Sharon Worcester

LAS VEGAS – Corticosteroids remain the initial treatment of choice for myositis and myositis-associated interstitial lung disease, but immunosuppressive agents, intravenous immunoglobulin, and biologics can also play a role in the treatment of one or both of these conditions, according to Dr. Chester V. Oddis.

For myositis in general, Dr. Oddis, professor of medicine and associate director of the rheumatology fellowship training program at the University of Pittsburgh, recommends an initial divided dose of 30 mg of prednisone twice daily, continued until serum creatine kinase (CK) levels fall to normal. At that time, the total daily prednisone dose can be consolidated into a single morning dose, he said at Perspectives in Rheumatic Diseases 2013.

The prednisone can then be tapered by 25% every 3-4 weeks down to a 5- to 10-mg daily maintenance dose that is continued until active disease is suppressed for 12 months. This is a general guideline that helps prevent disease flares, he noted.

Keep in mind that improvement in strength generally lags behind improvement in CK levels, he added.

Nonsteroidal immunosuppressives

Not all patients will need an additional immunosuppressive agent, but for those who do, methotrexate is a good option, Dr. Oddis said, noting that methotrexate is the drug he is most comfortable using in those cases.

The literature also supports the combined use of methotrexate and azathioprine, which when given together have been shown to be effective in treatment-resistant myositis and in those who failed either of the drugs alone.

"So that’s a regimen you might want to think about," he said.

Another immunosuppressive option is mycophenolate mofetil (MMF), which has been shown in several small studies and case series to be of benefit. In one study, 6 of 10 patients with dermatomyositis successfully tapered corticosteroids with MMF, and 10 of 12 in another study experienced improvement in cutaneous features of the disease.

The use of intravenous immunoglobulin (IVIg) as add-on therapy with MMF was effective in severe refractory patients, including four with polymyositis and three with dermatomyositis. In a retrospective review of 50 patients with juvenile dermatomyositis, MMF for 12 months was well tolerated, improved skin and muscle, and proved to be steroid-sparing, Dr. Oddis said.

Cyclosporine, tacrolimus, and cyclophosphamide are other immunosuppressive options.

While cyclophosphamide is more often used for myositis-associated interstitial lung disease (ILD), it can be of benefit for refractory skin disease, and can be useful in non-ILD myositis cases that involve severe skin disease.

The only available controlled data for IVIg alone are from a study published more than 20 years ago, but that randomized, double-blind, placebo-controlled study showed that treatment was safe, effective, and steroid sparing in 15 patients with dermatomyositis, he said.

Biologics

As for biologics, anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy and B-cell therapy have both been considered. Anti-TNF-alpha therapy makes sense because TNF-alpha and other proinflammatory cytokines are increased in muscle tissue of myositis patients; TNF-alpha is toxic to myofibers and prevents their regeneration; and TNF-alpha enhances other inflammatory cytokines in both dermatomyositis and polymyositis, but data are lacking on whether targeting TNF-alpha is worthwhile.

B cell therapy, on the other hand, is showing promise. In one open-label pilot study, rituximab was effective in seven patients with refractory dermatomyositis, and in others it was effective in anti-synthetase syndrome. Rituximab also was effective in two studies for refractory myositis and dermatomyositis rash, and it induced longstanding remission in some of the patients. In another study, however, rituximab was not effective for dermatomyositis rash.

The multicenter Rituximab in Myositis (RIM) study, the largest ever done in myositis, evaluated rituximab for the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis patients.

Although the primary and secondary endpoints of the RIM study were not achieved, 83% of refractory adult and juvenile myositis patients met the definition of improvement, there was a significant corticosteroid sparing effect between the baseline dose and the dose at study conclusion, and treatment was generally well tolerated, he said.

Other targets that are being explored include interleukin-6 and type 1 IFN genes. Findings suggest that coordinated dysregulation of type 1 IFN signaling and IL-6 production are contributors to dermatomyositis pathogenesis, he explained.

Treating myositis patients with ILD

The treatment approach to these patients is somewhat similar to those without ILD, with corticosteroids as initial treatment, Dr. Oddis said.

Cyclophosphamide and azathioprine have been used early on, and also in corticosteroid resistant cases, but with variable results. Cyclophosphamide can be given orally or by IV for 3-6 months.

MMF has been used with success in connective tissue disease–associated ILD, and based on small studies it appears to be effective in myositis-associated ILD as well.

Cyclosporine and tacrolimus have been used in both adult and pediatric patients with promising, steroid-sparing results, he said, noting that the use of anti-T-cell therapy in myositis-associated ILD makes sense, because findings from multiple studies have implicated activated CD8-positive T-cells in myositis-associated ILD.

"It’s an exciting time for therapeutic interventions in myositis, but even though we have all these therapeutic options, we have to temper our enthusiasm with what they do long term," he said.

Dr. Oddis has served on an advisory board for Questcor.

The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

LAS VEGAS – Corticosteroids remain the initial treatment of choice for myositis and myositis-associated interstitial lung disease, but immunosuppressive agents, intravenous immunoglobulin, and biologics can also play a role in the treatment of one or both of these conditions, according to Dr. Chester V. Oddis.

For myositis in general, Dr. Oddis, professor of medicine and associate director of the rheumatology fellowship training program at the University of Pittsburgh, recommends an initial divided dose of 30 mg of prednisone twice daily, continued until serum creatine kinase (CK) levels fall to normal. At that time, the total daily prednisone dose can be consolidated into a single morning dose, he said at Perspectives in Rheumatic Diseases 2013.

The prednisone can then be tapered by 25% every 3-4 weeks down to a 5- to 10-mg daily maintenance dose that is continued until active disease is suppressed for 12 months. This is a general guideline that helps prevent disease flares, he noted.

Keep in mind that improvement in strength generally lags behind improvement in CK levels, he added.

Nonsteroidal immunosuppressives

Not all patients will need an additional immunosuppressive agent, but for those who do, methotrexate is a good option, Dr. Oddis said, noting that methotrexate is the drug he is most comfortable using in those cases.

The literature also supports the combined use of methotrexate and azathioprine, which when given together have been shown to be effective in treatment-resistant myositis and in those who failed either of the drugs alone.

"So that’s a regimen you might want to think about," he said.

Another immunosuppressive option is mycophenolate mofetil (MMF), which has been shown in several small studies and case series to be of benefit. In one study, 6 of 10 patients with dermatomyositis successfully tapered corticosteroids with MMF, and 10 of 12 in another study experienced improvement in cutaneous features of the disease.

The use of intravenous immunoglobulin (IVIg) as add-on therapy with MMF was effective in severe refractory patients, including four with polymyositis and three with dermatomyositis. In a retrospective review of 50 patients with juvenile dermatomyositis, MMF for 12 months was well tolerated, improved skin and muscle, and proved to be steroid-sparing, Dr. Oddis said.

Cyclosporine, tacrolimus, and cyclophosphamide are other immunosuppressive options.

While cyclophosphamide is more often used for myositis-associated interstitial lung disease (ILD), it can be of benefit for refractory skin disease, and can be useful in non-ILD myositis cases that involve severe skin disease.

The only available controlled data for IVIg alone are from a study published more than 20 years ago, but that randomized, double-blind, placebo-controlled study showed that treatment was safe, effective, and steroid sparing in 15 patients with dermatomyositis, he said.

Biologics

As for biologics, anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy and B-cell therapy have both been considered. Anti-TNF-alpha therapy makes sense because TNF-alpha and other proinflammatory cytokines are increased in muscle tissue of myositis patients; TNF-alpha is toxic to myofibers and prevents their regeneration; and TNF-alpha enhances other inflammatory cytokines in both dermatomyositis and polymyositis, but data are lacking on whether targeting TNF-alpha is worthwhile.

B cell therapy, on the other hand, is showing promise. In one open-label pilot study, rituximab was effective in seven patients with refractory dermatomyositis, and in others it was effective in anti-synthetase syndrome. Rituximab also was effective in two studies for refractory myositis and dermatomyositis rash, and it induced longstanding remission in some of the patients. In another study, however, rituximab was not effective for dermatomyositis rash.

The multicenter Rituximab in Myositis (RIM) study, the largest ever done in myositis, evaluated rituximab for the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis patients.

Although the primary and secondary endpoints of the RIM study were not achieved, 83% of refractory adult and juvenile myositis patients met the definition of improvement, there was a significant corticosteroid sparing effect between the baseline dose and the dose at study conclusion, and treatment was generally well tolerated, he said.

Other targets that are being explored include interleukin-6 and type 1 IFN genes. Findings suggest that coordinated dysregulation of type 1 IFN signaling and IL-6 production are contributors to dermatomyositis pathogenesis, he explained.

Treating myositis patients with ILD

The treatment approach to these patients is somewhat similar to those without ILD, with corticosteroids as initial treatment, Dr. Oddis said.

Cyclophosphamide and azathioprine have been used early on, and also in corticosteroid resistant cases, but with variable results. Cyclophosphamide can be given orally or by IV for 3-6 months.

MMF has been used with success in connective tissue disease–associated ILD, and based on small studies it appears to be effective in myositis-associated ILD as well.

Cyclosporine and tacrolimus have been used in both adult and pediatric patients with promising, steroid-sparing results, he said, noting that the use of anti-T-cell therapy in myositis-associated ILD makes sense, because findings from multiple studies have implicated activated CD8-positive T-cells in myositis-associated ILD.

"It’s an exciting time for therapeutic interventions in myositis, but even though we have all these therapeutic options, we have to temper our enthusiasm with what they do long term," he said.

Dr. Oddis has served on an advisory board for Questcor.

The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

LAS VEGAS – Corticosteroids remain the initial treatment of choice for myositis and myositis-associated interstitial lung disease, but immunosuppressive agents, intravenous immunoglobulin, and biologics can also play a role in the treatment of one or both of these conditions, according to Dr. Chester V. Oddis.

For myositis in general, Dr. Oddis, professor of medicine and associate director of the rheumatology fellowship training program at the University of Pittsburgh, recommends an initial divided dose of 30 mg of prednisone twice daily, continued until serum creatine kinase (CK) levels fall to normal. At that time, the total daily prednisone dose can be consolidated into a single morning dose, he said at Perspectives in Rheumatic Diseases 2013.

The prednisone can then be tapered by 25% every 3-4 weeks down to a 5- to 10-mg daily maintenance dose that is continued until active disease is suppressed for 12 months. This is a general guideline that helps prevent disease flares, he noted.

Keep in mind that improvement in strength generally lags behind improvement in CK levels, he added.

Nonsteroidal immunosuppressives

Not all patients will need an additional immunosuppressive agent, but for those who do, methotrexate is a good option, Dr. Oddis said, noting that methotrexate is the drug he is most comfortable using in those cases.

The literature also supports the combined use of methotrexate and azathioprine, which when given together have been shown to be effective in treatment-resistant myositis and in those who failed either of the drugs alone.

"So that’s a regimen you might want to think about," he said.

Another immunosuppressive option is mycophenolate mofetil (MMF), which has been shown in several small studies and case series to be of benefit. In one study, 6 of 10 patients with dermatomyositis successfully tapered corticosteroids with MMF, and 10 of 12 in another study experienced improvement in cutaneous features of the disease.

The use of intravenous immunoglobulin (IVIg) as add-on therapy with MMF was effective in severe refractory patients, including four with polymyositis and three with dermatomyositis. In a retrospective review of 50 patients with juvenile dermatomyositis, MMF for 12 months was well tolerated, improved skin and muscle, and proved to be steroid-sparing, Dr. Oddis said.

Cyclosporine, tacrolimus, and cyclophosphamide are other immunosuppressive options.

