulating endothelial cells by day three (P