While cyclophosphamide is more often used for myositis-associated interstitial lung disease (ILD), it can be of benefit for refractory skin disease, and can be useful in non-ILD myositis cases that involve severe skin disease.

The only available controlled data for IVIg alone are from a study published more than 20 years ago, but that randomized, double-blind, placebo-controlled study showed that treatment was safe, effective, and steroid sparing in 15 patients with dermatomyositis, he said.

Biologics

As for biologics, anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy and B-cell therapy have both been considered. Anti-TNF-alpha therapy makes sense because TNF-alpha and other proinflammatory cytokines are increased in muscle tissue of myositis patients; TNF-alpha is toxic to myofibers and prevents their regeneration; and TNF-alpha enhances other inflammatory cytokines in both dermatomyositis and polymyositis, but data are lacking on whether targeting TNF-alpha is worthwhile.

B cell therapy, on the other hand, is showing promise. In one open-label pilot study, rituximab was effective in seven patients with refractory dermatomyositis, and in others it was effective in anti-synthetase syndrome. Rituximab also was effective in two studies for refractory myositis and dermatomyositis rash, and it induced longstanding remission in some of the patients. In another study, however, rituximab was not effective for dermatomyositis rash.

The multicenter Rituximab in Myositis (RIM) study, the largest ever done in myositis, evaluated rituximab for the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis patients.

Although the primary and secondary endpoints of the RIM study were not achieved, 83% of refractory adult and juvenile myositis patients met the definition of improvement, there was a significant corticosteroid sparing effect between the baseline dose and the dose at study conclusion, and treatment was generally well tolerated, he said.

Other targets that are being explored include interleukin-6 and type 1 IFN genes. Findings suggest that coordinated dysregulation of type 1 IFN signaling and IL-6 production are contributors to dermatomyositis pathogenesis, he explained.

Treating myositis patients with ILD

The treatment approach to these patients is somewhat similar to those without ILD, with corticosteroids as initial treatment, Dr. Oddis said.

Cyclophosphamide and azathioprine have been used early on, and also in corticosteroid resistant cases, but with variable results. Cyclophosphamide can be given orally or by IV for 3-6 months.

MMF has been used with success in connective tissue disease–associated ILD, and based on small studies it appears to be effective in myositis-associated ILD as well.

Cyclosporine and tacrolimus have been used in both adult and pediatric patients with promising, steroid-sparing results, he said, noting that the use of anti-T-cell therapy in myositis-associated ILD makes sense, because findings from multiple studies have implicated activated CD8-positive T-cells in myositis-associated ILD.

"It’s an exciting time for therapeutic interventions in myositis, but even though we have all these therapeutic options, we have to temper our enthusiasm with what they do long term," he said.

Dr. Oddis has served on an advisory board for Questcor.

The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

Noninvasive prenatal testing is moving from bench to bedside at a dizzying pace, and while this rapid integration into clinical practice is raising important clinical and ethical questions, it also is creating exciting new opportunities – such as the potential for antenatal treatment of Down syndrome.

In an editorial in Prenatal Diagnosis, Dr. Lyn S. Chitty and Dr. Diana W. Bianchi note that "we are in the midst of a paradigm shift in the way that prenatal screening and diagnosis are performed around the world."

The shift is occurring at a pace unprecedented in the history of prenatal care, and the available tests, which measure cell free fetal DNA (cfDNA) in the maternal blood and currently are used to detect trisomy 21, 18, and 13, as well as sex chromosome aneuploidies, provide a "readily accessible and generally safer option for prenatal testing than can be offered from 10 until 40 weeks of gestation," wrote Dr. Chitty of Great Ormond Street and University College London hospitals and Dr. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology of Tufts University, Boston (Prenatal Diagnosis 2013;33:511-13).

October will mark 2 years since the commercial debut of the first noninvasive prenatal test (NIPT) for aneuploidy in the United States – MaterniT21 (Sequenom, San Diego), a laboratory-developed test that detects increases in the amount of chromosomal 21, 18, and 13 material in maternal blood.

"This was followed by multiple publications, several professional society recommendations, and a logarithmic uptake in the number of tests ordered. The reason why noninvasive prenatal testing (NIPT) represents a paradigm shift is that it changes the algorithm of screening followed by invasive testing that has been in practice worldwide for the last 30 years," they said.

Rather than undergoing combined ultrasound screening and serum screening (the "combined test"), followed by more invasive chorionic villus sampling or amniocentesis to rule out aneuploidy for a positive combined test, more women now have the option of a simple blood test. The negative predictive value of NIPT is high, so fewer women are subjected to the invasive procedures, which increase the risk for miscarriage and other adverse outcomes.

The NIPT options are expanding quickly; since MaterniT21 became available, three other companies launched similar tests: Harmony (Ariosa Diagnostics, San Jose, Calif.), verifi (Verinata Health, Redwood City, Calif.), and – most recently – Panorama (Natera, San Carlos, Calif.).

None are approved by the Food and Drug Administration, but all are performed in Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories as laboratory-developed tests.

The tests are typically administered any time after 10 weeks’. gestation because that is generally when an adequate amount of fetal DNA is present in the maternal serum, Dr. Bianchi, also a geneticist and executive director of the Mother Infant Research Institute at Tufts, explained during an NIPT symposium at the annual meeting of the American College of Obstetricians and Gynecologists in New Orleans.

Some of the tests use massively parallel sequencing, which can be used to "look at everything," including sex chromosome aneuploidies, although most laboratories use software that masks all but the results of interest. Other tests use more targeted sequencing to focus on the chromosomes of interest.

Studies suggest that NIPT is at least 99% accurate for detecting trisomy 21 and trisomy 18, and between 79% and 92% accurate for trisomy 13, with a false positive rate of less than 1% for each, according to a 2012 fact sheet developed by the National Coalition for Health Professional Education in Genetics and the National Society of Genetic Counselors.

Serum screening, by comparison, has an 80%-95% detection rate for trisomy 21 and trisomy 18, with false-positive rates of 3% -5%. The rates for trisomy 13 are uncertain, according to the fact sheet.

Most studies to date have included mainly women with singleton pregnancies at high risk of trisomy 21 due to advanced maternal age, an abnormal serum screen, a personal or family history of aneuploidy, or an abnormal ultrasound, and as a result most current recommendations support screening only in this population.

A December 2012 opinion from the American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee, for example, notes that NIPT "offers tremendous potential as a screening tool for fetal aneuploidy," but that it should be offered, after pretest counseling, only to women with high-risk singleton pregnancies. Cell-free fetal DNA testing has not been sufficiently evaluated in those at low risk or with multiple gestations, the committee said (Obstet. Gynecol. 2012;120:1532-4).

In January 2013, the National Society of Genetic Counselors released a similar position statement (J. Genet. Counsel. 2013 [doi: 10.1007/s10897-012-9564-0]).

New evidence, however, suggests that NIPT also is feasible in low-risk pregnancies.

For example, two studies in the July issue of Ultrasound in Obstetrics and Gynecology indicate that both routine and contingent implementation of NIPT for first trimester trisomy screening are feasible.

In one of the studies, Dr. M.M. Gil of King’s College Hospital, London, and his colleagues demonstrated that in 1,005 singleton pregnancies, routine NIPT for trisomies 21, 18, and 13 at 10 weeks’ gestation had a lower false positive rate than did the combined test performed at 12 weeks (0.1% vs. 3.4%), although abnormal results required confirmation using invasive testing.

"This study has shown that routine screening for trisomies by cfDNA testing at 10 weeks is feasible, allowing diagnosis of aneuploidies and the option of pregnancy termination within the first trimester," the investigators concluded (Ultrasound Obstet. Gynecol. 2013;42:34-40).

In the second study, which involved women with singleton pregnancies who underwent screening between March 2006 and May 2012, Dr. K.H. Nicolaides, also of King’s College Hospital, London, and his colleagues demonstrated that effective first trimester screening for Down syndrome can be achieved – with a 98% detection rate and an invasive testing rate below 0.5% – using contingent screening (Ultrasound Obstet. Gynecol. 2013;42:41-50).

"The results demonstrate that in contingent screening, a detection rate of 98% in fetuses with trisomy 21, at an overall invasive testing rate less than 0.5%, could be achieved by offering the cfDNA test to about 36%, 21%, and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum placental growth factor and alpha-fetoprotein, and using the combined test with the addition of placental growth factor, alpha-fetoprotein, and ductus venosus pulsatility index for veins, respectively," they said. "Screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing," they concluded.

Data also suggest that NIPT can be used successfully in twin pregnancies, albeit with the caveat that deeper sequencing may be necessary in these pregnancies, Dr. Bianchi noted.

These findings suggest that even wider implementation of NIPT is likely, she said, adding that there are major concerns about such implementation – not the least of which is fitting adequate pre- and posttest counseling into busy practices.

"It is not straightforward – there are multiple issues that need to be discussed," she said.

Questions also remain about the performance of the tests in normal- vs. high-risk pregnancies, she said.

Recently, a Blue Cross Blue Shield Technology Evaluation Center report concluded that NIPT meets the company’s criteria for both normal- and high-risk pregnancies, Dr. Bianchi noted.

"We’ll be hearing more about this in the coming year. Everyone is looking for more data," she said.

The results thus far – with more than 100,000 tests performed – undoubtedly have been encouraging. Since the integration of these tests into clinical practice began, many medical centers already are witnessing significant declines in the number of invasive procedures being performed for aneuploidy, Dr. Bianchi said, noting that such procedures have decreased by 34% in the first year at Tufts Medical Center, where NIPT is routinely offered as an option to high-risk women, and as an alternative to invasive procedures in average-risk women who test positive on traditional screening. Invasive procedures are strongly encouraged in those with aneuploidy detected on NIPT.

As a result of these outcomes, every aspect of the current standard of care is being questioned, Dr. Chitty and Dr. Bianchi wrote in their editorial. "For example, do we still need to measure maternal serum biomarkers, and what is the place of nuchal translucency measurement?" they asked.

The use of NIPT and the rapid advances taking place in the field, also raise important ethical questions.

Even before Sequenom introduced the MaterniT21 test to the market, the ethical implications of NIPT were being weighed. In a 2009 paper, Dr. Antina de Jong of Maastricht (the Netherlands) University and colleagues noted that although the introduction of NIPT would have some "ethically favorable consequences," such as the absence of iatrogenic miscarriage resulting from a test, earlier reassurance of a healthy fetus, a longer period for decision-making and the possibility of an early abortion, "which may be physically and psychologically less burdening and ethically less problematic because of presumed lower mortal fetal status," the possibility that NIPT would eventually include testing for a broader scope of abnormalities complicates the ethical issues.

Notwithstanding the potential benefits with respect to earlier decision making, one concern is the "normalization and trivialization of early selective abortion," they said, adding that "more generalized use of noninvasive testing could facilitate selective terminations of pregnancy in a range of conditions hitherto not diagnosed prenatally and where the arguments for and against termination may not have received sufficient scrutiny."

Also, testing for a broader scope of abnormalities has important implications regarding informed consent, they said (Eur. J. Hum. Genet. 2009 [doi:10.1038/ejhg.2009.203]).

"Informed consent will become far more challenging – if attainable at all. Moreover, should [NIPT] testing become available for a wider range of disorders including late-onset disease, this may lead to the same ethical difficulties as with regard to wide range testing of newborns, in which the dominant view is that the child’s right not to know should be respected," the authors wrote. "It is difficult to see how this respect can be upheld when, after broadening prenatal testing, children will be born with a positive test result for a serious late-onset disease."

Another facet of NIPT that is rife with ethical implications is noninvasive fetal whole genome sequencing, which was shown in a recent proof-of-concept study to be possible using only parental DNA samples and plasma. That study is revisited from a clinical standpoint in an article published in the same issue of Prenatal Diagnosis along with the editorial by Dr. Chitty and Dr. Bianchi and a number of other related articles and studies. (To give readers an overview of "this rapidly changing field," both the June and July issues of the journal are dedicated to NIPT, said Dr. Bianchi, the journal’s editor-in-chief).

"If noninvasive determination of the entire fetal genomic sequence becomes clinically available, there will be a significant increase in the number of ethical issues that arise," Dr. Chitty and Dr. Bianchi noted.

"You can imagine, it’s hard enough now to counsel about serum screening results for Down syndrome. Imagine if you had to deal with the entire human genome. But it’s coming – it’s coming, so we have to figure out ... what’s to be communicated to expectant couples," Dr. Bianchi said, adding that she hopes much of the groundwork for dealing with these issues will be laid in adult and pediatric populations before they have to be considered for fetuses.

While these advances bring with them ethical concerns, they also open doors to exciting opportunities, she said.

"The challenge now is to translate this technology into practice that is accessible to all pregnant women and in an ethical way that preserves informed parental choice, while not increasing overall costs to the health care system," Dr. Chitty and Dr. Bianchi said.

Dr. Bianchi is chair of the clinical advisory board for Verinata Health Inc., and has received honorarium and research funding from the company. She is editor-in-chief of the Journal of Prenatal Diagnosis, and has received honorarium from the company. Dr. Nicolaides’ and Dr. Gil’s studies were funded by grants from the Fetal Medicine Foundation. Dr. de Jong’s research was supported by the Centre for Society and Genomics in the Netherlands, funded by the Netherlands Genomics Initiative, and the Netherlands Organisation for Scientific Research Zonmw Prevention Fund.

Noninvasive prenatal testing is moving from bench to bedside at a dizzying pace, and while this rapid integration into clinical practice is raising important clinical and ethical questions, it also is creating exciting new opportunities – such as the potential for antenatal treatment of Down syndrome.

In an editorial in Prenatal Diagnosis, Dr. Lyn S. Chitty and Dr. Diana W. Bianchi note that "we are in the midst of a paradigm shift in the way that prenatal screening and diagnosis are performed around the world."

The shift is occurring at a pace unprecedented in the history of prenatal care, and the available tests, which measure cell free fetal DNA (cfDNA) in the maternal blood and currently are used to detect trisomy 21, 18, and 13, as well as sex chromosome aneuploidies, provide a "readily accessible and generally safer option for prenatal testing than can be offered from 10 until 40 weeks of gestation," wrote Dr. Chitty of Great Ormond Street and University College London hospitals and Dr. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology of Tufts University, Boston (Prenatal Diagnosis 2013;33:511-13).

October will mark 2 years since the commercial debut of the first noninvasive prenatal test (NIPT) for aneuploidy in the United States – MaterniT21 (Sequenom, San Diego), a laboratory-developed test that detects increases in the amount of chromosomal 21, 18, and 13 material in maternal blood.

"This was followed by multiple publications, several professional society recommendations, and a logarithmic uptake in the number of tests ordered. The reason why noninvasive prenatal testing (NIPT) represents a paradigm shift is that it changes the algorithm of screening followed by invasive testing that has been in practice worldwide for the last 30 years," they said.

Rather than undergoing combined ultrasound screening and serum screening (the "combined test"), followed by more invasive chorionic villus sampling or amniocentesis to rule out aneuploidy for a positive combined test, more women now have the option of a simple blood test. The negative predictive value of NIPT is high, so fewer women are subjected to the invasive procedures, which increase the risk for miscarriage and other adverse outcomes.

The NIPT options are expanding quickly; since MaterniT21 became available, three other companies launched similar tests: Harmony (Ariosa Diagnostics, San Jose, Calif.), verifi (Verinata Health, Redwood City, Calif.), and – most recently – Panorama (Natera, San Carlos, Calif.).

None are approved by the Food and Drug Administration, but all are performed in Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories as laboratory-developed tests.

The tests are typically administered any time after 10 weeks’. gestation because that is generally when an adequate amount of fetal DNA is present in the maternal serum, Dr. Bianchi, also a geneticist and executive director of the Mother Infant Research Institute at Tufts, explained during an NIPT symposium at the annual meeting of the American College of Obstetricians and Gynecologists in New Orleans.

Some of the tests use massively parallel sequencing, which can be used to "look at everything," including sex chromosome aneuploidies, although most laboratories use software that masks all but the results of interest. Other tests use more targeted sequencing to focus on the chromosomes of interest.

Studies suggest that NIPT is at least 99% accurate for detecting trisomy 21 and trisomy 18, and between 79% and 92% accurate for trisomy 13, with a false positive rate of less than 1% for each, according to a 2012 fact sheet developed by the National Coalition for Health Professional Education in Genetics and the National Society of Genetic Counselors.

Serum screening, by comparison, has an 80%-95% detection rate for trisomy 21 and trisomy 18, with false-positive rates of 3% -5%. The rates for trisomy 13 are uncertain, according to the fact sheet.

Most studies to date have included mainly women with singleton pregnancies at high risk of trisomy 21 due to advanced maternal age, an abnormal serum screen, a personal or family history of aneuploidy, or an abnormal ultrasound, and as a result most current recommendations support screening only in this population.

A December 2012 opinion from the American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee, for example, notes that NIPT "offers tremendous potential as a screening tool for fetal aneuploidy," but that it should be offered, after pretest counseling, only to women with high-risk singleton pregnancies. Cell-free fetal DNA testing has not been sufficiently evaluated in those at low risk or with multiple gestations, the committee said (Obstet. Gynecol. 2012;120:1532-4).

In January 2013, the National Society of Genetic Counselors released a similar position statement (J. Genet. Counsel. 2013 [doi: 10.1007/s10897-012-9564-0]).

New evidence, however, suggests that NIPT also is feasible in low-risk pregnancies.

For example, two studies in the July issue of Ultrasound in Obstetrics and Gynecology indicate that both routine and contingent implementation of NIPT for first trimester trisomy screening are feasible.

In one of the studies, Dr. M.M. Gil of King’s College Hospital, London, and his colleagues demonstrated that in 1,005 singleton pregnancies, routine NIPT for trisomies 21, 18, and 13 at 10 weeks’ gestation had a lower false positive rate than did the combined test performed at 12 weeks (0.1% vs. 3.4%), although abnormal results required confirmation using invasive testing.

"This study has shown that routine screening for trisomies by cfDNA testing at 10 weeks is feasible, allowing diagnosis of aneuploidies and the option of pregnancy termination within the first trimester," the investigators concluded (Ultrasound Obstet. Gynecol. 2013;42:34-40).

In the second study, which involved women with singleton pregnancies who underwent screening between March 2006 and May 2012, Dr. K.H. Nicolaides, also of King’s College Hospital, London, and his colleagues demonstrated that effective first trimester screening for Down syndrome can be achieved – with a 98% detection rate and an invasive testing rate below 0.5% – using contingent screening (Ultrasound Obstet. Gynecol. 2013;42:41-50).

"The results demonstrate that in contingent screening, a detection rate of 98% in fetuses with trisomy 21, at an overall invasive testing rate less than 0.5%, could be achieved by offering the cfDNA test to about 36%, 21%, and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum placental growth factor and alpha-fetoprotein, and using the combined test with the addition of placental growth factor, alpha-fetoprotein, and ductus venosus pulsatility index for veins, respectively," they said. "Screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing," they concluded.

Data also suggest that NIPT can be used successfully in twin pregnancies, albeit with the caveat that deeper sequencing may be necessary in these pregnancies, Dr. Bianchi noted.

These findings suggest that even wider implementation of NIPT is likely, she said, adding that there are major concerns about such implementation – not the least of which is fitting adequate pre- and posttest counseling into busy practices.

"It is not straightforward – there are multiple issues that need to be discussed," she said.

Questions also remain about the performance of the tests in normal- vs. high-risk pregnancies, she said.

Recently, a Blue Cross Blue Shield Technology Evaluation Center report concluded that NIPT meets the company’s criteria for both normal- and high-risk pregnancies, Dr. Bianchi noted.

"We’ll be hearing more about this in the coming year. Everyone is looking for more data," she said.

The results thus far – with more than 100,000 tests performed – undoubtedly have been encouraging. Since the integration of these tests into clinical practice began, many medical centers already are witnessing significant declines in the number of invasive procedures being performed for aneuploidy, Dr. Bianchi said, noting that such procedures have decreased by 34% in the first year at Tufts Medical Center, where NIPT is routinely offered as an option to high-risk women, and as an alternative to invasive procedures in average-risk women who test positive on traditional screening. Invasive procedures are strongly encouraged in those with aneuploidy detected on NIPT.

As a result of these outcomes, every aspect of the current standard of care is being questioned, Dr. Chitty and Dr. Bianchi wrote in their editorial. "For example, do we still need to measure maternal serum biomarkers, and what is the place of nuchal translucency measurement?" they asked.

The use of NIPT and the rapid advances taking place in the field, also raise important ethical questions.

Even before Sequenom introduced the MaterniT21 test to the market, the ethical implications of NIPT were being weighed. In a 2009 paper, Dr. Antina de Jong of Maastricht (the Netherlands) University and colleagues noted that although the introduction of NIPT would have some "ethically favorable consequences," such as the absence of iatrogenic miscarriage resulting from a test, earlier reassurance of a healthy fetus, a longer period for decision-making and the possibility of an early abortion, "which may be physically and psychologically less burdening and ethically less problematic because of presumed lower mortal fetal status," the possibility that NIPT would eventually include testing for a broader scope of abnormalities complicates the ethical issues.

Notwithstanding the potential benefits with respect to earlier decision making, one concern is the "normalization and trivialization of early selective abortion," they said, adding that "more generalized use of noninvasive testing could facilitate selective terminations of pregnancy in a range of conditions hitherto not diagnosed prenatally and where the arguments for and against termination may not have received sufficient scrutiny."

Also, testing for a broader scope of abnormalities has important implications regarding informed consent, they said (Eur. J. Hum. Genet. 2009 [doi:10.1038/ejhg.2009.203]).

"Informed consent will become far more challenging – if attainable at all. Moreover, should [NIPT] testing become available for a wider range of disorders including late-onset disease, this may lead to the same ethical difficulties as with regard to wide range testing of newborns, in which the dominant view is that the child’s right not to know should be respected," the authors wrote. "It is difficult to see how this respect can be upheld when, after broadening prenatal testing, children will be born with a positive test result for a serious late-onset disease."

Another facet of NIPT that is rife with ethical implications is noninvasive fetal whole genome sequencing, which was shown in a recent proof-of-concept study to be possible using only parental DNA samples and plasma. That study is revisited from a clinical standpoint in an article published in the same issue of Prenatal Diagnosis along with the editorial by Dr. Chitty and Dr. Bianchi and a number of other related articles and studies. (To give readers an overview of "this rapidly changing field," both the June and July issues of the journal are dedicated to NIPT, said Dr. Bianchi, the journal’s editor-in-chief).

"If noninvasive determination of the entire fetal genomic sequence becomes clinically available, there will be a significant increase in the number of ethical issues that arise," Dr. Chitty and Dr. Bianchi noted.

"You can imagine, it’s hard enough now to counsel about serum screening results for Down syndrome. Imagine if you had to deal with the entire human genome. But it’s coming – it’s coming, so we have to figure out ... what’s to be communicated to expectant couples," Dr. Bianchi said, adding that she hopes much of the groundwork for dealing with these issues will be laid in adult and pediatric populations before they have to be considered for fetuses.

While these advances bring with them ethical concerns, they also open doors to exciting opportunities, she said.

"The challenge now is to translate this technology into practice that is accessible to all pregnant women and in an ethical way that preserves informed parental choice, while not increasing overall costs to the health care system," Dr. Chitty and Dr. Bianchi said.

Dr. Bianchi is chair of the clinical advisory board for Verinata Health Inc., and has received honorarium and research funding from the company. She is editor-in-chief of the Journal of Prenatal Diagnosis, and has received honorarium from the company. Dr. Nicolaides’ and Dr. Gil’s studies were funded by grants from the Fetal Medicine Foundation. Dr. de Jong’s research was supported by the Centre for Society and Genomics in the Netherlands, funded by the Netherlands Genomics Initiative, and the Netherlands Organisation for Scientific Research Zonmw Prevention Fund.

Noninvasive prenatal testing is moving from bench to bedside at a dizzying pace, and while this rapid integration into clinical practice is raising important clinical and ethical questions, it also is creating exciting new opportunities – such as the potential for antenatal treatment of Down syndrome.

In an editorial in Prenatal Diagnosis, Dr. Lyn S. Chitty and Dr. Diana W. Bianchi note that "we are in the midst of a paradigm shift in the way that prenatal screening and diagnosis are performed around the world."

The shift is occurring at a pace unprecedented in the history of prenatal care, and the available tests, which measure cell free fetal DNA (cfDNA) in the maternal blood and currently are used to detect trisomy 21, 18, and 13, as well as sex chromosome aneuploidies, provide a "readily accessible and generally safer option for prenatal testing than can be offered from 10 until 40 weeks of gestation," wrote Dr. Chitty of Great Ormond Street and University College London hospitals and Dr. Bianchi, the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology of Tufts University, Boston (Prenatal Diagnosis 2013;33:511-13).

October will mark 2 years since the commercial debut of the first noninvasive prenatal test (NIPT) for aneuploidy in the United States – MaterniT21 (Sequenom, San Diego), a laboratory-developed test that detects increases in the amount of chromosomal 21, 18, and 13 material in maternal blood.

"This was followed by multiple publications, several professional society recommendations, and a logarithmic uptake in the number of tests ordered. The reason why noninvasive prenatal testing (NIPT) represents a paradigm shift is that it changes the algorithm of screening followed by invasive testing that has been in practice worldwide for the last 30 years," they said.

Rather than undergoing combined ultrasound screening and serum screening (the "combined test"), followed by more invasive chorionic villus sampling or amniocentesis to rule out aneuploidy for a positive combined test, more women now have the option of a simple blood test. The negative predictive value of NIPT is high, so fewer women are subjected to the invasive procedures, which increase the risk for miscarriage and other adverse outcomes.

The NIPT options are expanding quickly; since MaterniT21 became available, three other companies launched similar tests: Harmony (Ariosa Diagnostics, San Jose, Calif.), verifi (Verinata Health, Redwood City, Calif.), and – most recently – Panorama (Natera, San Carlos, Calif.).

None are approved by the Food and Drug Administration, but all are performed in Clinical Laboratory Improvement Amendments (CLIA)–approved laboratories as laboratory-developed tests.

The tests are typically administered any time after 10 weeks’. gestation because that is generally when an adequate amount of fetal DNA is present in the maternal serum, Dr. Bianchi, also a geneticist and executive director of the Mother Infant Research Institute at Tufts, explained during an NIPT symposium at the annual meeting of the American College of Obstetricians and Gynecologists in New Orleans.

Some of the tests use massively parallel sequencing, which can be used to "look at everything," including sex chromosome aneuploidies, although most laboratories use software that masks all but the results of interest. Other tests use more targeted sequencing to focus on the chromosomes of interest.

Studies suggest that NIPT is at least 99% accurate for detecting trisomy 21 and trisomy 18, and between 79% and 92% accurate for trisomy 13, with a false positive rate of less than 1% for each, according to a 2012 fact sheet developed by the National Coalition for Health Professional Education in Genetics and the National Society of Genetic Counselors.

Serum screening, by comparison, has an 80%-95% detection rate for trisomy 21 and trisomy 18, with false-positive rates of 3% -5%. The rates for trisomy 13 are uncertain, according to the fact sheet.

Most studies to date have included mainly women with singleton pregnancies at high risk of trisomy 21 due to advanced maternal age, an abnormal serum screen, a personal or family history of aneuploidy, or an abnormal ultrasound, and as a result most current recommendations support screening only in this population.

A December 2012 opinion from the American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee, for example, notes that NIPT "offers tremendous potential as a screening tool for fetal aneuploidy," but that it should be offered, after pretest counseling, only to women with high-risk singleton pregnancies. Cell-free fetal DNA testing has not been sufficiently evaluated in those at low risk or with multiple gestations, the committee said (Obstet. Gynecol. 2012;120:1532-4).

In January 2013, the National Society of Genetic Counselors released a similar position statement (J. Genet. Counsel. 2013 [doi: 10.1007/s10897-012-9564-0]).

New evidence, however, suggests that NIPT also is feasible in low-risk pregnancies.

For example, two studies in the July issue of Ultrasound in Obstetrics and Gynecology indicate that both routine and contingent implementation of NIPT for first trimester trisomy screening are feasible.

In one of the studies, Dr. M.M. Gil of King’s College Hospital, London, and his colleagues demonstrated that in 1,005 singleton pregnancies, routine NIPT for trisomies 21, 18, and 13 at 10 weeks’ gestation had a lower false positive rate than did the combined test performed at 12 weeks (0.1% vs. 3.4%), although abnormal results required confirmation using invasive testing.

"This study has shown that routine screening for trisomies by cfDNA testing at 10 weeks is feasible, allowing diagnosis of aneuploidies and the option of pregnancy termination within the first trimester," the investigators concluded (Ultrasound Obstet. Gynecol. 2013;42:34-40).

In the second study, which involved women with singleton pregnancies who underwent screening between March 2006 and May 2012, Dr. K.H. Nicolaides, also of King’s College Hospital, London, and his colleagues demonstrated that effective first trimester screening for Down syndrome can be achieved – with a 98% detection rate and an invasive testing rate below 0.5% – using contingent screening (Ultrasound Obstet. Gynecol. 2013;42:41-50).

"The results demonstrate that in contingent screening, a detection rate of 98% in fetuses with trisomy 21, at an overall invasive testing rate less than 0.5%, could be achieved by offering the cfDNA test to about 36%, 21%, and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum placental growth factor and alpha-fetoprotein, and using the combined test with the addition of placental growth factor, alpha-fetoprotein, and ductus venosus pulsatility index for veins, respectively," they said. "Screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing," they concluded.

Data also suggest that NIPT can be used successfully in twin pregnancies, albeit with the caveat that deeper sequencing may be necessary in these pregnancies, Dr. Bianchi noted.

These findings suggest that even wider implementation of NIPT is likely, she said, adding that there are major concerns about such implementation – not the least of which is fitting adequate pre- and posttest counseling into busy practices.

"It is not straightforward – there are multiple issues that need to be discussed," she said.

Questions also remain about the performance of the tests in normal- vs. high-risk pregnancies, she said.

Recently, a Blue Cross Blue Shield Technology Evaluation Center report concluded that NIPT meets the company’s criteria for both normal- and high-risk pregnancies, Dr. Bianchi noted.

"We’ll be hearing more about this in the coming year. Everyone is looking for more data," she said.

The results thus far – with more than 100,000 tests performed – undoubtedly have been encouraging. Since the integration of these tests into clinical practice began, many medical centers already are witnessing significant declines in the number of invasive procedures being performed for aneuploidy, Dr. Bianchi said, noting that such procedures have decreased by 34% in the first year at Tufts Medical Center, where NIPT is routinely offered as an option to high-risk women, and as an alternative to invasive procedures in average-risk women who test positive on traditional screening. Invasive procedures are strongly encouraged in those with aneuploidy detected on NIPT.

As a result of these outcomes, every aspect of the current standard of care is being questioned, Dr. Chitty and Dr. Bianchi wrote in their editorial. "For example, do we still need to measure maternal serum biomarkers, and what is the place of nuchal translucency measurement?" they asked.

The use of NIPT and the rapid advances taking place in the field, also raise important ethical questions.

Even before Sequenom introduced the MaterniT21 test to the market, the ethical implications of NIPT were being weighed. In a 2009 paper, Dr. Antina de Jong of Maastricht (the Netherlands) University and colleagues noted that although the introduction of NIPT would have some "ethically favorable consequences," such as the absence of iatrogenic miscarriage resulting from a test, earlier reassurance of a healthy fetus, a longer period for decision-making and the possibility of an early abortion, "which may be physically and psychologically less burdening and ethically less problematic because of presumed lower mortal fetal status," the possibility that NIPT would eventually include testing for a broader scope of abnormalities complicates the ethical issues.

Notwithstanding the potential benefits with respect to earlier decision making, one concern is the "normalization and trivialization of early selective abortion," they said, adding that "more generalized use of noninvasive testing could facilitate selective terminations of pregnancy in a range of conditions hitherto not diagnosed prenatally and where the arguments for and against termination may not have received sufficient scrutiny."

Also, testing for a broader scope of abnormalities has important implications regarding informed consent, they said (Eur. J. Hum. Genet. 2009 [doi:10.1038/ejhg.2009.203]).

"Informed consent will become far more challenging – if attainable at all. Moreover, should [NIPT] testing become available for a wider range of disorders including late-onset disease, this may lead to the same ethical difficulties as with regard to wide range testing of newborns, in which the dominant view is that the child’s right not to know should be respected," the authors wrote. "It is difficult to see how this respect can be upheld when, after broadening prenatal testing, children will be born with a positive test result for a serious late-onset disease."

Another facet of NIPT that is rife with ethical implications is noninvasive fetal whole genome sequencing, which was shown in a recent proof-of-concept study to be possible using only parental DNA samples and plasma. That study is revisited from a clinical standpoint in an article published in the same issue of Prenatal Diagnosis along with the editorial by Dr. Chitty and Dr. Bianchi and a number of other related articles and studies. (To give readers an overview of "this rapidly changing field," both the June and July issues of the journal are dedicated to NIPT, said Dr. Bianchi, the journal’s editor-in-chief).

"If noninvasive determination of the entire fetal genomic sequence becomes clinically available, there will be a significant increase in the number of ethical issues that arise," Dr. Chitty and Dr. Bianchi noted.

"You can imagine, it’s hard enough now to counsel about serum screening results for Down syndrome. Imagine if you had to deal with the entire human genome. But it’s coming – it’s coming, so we have to figure out ... what’s to be communicated to expectant couples," Dr. Bianchi said, adding that she hopes much of the groundwork for dealing with these issues will be laid in adult and pediatric populations before they have to be considered for fetuses.

While these advances bring with them ethical concerns, they also open doors to exciting opportunities, she said.

"The challenge now is to translate this technology into practice that is accessible to all pregnant women and in an ethical way that preserves informed parental choice, while not increasing overall costs to the health care system," Dr. Chitty and Dr. Bianchi said.

Dr. Bianchi is chair of the clinical advisory board for Verinata Health Inc., and has received honorarium and research funding from the company. She is editor-in-chief of the Journal of Prenatal Diagnosis, and has received honorarium from the company. Dr. Nicolaides’ and Dr. Gil’s studies were funded by grants from the Fetal Medicine Foundation. Dr. de Jong’s research was supported by the Centre for Society and Genomics in the Netherlands, funded by the Netherlands Genomics Initiative, and the Netherlands Organisation for Scientific Research Zonmw Prevention Fund.

Varenicline successfully promoted durable smoking cessation without exacerbating depression or anxiety in a randomized, phase IV, industry-funded study of patients with stably treated major depressive disorder.

Smoking cessation, defined as carbon monoxide–confirmed continuous abstinence, was higher at weeks 9-12 among 256 subjects in the double-blind study who were randomized to receive varenicline, compared with 269 who received placebo (35.9% vs. 15.6%; odds ratio, 3.35), Dr. Robert M. Anthenelli of the University of California, San Diego, and his colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The differences between the groups were also significant for weeks 9-24 (20.3% vs. 10.4%; OR, 2.36) and for weeks 9-52 (25% vs. 12.3%; OR, 2.36), the investigators said (Ann. Intern. Med. 2013;159:390-400).*

© milosluz/istockphoto.com

No clinically relevant differences were seen between the groups in suicidal ideation or behavior as captured by the Columbia Suicide Severity Rating Scale. Furthermore, no overall worsening of depression or anxiety occurred in either group. In fact, trajectories of mood and anxiety rating trended slightly toward improvement in both groups, they said.

Participants in the multicenter study were adults aged 19-73 years who had no recent cardiovascular events, who smoked at least 10 cigarettes daily, and who had current or past stably treated unipolar major depressive disorder without psychotic features. They were recruited from 38 centers in 8 countries between March 2010 and June 2012. Randomization was stratified by antidepressant use at baseline (any vs. none) and by baseline depression score (Montgomery-Asberg Depression Rating Scale score 11 or less vs. greater than 11). Patients received either placebo or varenicline titrated to a dose of 1 mg twice daily for 12 weeks, with a 40-week nontreatment follow-up phase.

Treatment was relatively safe; although 72.3% and 66.9% of the treatment and placebo groups, respectively, experienced treatment-emergent adverse events, most were mild or moderate. The most frequent adverse events in the treatment vs. placebo groups were nausea (27.0% vs. 10.4%, respectively), headaches (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), irritability (10.9% vs. 8.2%), and insomnia (10.9% vs. 4.8%). Two patients in the treatment group died during the nontreatment phase, but neither death was considered to be related to treatment, the investigators said.

The findings suggest that varenicline, like other FDA-approved smoking cessation aids effective in non–psychiatrically ill smokers, are similarly effective in smokers with a history of depression – without increasing depressive symptoms; in the case of varenicline, as demonstrated in this study, this also applies to patients with depression who are using antidepressant medications.

"Varenicline is a partial agonist of brain alpha4beta 2 nicotinic acetylcholine receptors and is believed to alleviate nicotine withdrawal while simultaneously blocking its rewarding effects. Because depressed smokers are prone to more severe nicotine withdrawal than nonpsychiatric smokers, mitigating withdrawal symptoms may be important in this population," the investigators said. Depressed smokers who lapse into smoking while attempting to regulate mood may find cigarettes less reinforcing while taking varenicline, thus facilitating prolonged abstinence, they noted.

Although the findings may not extrapolate to untreated or actively depressed smokers and those with other psychiatric conditions, since only stably treated patients without psychotic features and other disorders frequently associated with major depressive disorder (such as bipolar disorder and current substance use disorders) were included, the findings nevertheless suggest an important role for varenicline in smokers with a history of stably treated depression.

"With 350 million individuals having the disease worldwide and because a large proportion of smokers that seeks treatment has a lifetime history of MDD, these results have the potential to reduce morbidity and mortality in many smokers," they concluded.

The researchers noted several study limitations, including their selection of "a population of smokers who were stably treated for or remitted from depression." Thus, they wrote, "our findings may not extrapolate to untreated or actively depressed smokers, whom many consider to be poor candidates for smoking cessation until their condition stabilizes." They also excluded individuals with "with psychotic features, bipolar disorder, current substance use disorders, and other conditions frequently associated with major depressive disorder; patients receiving medication for mania or psychosis were also excluded. Missing data resulting from attrition in both treatment groups may have affected the outcomes, the authors further noted.

This study was funded by Pfizer. Individual authors reported receiving support from the Department of Veterans Affairs; the National Institute on Alcohol Abuse and Alcoholism; the University of California, San Francisco; the Smoking Cessation Leadership Center; and/or the Colorado Department of Public Health and Environment. Detailed disclosures are available at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0777.

*CORRECTION, 10/10/13: An earlier version of this article misstated the citation for the journal article referenced in the story.

Varenicline successfully promoted durable smoking cessation without exacerbating depression or anxiety in a randomized, phase IV, industry-funded study of patients with stably treated major depressive disorder.

Smoking cessation, defined as carbon monoxide–confirmed continuous abstinence, was higher at weeks 9-12 among 256 subjects in the double-blind study who were randomized to receive varenicline, compared with 269 who received placebo (35.9% vs. 15.6%; odds ratio, 3.35), Dr. Robert M. Anthenelli of the University of California, San Diego, and his colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The differences between the groups were also significant for weeks 9-24 (20.3% vs. 10.4%; OR, 2.36) and for weeks 9-52 (25% vs. 12.3%; OR, 2.36), the investigators said (Ann. Intern. Med. 2013;159:390-400).*

© milosluz/istockphoto.com

No clinically relevant differences were seen between the groups in suicidal ideation or behavior as captured by the Columbia Suicide Severity Rating Scale. Furthermore, no overall worsening of depression or anxiety occurred in either group. In fact, trajectories of mood and anxiety rating trended slightly toward improvement in both groups, they said.

Participants in the multicenter study were adults aged 19-73 years who had no recent cardiovascular events, who smoked at least 10 cigarettes daily, and who had current or past stably treated unipolar major depressive disorder without psychotic features. They were recruited from 38 centers in 8 countries between March 2010 and June 2012. Randomization was stratified by antidepressant use at baseline (any vs. none) and by baseline depression score (Montgomery-Asberg Depression Rating Scale score 11 or less vs. greater than 11). Patients received either placebo or varenicline titrated to a dose of 1 mg twice daily for 12 weeks, with a 40-week nontreatment follow-up phase.

Treatment was relatively safe; although 72.3% and 66.9% of the treatment and placebo groups, respectively, experienced treatment-emergent adverse events, most were mild or moderate. The most frequent adverse events in the treatment vs. placebo groups were nausea (27.0% vs. 10.4%, respectively), headaches (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), irritability (10.9% vs. 8.2%), and insomnia (10.9% vs. 4.8%). Two patients in the treatment group died during the nontreatment phase, but neither death was considered to be related to treatment, the investigators said.

The findings suggest that varenicline, like other FDA-approved smoking cessation aids effective in non–psychiatrically ill smokers, are similarly effective in smokers with a history of depression – without increasing depressive symptoms; in the case of varenicline, as demonstrated in this study, this also applies to patients with depression who are using antidepressant medications.

"Varenicline is a partial agonist of brain alpha4beta 2 nicotinic acetylcholine receptors and is believed to alleviate nicotine withdrawal while simultaneously blocking its rewarding effects. Because depressed smokers are prone to more severe nicotine withdrawal than nonpsychiatric smokers, mitigating withdrawal symptoms may be important in this population," the investigators said. Depressed smokers who lapse into smoking while attempting to regulate mood may find cigarettes less reinforcing while taking varenicline, thus facilitating prolonged abstinence, they noted.

Although the findings may not extrapolate to untreated or actively depressed smokers and those with other psychiatric conditions, since only stably treated patients without psychotic features and other disorders frequently associated with major depressive disorder (such as bipolar disorder and current substance use disorders) were included, the findings nevertheless suggest an important role for varenicline in smokers with a history of stably treated depression.

"With 350 million individuals having the disease worldwide and because a large proportion of smokers that seeks treatment has a lifetime history of MDD, these results have the potential to reduce morbidity and mortality in many smokers," they concluded.

The researchers noted several study limitations, including their selection of "a population of smokers who were stably treated for or remitted from depression." Thus, they wrote, "our findings may not extrapolate to untreated or actively depressed smokers, whom many consider to be poor candidates for smoking cessation until their condition stabilizes." They also excluded individuals with "with psychotic features, bipolar disorder, current substance use disorders, and other conditions frequently associated with major depressive disorder; patients receiving medication for mania or psychosis were also excluded. Missing data resulting from attrition in both treatment groups may have affected the outcomes, the authors further noted.

This study was funded by Pfizer. Individual authors reported receiving support from the Department of Veterans Affairs; the National Institute on Alcohol Abuse and Alcoholism; the University of California, San Francisco; the Smoking Cessation Leadership Center; and/or the Colorado Department of Public Health and Environment. Detailed disclosures are available at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0777.

*CORRECTION, 10/10/13: An earlier version of this article misstated the citation for the journal article referenced in the story.

Varenicline successfully promoted durable smoking cessation without exacerbating depression or anxiety in a randomized, phase IV, industry-funded study of patients with stably treated major depressive disorder.

Smoking cessation, defined as carbon monoxide–confirmed continuous abstinence, was higher at weeks 9-12 among 256 subjects in the double-blind study who were randomized to receive varenicline, compared with 269 who received placebo (35.9% vs. 15.6%; odds ratio, 3.35), Dr. Robert M. Anthenelli of the University of California, San Diego, and his colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The differences between the groups were also significant for weeks 9-24 (20.3% vs. 10.4%; OR, 2.36) and for weeks 9-52 (25% vs. 12.3%; OR, 2.36), the investigators said (Ann. Intern. Med. 2013;159:390-400).*

© milosluz/istockphoto.com

No clinically relevant differences were seen between the groups in suicidal ideation or behavior as captured by the Columbia Suicide Severity Rating Scale. Furthermore, no overall worsening of depression or anxiety occurred in either group. In fact, trajectories of mood and anxiety rating trended slightly toward improvement in both groups, they said.

Participants in the multicenter study were adults aged 19-73 years who had no recent cardiovascular events, who smoked at least 10 cigarettes daily, and who had current or past stably treated unipolar major depressive disorder without psychotic features. They were recruited from 38 centers in 8 countries between March 2010 and June 2012. Randomization was stratified by antidepressant use at baseline (any vs. none) and by baseline depression score (Montgomery-Asberg Depression Rating Scale score 11 or less vs. greater than 11). Patients received either placebo or varenicline titrated to a dose of 1 mg twice daily for 12 weeks, with a 40-week nontreatment follow-up phase.

Treatment was relatively safe; although 72.3% and 66.9% of the treatment and placebo groups, respectively, experienced treatment-emergent adverse events, most were mild or moderate. The most frequent adverse events in the treatment vs. placebo groups were nausea (27.0% vs. 10.4%, respectively), headaches (16.8% vs. 11.2%), abnormal dreams (11.3% vs. 8.2%), irritability (10.9% vs. 8.2%), and insomnia (10.9% vs. 4.8%). Two patients in the treatment group died during the nontreatment phase, but neither death was considered to be related to treatment, the investigators said.

The findings suggest that varenicline, like other FDA-approved smoking cessation aids effective in non–psychiatrically ill smokers, are similarly effective in smokers with a history of depression – without increasing depressive symptoms; in the case of varenicline, as demonstrated in this study, this also applies to patients with depression who are using antidepressant medications.

"Varenicline is a partial agonist of brain alpha4beta 2 nicotinic acetylcholine receptors and is believed to alleviate nicotine withdrawal while simultaneously blocking its rewarding effects. Because depressed smokers are prone to more severe nicotine withdrawal than nonpsychiatric smokers, mitigating withdrawal symptoms may be important in this population," the investigators said. Depressed smokers who lapse into smoking while attempting to regulate mood may find cigarettes less reinforcing while taking varenicline, thus facilitating prolonged abstinence, they noted.

Although the findings may not extrapolate to untreated or actively depressed smokers and those with other psychiatric conditions, since only stably treated patients without psychotic features and other disorders frequently associated with major depressive disorder (such as bipolar disorder and current substance use disorders) were included, the findings nevertheless suggest an important role for varenicline in smokers with a history of stably treated depression.

"With 350 million individuals having the disease worldwide and because a large proportion of smokers that seeks treatment has a lifetime history of MDD, these results have the potential to reduce morbidity and mortality in many smokers," they concluded.

The researchers noted several study limitations, including their selection of "a population of smokers who were stably treated for or remitted from depression." Thus, they wrote, "our findings may not extrapolate to untreated or actively depressed smokers, whom many consider to be poor candidates for smoking cessation until their condition stabilizes." They also excluded individuals with "with psychotic features, bipolar disorder, current substance use disorders, and other conditions frequently associated with major depressive disorder; patients receiving medication for mania or psychosis were also excluded. Missing data resulting from attrition in both treatment groups may have affected the outcomes, the authors further noted.

This study was funded by Pfizer. Individual authors reported receiving support from the Department of Veterans Affairs; the National Institute on Alcohol Abuse and Alcoholism; the University of California, San Francisco; the Smoking Cessation Leadership Center; and/or the Colorado Department of Public Health and Environment. Detailed disclosures are available at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0777.

*CORRECTION, 10/10/13: An earlier version of this article misstated the citation for the journal article referenced in the story.

Young women who elect contralateral prophylactic mastectomy do so, in part, because they want to improve their chances for survival, even though they realize there is no convincing evidence of a survival benefit, based on results from a survey.

Moreover, many women, particularly those without a known BRCA mutation, substantially overestimate their risk of developing cancer in the unaffected breast, Shoshana M. Rosenberg, Sc.D., of the Dana-Farber Cancer Institute and the Harvard School of Public Health, both in Boston, and her colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The findings suggest "some degree of cognitive dissonance," since almost all respondents cited both the desire to improve survival or extend life and a desire to prevent metastatic disease as extremely or very important reasons for choosing contralateral prophylactic mastectomy, while also demonstrating awareness that bilateral mastectomy would not extend survival, the researchers said. Anxiety and fear of recurrence likely influenced the decision-making process and led women to identify their desire to extend life and prevent metastatic disease as among the most important reasons for having contralateral prophylactic mastectomy.

Of 550 women diagnosed at age 40 years or younger with breast cancer in one breast, 123 (22%) who underwent bilateral mastectomy were included in the analysis. Of those women, 94% said the desire to improve survival was an extremely or very important factor in their decision to undergo contralateral prophylactic mastectomy. Yet 74% of mutation carriers and 84% of noncarriers acknowledged that most women who are diagnosed with early-stage breast cancer and undergo treatment will ultimately die of something other than breast cancer.

Also, 98% cited a desire to decrease their risk of contralateral breast cancer and 95% cited a desire for peace of mind as extremely or very important factors in their decision (Ann. Intern. Med. 2013;17:373-81).

Mutation carriers estimated their risk of developing cancer in the contralateral breast in the 5 years after unilateral treatment at 20%, noncarriers estimated that risk at 10%. The risk for women with BRCA mutations is estimated to be 24%-31%. The group without mutations overestimated their risk, which is actually about 2%-4% over 5 years. Women in both groups estimated the risk of chest wall recurrence after bilateral mastectomy at 5%, which is actually estimated at less than 1%, the researchers noted.

Survey participants were women whose median age was 37 years at cancer diagnosis and who were recruited from four academic and five community hospitals in Massachusetts, and from one academic site in Toronto between November 2006 and November 2010. The participants were recruited as part of the Helping Ourselves, Helping Others: Young Women’s Breast Cancer Study. Most had stage I or stage II breast cancer, and all were believed to have breast cancer only in one breast. About 60% of tumors were estrogen receptor–positive, and about 25% of the women were BRCAmutation carriers.

The survey was a one-time supplement to the ongoing prospective cohort study. It is one of the largest surveys to date to examine decision-making, risk perceptions, and psychosocial aspects of contralateral prophylactic mastectomy among young women with breast cancer, the investigators said. The survey findings are important, given that the rates of contralateral prophylactic mastectomy have increased dramatically in recent years, from 4%-6% in the late 1990s to 11%-25% in more recent reports, even though "the value of the procedure for most women with unilateral early-stage breast cancer is unclear," the researchers said.

The study was limited by the lack of validation of the survey, the possibility of recall bias (since the women were surveyed an average of 2 years following surgery), and the possibility of limited generalizability of the findings because the study population was primarily white, non-Hispanic, and college educated. Yet, the findings highlight a need for improved communication with patients, they said.

Although 96%-97% of participants believed they were clear about benefits and risks, and which mattered most, many women reported that several outcomes associated with surgery were worse than they had expected. For example, 33% reported needing a higher-than-expected number of operations or procedures, and 28% said that numbness or tingling in the chest was worse than expected.

"With respect to QOL outcomes, 42% reported that their sense of sexuality was worse than they expected after surgery, and nearly one-third indicated that self-consciousness about appearance was also worse than expected," the researchers reported.

Only about half of the participants indicated that their physicians had talked at least to some degree about reasons not to have contralateral prophylactic mastectomy, suggesting a potential role for "interventions that ensure women are sufficiently informed and the actual risk for contralateral disease is effectively communicated," the investigators said.

Additional clarification of these conflicting responses would be helpful, they said, suggesting that future investigation "might include focus groups or collection of qualitative data with the goal of elucidating the role of cognitive biases in making treatment decisions."

This study was primarily funded by Susan G. Komen for the Cure. Dr. Rosenberg reported receiving support from the National Cancer Institute.

Young women who elect contralateral prophylactic mastectomy do so, in part, because they want to improve their chances for survival, even though they realize there is no convincing evidence of a survival benefit, based on results from a survey.

Moreover, many women, particularly those without a known BRCA mutation, substantially overestimate their risk of developing cancer in the unaffected breast, Shoshana M. Rosenberg, Sc.D., of the Dana-Farber Cancer Institute and the Harvard School of Public Health, both in Boston, and her colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The findings suggest "some degree of cognitive dissonance," since almost all respondents cited both the desire to improve survival or extend life and a desire to prevent metastatic disease as extremely or very important reasons for choosing contralateral prophylactic mastectomy, while also demonstrating awareness that bilateral mastectomy would not extend survival, the researchers said. Anxiety and fear of recurrence likely influenced the decision-making process and led women to identify their desire to extend life and prevent metastatic disease as among the most important reasons for having contralateral prophylactic mastectomy.

Of 550 women diagnosed at age 40 years or younger with breast cancer in one breast, 123 (22%) who underwent bilateral mastectomy were included in the analysis. Of those women, 94% said the desire to improve survival was an extremely or very important factor in their decision to undergo contralateral prophylactic mastectomy. Yet 74% of mutation carriers and 84% of noncarriers acknowledged that most women who are diagnosed with early-stage breast cancer and undergo treatment will ultimately die of something other than breast cancer.

Also, 98% cited a desire to decrease their risk of contralateral breast cancer and 95% cited a desire for peace of mind as extremely or very important factors in their decision (Ann. Intern. Med. 2013;17:373-81).

Mutation carriers estimated their risk of developing cancer in the contralateral breast in the 5 years after unilateral treatment at 20%, noncarriers estimated that risk at 10%. The risk for women with BRCA mutations is estimated to be 24%-31%. The group without mutations overestimated their risk, which is actually about 2%-4% over 5 years. Women in both groups estimated the risk of chest wall recurrence after bilateral mastectomy at 5%, which is actually estimated at less than 1%, the researchers noted.

Survey participants were women whose median age was 37 years at cancer diagnosis and who were recruited from four academic and five community hospitals in Massachusetts, and from one academic site in Toronto between November 2006 and November 2010. The participants were recruited as part of the Helping Ourselves, Helping Others: Young Women’s Breast Cancer Study. Most had stage I or stage II breast cancer, and all were believed to have breast cancer only in one breast. About 60% of tumors were estrogen receptor–positive, and about 25% of the women were BRCAmutation carriers.

The survey was a one-time supplement to the ongoing prospective cohort study. It is one of the largest surveys to date to examine decision-making, risk perceptions, and psychosocial aspects of contralateral prophylactic mastectomy among young women with breast cancer, the investigators said. The survey findings are important, given that the rates of contralateral prophylactic mastectomy have increased dramatically in recent years, from 4%-6% in the late 1990s to 11%-25% in more recent reports, even though "the value of the procedure for most women with unilateral early-stage breast cancer is unclear," the researchers said.

The study was limited by the lack of validation of the survey, the possibility of recall bias (since the women were surveyed an average of 2 years following surgery), and the possibility of limited generalizability of the findings because the study population was primarily white, non-Hispanic, and college educated. Yet, the findings highlight a need for improved communication with patients, they said.

Although 96%-97% of participants believed they were clear about benefits and risks, and which mattered most, many women reported that several outcomes associated with surgery were worse than they had expected. For example, 33% reported needing a higher-than-expected number of operations or procedures, and 28% said that numbness or tingling in the chest was worse than expected.

"With respect to QOL outcomes, 42% reported that their sense of sexuality was worse than they expected after surgery, and nearly one-third indicated that self-consciousness about appearance was also worse than expected," the researchers reported.

Only about half of the participants indicated that their physicians had talked at least to some degree about reasons not to have contralateral prophylactic mastectomy, suggesting a potential role for "interventions that ensure women are sufficiently informed and the actual risk for contralateral disease is effectively communicated," the investigators said.

Additional clarification of these conflicting responses would be helpful, they said, suggesting that future investigation "might include focus groups or collection of qualitative data with the goal of elucidating the role of cognitive biases in making treatment decisions."

This study was primarily funded by Susan G. Komen for the Cure. Dr. Rosenberg reported receiving support from the National Cancer Institute.

Young women who elect contralateral prophylactic mastectomy do so, in part, because they want to improve their chances for survival, even though they realize there is no convincing evidence of a survival benefit, based on results from a survey.

Moreover, many women, particularly those without a known BRCA mutation, substantially overestimate their risk of developing cancer in the unaffected breast, Shoshana M. Rosenberg, Sc.D., of the Dana-Farber Cancer Institute and the Harvard School of Public Health, both in Boston, and her colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The findings suggest "some degree of cognitive dissonance," since almost all respondents cited both the desire to improve survival or extend life and a desire to prevent metastatic disease as extremely or very important reasons for choosing contralateral prophylactic mastectomy, while also demonstrating awareness that bilateral mastectomy would not extend survival, the researchers said. Anxiety and fear of recurrence likely influenced the decision-making process and led women to identify their desire to extend life and prevent metastatic disease as among the most important reasons for having contralateral prophylactic mastectomy.

Of 550 women diagnosed at age 40 years or younger with breast cancer in one breast, 123 (22%) who underwent bilateral mastectomy were included in the analysis. Of those women, 94% said the desire to improve survival was an extremely or very important factor in their decision to undergo contralateral prophylactic mastectomy. Yet 74% of mutation carriers and 84% of noncarriers acknowledged that most women who are diagnosed with early-stage breast cancer and undergo treatment will ultimately die of something other than breast cancer.

Also, 98% cited a desire to decrease their risk of contralateral breast cancer and 95% cited a desire for peace of mind as extremely or very important factors in their decision (Ann. Intern. Med. 2013;17:373-81).

Mutation carriers estimated their risk of developing cancer in the contralateral breast in the 5 years after unilateral treatment at 20%, noncarriers estimated that risk at 10%. The risk for women with BRCA mutations is estimated to be 24%-31%. The group without mutations overestimated their risk, which is actually about 2%-4% over 5 years. Women in both groups estimated the risk of chest wall recurrence after bilateral mastectomy at 5%, which is actually estimated at less than 1%, the researchers noted.

Survey participants were women whose median age was 37 years at cancer diagnosis and who were recruited from four academic and five community hospitals in Massachusetts, and from one academic site in Toronto between November 2006 and November 2010. The participants were recruited as part of the Helping Ourselves, Helping Others: Young Women’s Breast Cancer Study. Most had stage I or stage II breast cancer, and all were believed to have breast cancer only in one breast. About 60% of tumors were estrogen receptor–positive, and about 25% of the women were BRCAmutation carriers.

The survey was a one-time supplement to the ongoing prospective cohort study. It is one of the largest surveys to date to examine decision-making, risk perceptions, and psychosocial aspects of contralateral prophylactic mastectomy among young women with breast cancer, the investigators said. The survey findings are important, given that the rates of contralateral prophylactic mastectomy have increased dramatically in recent years, from 4%-6% in the late 1990s to 11%-25% in more recent reports, even though "the value of the procedure for most women with unilateral early-stage breast cancer is unclear," the researchers said.

The study was limited by the lack of validation of the survey, the possibility of recall bias (since the women were surveyed an average of 2 years following surgery), and the possibility of limited generalizability of the findings because the study population was primarily white, non-Hispanic, and college educated. Yet, the findings highlight a need for improved communication with patients, they said.

Although 96%-97% of participants believed they were clear about benefits and risks, and which mattered most, many women reported that several outcomes associated with surgery were worse than they had expected. For example, 33% reported needing a higher-than-expected number of operations or procedures, and 28% said that numbness or tingling in the chest was worse than expected.

"With respect to QOL outcomes, 42% reported that their sense of sexuality was worse than they expected after surgery, and nearly one-third indicated that self-consciousness about appearance was also worse than expected," the researchers reported.

Only about half of the participants indicated that their physicians had talked at least to some degree about reasons not to have contralateral prophylactic mastectomy, suggesting a potential role for "interventions that ensure women are sufficiently informed and the actual risk for contralateral disease is effectively communicated," the investigators said.

Additional clarification of these conflicting responses would be helpful, they said, suggesting that future investigation "might include focus groups or collection of qualitative data with the goal of elucidating the role of cognitive biases in making treatment decisions."

This study was primarily funded by Susan G. Komen for the Cure. Dr. Rosenberg reported receiving support from the National Cancer Institute.

Selenium supplementation provided no benefit over placebo for the prevention of second primary tumors in patients with completely resected stage 1 non–small cell lung cancer in a randomized phase III trial.

In 1,040 patients who were randomized to receive selenium and 521 patients randomized to receive placebo, the incidence rates of lung and overall second primary tumors (SPTs) were similar (1.62 and 3.54 per 100 person-years vs. 1.30 and 3.39 per 100 person-years, respectively). Five-year disease-free survival (DFS) rates were 74.4% and 79.6% for the selenium and placebo groups, respectively, Dr. Daniel D. Karp of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported.

© Bert Folsom/Fotolia.com

The findings were published online Sept. 3 ahead of print in the Journal of Clinical Oncology.

Patients included in the double-blind study were adults aged 18 years or older who were 6-36 months out from complete resection of histologically proven stage 1A or 1B non–small cell lung cancer (NSCLC). Selenium was given at a dose of 200 mcg daily for up to 48 months (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173]).

At a planned interim analysis in October 2009, a data monitoring committee determined that "it was highly unlikely that this study could eventually show significant evidence of benefit from selenium," and the following month accrual was discontinued and participating patients discontinued treatment and entered the follow-up phase.

At the interim analysis, there were 83 cases of lung SPT, corresponding to 46% of the originally planned end points. The incidence rates of lung SPT were 1.91 and 1.36 per 100 person-years in the selenium and placebo groups, respectively.

"Overall, the SPT incidence rate was higher in the selenium arm but not significantly. Five-year DFS was 72% for selenium and 78% for placebo," the authors noted.

At the more recent analysis in June, 2011, there were 252 reported SPTs in 224 patients. Of these, 98 were lung cancers, corresponding to 56% of the originally planned end points.

Although prior studies suggested a possible benefit of selenium for tertiary chemoprevention in completely resected NSCLC patients, the findings of the current study suggest otherwise. Although selenium treatment was safe, with similar rates of grade 1 to 2 toxicity (31% and 26%, respectively), and grade 3 or greater toxicity (2% and 3%, respectively) occurring in the treatment and placebo groups, and no increased risk of diabetes or skin cancer among those treated with selenium, no significant differences were seen with respect to SPT prevention, the investigators said.

However, a recurring theme in this and prior SPT prevention trials in lung cancer and head and neck cancer – including studies evaluating retinoids for chemoprevention – is that the lowest rates of SPTs tend to be seen in never-smokers, followed by former smokers, they noted.

In the current study, active smokers in the selenium group had a 30% risk of recurrence or SPT, compared with a 24% risk for former smokers and a 20% risk for never-smokers. Also, the 3- and 5-year overall survival rates were 85.5% and 74.9%, respectively, in those who were active smokers or who had stopped smoking within 1 year, compared with 90% and 83.6%, respectively, for never-smokers.

"It is now clear that there is no demonstrable benefit in giving supplements such as selenium or retinoids to current smokers. However, the data suggest that a better approach might be to treat never-smokers with low serum selenium levels," they said, explaining that descriptive data from the current study suggest that any beneficial effect of selenium is limited to patients with a low baseline selenium level.

"In the current era of molecularly targeted therapies for lung cancer, it seems that persisting with broad approaches in genomically unselected patient populations who continue to smoke is highly unlikely to be successful," they said.

This study was supported by Public Health Service Grants and grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. One coauthor of this study, Dr. David H. Johnson, reported serving as a consultant or adviser for Peloton Therapeutics. The remaining authors reported having no disclosures.

Selenium supplementation provided no benefit over placebo for the prevention of second primary tumors in patients with completely resected stage 1 non–small cell lung cancer in a randomized phase III trial.

In 1,040 patients who were randomized to receive selenium and 521 patients randomized to receive placebo, the incidence rates of lung and overall second primary tumors (SPTs) were similar (1.62 and 3.54 per 100 person-years vs. 1.30 and 3.39 per 100 person-years, respectively). Five-year disease-free survival (DFS) rates were 74.4% and 79.6% for the selenium and placebo groups, respectively, Dr. Daniel D. Karp of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported.

© Bert Folsom/Fotolia.com

The findings were published online Sept. 3 ahead of print in the Journal of Clinical Oncology.

Patients included in the double-blind study were adults aged 18 years or older who were 6-36 months out from complete resection of histologically proven stage 1A or 1B non–small cell lung cancer (NSCLC). Selenium was given at a dose of 200 mcg daily for up to 48 months (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173]).

At a planned interim analysis in October 2009, a data monitoring committee determined that "it was highly unlikely that this study could eventually show significant evidence of benefit from selenium," and the following month accrual was discontinued and participating patients discontinued treatment and entered the follow-up phase.

At the interim analysis, there were 83 cases of lung SPT, corresponding to 46% of the originally planned end points. The incidence rates of lung SPT were 1.91 and 1.36 per 100 person-years in the selenium and placebo groups, respectively.

"Overall, the SPT incidence rate was higher in the selenium arm but not significantly. Five-year DFS was 72% for selenium and 78% for placebo," the authors noted.

At the more recent analysis in June, 2011, there were 252 reported SPTs in 224 patients. Of these, 98 were lung cancers, corresponding to 56% of the originally planned end points.

Although prior studies suggested a possible benefit of selenium for tertiary chemoprevention in completely resected NSCLC patients, the findings of the current study suggest otherwise. Although selenium treatment was safe, with similar rates of grade 1 to 2 toxicity (31% and 26%, respectively), and grade 3 or greater toxicity (2% and 3%, respectively) occurring in the treatment and placebo groups, and no increased risk of diabetes or skin cancer among those treated with selenium, no significant differences were seen with respect to SPT prevention, the investigators said.

However, a recurring theme in this and prior SPT prevention trials in lung cancer and head and neck cancer – including studies evaluating retinoids for chemoprevention – is that the lowest rates of SPTs tend to be seen in never-smokers, followed by former smokers, they noted.

In the current study, active smokers in the selenium group had a 30% risk of recurrence or SPT, compared with a 24% risk for former smokers and a 20% risk for never-smokers. Also, the 3- and 5-year overall survival rates were 85.5% and 74.9%, respectively, in those who were active smokers or who had stopped smoking within 1 year, compared with 90% and 83.6%, respectively, for never-smokers.

"It is now clear that there is no demonstrable benefit in giving supplements such as selenium or retinoids to current smokers. However, the data suggest that a better approach might be to treat never-smokers with low serum selenium levels," they said, explaining that descriptive data from the current study suggest that any beneficial effect of selenium is limited to patients with a low baseline selenium level.

"In the current era of molecularly targeted therapies for lung cancer, it seems that persisting with broad approaches in genomically unselected patient populations who continue to smoke is highly unlikely to be successful," they said.

This study was supported by Public Health Service Grants and grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. One coauthor of this study, Dr. David H. Johnson, reported serving as a consultant or adviser for Peloton Therapeutics. The remaining authors reported having no disclosures.

Selenium supplementation provided no benefit over placebo for the prevention of second primary tumors in patients with completely resected stage 1 non–small cell lung cancer in a randomized phase III trial.

In 1,040 patients who were randomized to receive selenium and 521 patients randomized to receive placebo, the incidence rates of lung and overall second primary tumors (SPTs) were similar (1.62 and 3.54 per 100 person-years vs. 1.30 and 3.39 per 100 person-years, respectively). Five-year disease-free survival (DFS) rates were 74.4% and 79.6% for the selenium and placebo groups, respectively, Dr. Daniel D. Karp of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported.

© Bert Folsom/Fotolia.com

The findings were published online Sept. 3 ahead of print in the Journal of Clinical Oncology.

Patients included in the double-blind study were adults aged 18 years or older who were 6-36 months out from complete resection of histologically proven stage 1A or 1B non–small cell lung cancer (NSCLC). Selenium was given at a dose of 200 mcg daily for up to 48 months (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173]).

At a planned interim analysis in October 2009, a data monitoring committee determined that "it was highly unlikely that this study could eventually show significant evidence of benefit from selenium," and the following month accrual was discontinued and participating patients discontinued treatment and entered the follow-up phase.

At the interim analysis, there were 83 cases of lung SPT, corresponding to 46% of the originally planned end points. The incidence rates of lung SPT were 1.91 and 1.36 per 100 person-years in the selenium and placebo groups, respectively.

"Overall, the SPT incidence rate was higher in the selenium arm but not significantly. Five-year DFS was 72% for selenium and 78% for placebo," the authors noted.

At the more recent analysis in June, 2011, there were 252 reported SPTs in 224 patients. Of these, 98 were lung cancers, corresponding to 56% of the originally planned end points.

Although prior studies suggested a possible benefit of selenium for tertiary chemoprevention in completely resected NSCLC patients, the findings of the current study suggest otherwise. Although selenium treatment was safe, with similar rates of grade 1 to 2 toxicity (31% and 26%, respectively), and grade 3 or greater toxicity (2% and 3%, respectively) occurring in the treatment and placebo groups, and no increased risk of diabetes or skin cancer among those treated with selenium, no significant differences were seen with respect to SPT prevention, the investigators said.

However, a recurring theme in this and prior SPT prevention trials in lung cancer and head and neck cancer – including studies evaluating retinoids for chemoprevention – is that the lowest rates of SPTs tend to be seen in never-smokers, followed by former smokers, they noted.

In the current study, active smokers in the selenium group had a 30% risk of recurrence or SPT, compared with a 24% risk for former smokers and a 20% risk for never-smokers. Also, the 3- and 5-year overall survival rates were 85.5% and 74.9%, respectively, in those who were active smokers or who had stopped smoking within 1 year, compared with 90% and 83.6%, respectively, for never-smokers.

"It is now clear that there is no demonstrable benefit in giving supplements such as selenium or retinoids to current smokers. However, the data suggest that a better approach might be to treat never-smokers with low serum selenium levels," they said, explaining that descriptive data from the current study suggest that any beneficial effect of selenium is limited to patients with a low baseline selenium level.

"In the current era of molecularly targeted therapies for lung cancer, it seems that persisting with broad approaches in genomically unselected patient populations who continue to smoke is highly unlikely to be successful," they said.

This study was supported by Public Health Service Grants and grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. One coauthor of this study, Dr. David H. Johnson, reported serving as a consultant or adviser for Peloton Therapeutics. The remaining authors reported having no disclosures.

Danish researchers report that rheumatoid arthritis patients’ baseline patient global score component of the Disease-Activity Score–28 tool was most strongly correlated with patient-reported outcomes and was the best predictor of a gain in quality adjusted life years following 1 year of biological therapy in a prospective observational study.

An objective C-reactive protein (CRP) measure, however, had no predictive value, and no sharp demarcation between objective and subjective variables was apparent.

The finding that patient global score at baseline may drive a gain in quality adjusted life years (QALY) could improve understanding of which disease-related factors might affect the cost per QALY gains (an important measure for comparing the cost-effectiveness of treatments) and predict treatment response, according to Dr. Louise Linde of the DANBIO Registry, Glostrup, Denmark, and her colleagues (J. Rheumatol. 2013;40:1479-86).

Of 282 patients who completed the study, 68% gained QALYs following 1 year of biological therapy (mean of 0.14), 61% were European League Against Rheumatism (EULAR) criteria responders, and 62% achieved minimally important differences based on the European Quality of Life 5 Dimensions (EQ-5D) questionnaire.

The proportion of patients achieving both a EULAR and EQ-5D response was 55%. Cross-tabulation by response groups (EULAR response/EQ-5D response, EULAR no response/EQ-5D no response, EULAR response/EQ-5D no response, and EULAR no response/EQ-5D response) showed that the mean reduction in swollen joints across the groups ranged from 0 to 6 with clinically and statistically significant differences in three of six possible comparisons.

Similar patterns were seen for tender joints and patient global score, the investigators said.

"Thus, the mean reduction in tender joints ranged from –1 to 9 across the response groups. In addition, the EULAR no response/EQ-5D response group could be discriminated from the EULAR response/EQ-5D response group, leading to significant differences (3-9 tender joints) in four of six comparisons. Similarly, the mean reduction in patient global score ranged from –0.7 to 4.0 cm across the response groups, and highly significant differences of 2.0-4.7 cm were observed between the response groups in five of six comparisons," they said.

However, the mean reduction in CRP, which ranged from 6.0 to 16.5 mg/L across the response groups, distinguished only the EULAR response/EQ-5D response from the EULAR nonresponders.

All EULAR responders experienced significant reductions in swollen and tender joints, CRP, and patient global scores – regardless of EQ-5D status – and the EULAR nonresponders who had an EQ-5D response experienced similar improvements. However, those with no EQ-5D response experienced a worsening in patient global score of 0.7.

Patient global score was strongly correlated with responses on both the EULAR and European Quality of Life 5 Dimensions EQ-5D.

Regression analysis demonstrated that "the gain in QALY after 1 year of biological therapy increased with increasing baseline patient global score and number of swollen joints, and patients with two or more extraarticular manifestations gained more QALY compared with those without such manifestations," the investigators wrote.

"This finding may reflect the likely scenario that patients with very active or severe disease have more room for improvement. This does not imply, however that such patients will have a more favorable final status than those with less active or less severe disease at baseline, a conclusion not supported by our observational data," they noted.

The mean age of the patients in this study was 55 years. They were recruited from 17 routine care sites between November 2005 and July 2007. Clinical and patient-reported data were collected at baseline and after 3, 6, and 12 months of therapy. Clinical data were obtained via the Danish DANBIO registry, which includes 90% of Danish patients with RA who are receiving biological therapy. Collected clinical data included disease duration, 28 swollen and tender joint counts, CRP, patient global score on a visual analog scale, IgM-rheumatoid factor status, number of previous biological therapies, and concomitant use of methotrexate and glucocorticoids. Self-reported patient data included marital status, education, smoking behavior, body mass index, exercise habits, extra-articular features, joint surgery, and comorbidities.

In addition to the EQ-5D, participants also completed the validated Danish Health Assessment Questionnaire.

Though limited by the factors inherent in observational study design, the study is strengthened by the nationwide recruitment, the fact that is was carried out in a clinical setting, and the fact that the study population had similar baseline demographic, clinical, and patent-reported values as have been reported for other RA patients treated with biological therapies in routine care in several other registries.

"This result suggests that our findings may be generalizable to patients with RA treated in routine care with biologicals in countries with a public healthcare system similar to the Danish model," the investigators wrote.

Danish researchers report that rheumatoid arthritis patients’ baseline patient global score component of the Disease-Activity Score–28 tool was most strongly correlated with patient-reported outcomes and was the best predictor of a gain in quality adjusted life years following 1 year of biological therapy in a prospective observational study.

An objective C-reactive protein (CRP) measure, however, had no predictive value, and no sharp demarcation between objective and subjective variables was apparent.

The finding that patient global score at baseline may drive a gain in quality adjusted life years (QALY) could improve understanding of which disease-related factors might affect the cost per QALY gains (an important measure for comparing the cost-effectiveness of treatments) and predict treatment response, according to Dr. Louise Linde of the DANBIO Registry, Glostrup, Denmark, and her colleagues (J. Rheumatol. 2013;40:1479-86).

Of 282 patients who completed the study, 68% gained QALYs following 1 year of biological therapy (mean of 0.14), 61% were European League Against Rheumatism (EULAR) criteria responders, and 62% achieved minimally important differences based on the European Quality of Life 5 Dimensions (EQ-5D) questionnaire.

The proportion of patients achieving both a EULAR and EQ-5D response was 55%. Cross-tabulation by response groups (EULAR response/EQ-5D response, EULAR no response/EQ-5D no response, EULAR response/EQ-5D no response, and EULAR no response/EQ-5D response) showed that the mean reduction in swollen joints across the groups ranged from 0 to 6 with clinically and statistically significant differences in three of six possible comparisons.

Similar patterns were seen for tender joints and patient global score, the investigators said.

"Thus, the mean reduction in tender joints ranged from –1 to 9 across the response groups. In addition, the EULAR no response/EQ-5D response group could be discriminated from the EULAR response/EQ-5D response group, leading to significant differences (3-9 tender joints) in four of six comparisons. Similarly, the mean reduction in patient global score ranged from –0.7 to 4.0 cm across the response groups, and highly significant differences of 2.0-4.7 cm were observed between the response groups in five of six comparisons," they said.

However, the mean reduction in CRP, which ranged from 6.0 to 16.5 mg/L across the response groups, distinguished only the EULAR response/EQ-5D response from the EULAR nonresponders.

All EULAR responders experienced significant reductions in swollen and tender joints, CRP, and patient global scores – regardless of EQ-5D status – and the EULAR nonresponders who had an EQ-5D response experienced similar improvements. However, those with no EQ-5D response experienced a worsening in patient global score of 0.7.

Patient global score was strongly correlated with responses on both the EULAR and European Quality of Life 5 Dimensions EQ-5D.

Regression analysis demonstrated that "the gain in QALY after 1 year of biological therapy increased with increasing baseline patient global score and number of swollen joints, and patients with two or more extraarticular manifestations gained more QALY compared with those without such manifestations," the investigators wrote.

"This finding may reflect the likely scenario that patients with very active or severe disease have more room for improvement. This does not imply, however that such patients will have a more favorable final status than those with less active or less severe disease at baseline, a conclusion not supported by our observational data," they noted.

The mean age of the patients in this study was 55 years. They were recruited from 17 routine care sites between November 2005 and July 2007. Clinical and patient-reported data were collected at baseline and after 3, 6, and 12 months of therapy. Clinical data were obtained via the Danish DANBIO registry, which includes 90% of Danish patients with RA who are receiving biological therapy. Collected clinical data included disease duration, 28 swollen and tender joint counts, CRP, patient global score on a visual analog scale, IgM-rheumatoid factor status, number of previous biological therapies, and concomitant use of methotrexate and glucocorticoids. Self-reported patient data included marital status, education, smoking behavior, body mass index, exercise habits, extra-articular features, joint surgery, and comorbidities.

In addition to the EQ-5D, participants also completed the validated Danish Health Assessment Questionnaire.

Though limited by the factors inherent in observational study design, the study is strengthened by the nationwide recruitment, the fact that is was carried out in a clinical setting, and the fact that the study population had similar baseline demographic, clinical, and patent-reported values as have been reported for other RA patients treated with biological therapies in routine care in several other registries.

"This result suggests that our findings may be generalizable to patients with RA treated in routine care with biologicals in countries with a public healthcare system similar to the Danish model," the investigators wrote.

Danish researchers report that rheumatoid arthritis patients’ baseline patient global score component of the Disease-Activity Score–28 tool was most strongly correlated with patient-reported outcomes and was the best predictor of a gain in quality adjusted life years following 1 year of biological therapy in a prospective observational study.

An objective C-reactive protein (CRP) measure, however, had no predictive value, and no sharp demarcation between objective and subjective variables was apparent.

The finding that patient global score at baseline may drive a gain in quality adjusted life years (QALY) could improve understanding of which disease-related factors might affect the cost per QALY gains (an important measure for comparing the cost-effectiveness of treatments) and predict treatment response, according to Dr. Louise Linde of the DANBIO Registry, Glostrup, Denmark, and her colleagues (J. Rheumatol. 2013;40:1479-86).

Of 282 patients who completed the study, 68% gained QALYs following 1 year of biological therapy (mean of 0.14), 61% were European League Against Rheumatism (EULAR) criteria responders, and 62% achieved minimally important differences based on the European Quality of Life 5 Dimensions (EQ-5D) questionnaire.

The proportion of patients achieving both a EULAR and EQ-5D response was 55%. Cross-tabulation by response groups (EULAR response/EQ-5D response, EULAR no response/EQ-5D no response, EULAR response/EQ-5D no response, and EULAR no response/EQ-5D response) showed that the mean reduction in swollen joints across the groups ranged from 0 to 6 with clinically and statistically significant differences in three of six possible comparisons.

Similar patterns were seen for tender joints and patient global score, the investigators said.

"Thus, the mean reduction in tender joints ranged from –1 to 9 across the response groups. In addition, the EULAR no response/EQ-5D response group could be discriminated from the EULAR response/EQ-5D response group, leading to significant differences (3-9 tender joints) in four of six comparisons. Similarly, the mean reduction in patient global score ranged from –0.7 to 4.0 cm across the response groups, and highly significant differences of 2.0-4.7 cm were observed between the response groups in five of six comparisons," they said.

However, the mean reduction in CRP, which ranged from 6.0 to 16.5 mg/L across the response groups, distinguished only the EULAR response/EQ-5D response from the EULAR nonresponders.

All EULAR responders experienced significant reductions in swollen and tender joints, CRP, and patient global scores – regardless of EQ-5D status – and the EULAR nonresponders who had an EQ-5D response experienced similar improvements. However, those with no EQ-5D response experienced a worsening in patient global score of 0.7.

Patient global score was strongly correlated with responses on both the EULAR and European Quality of Life 5 Dimensions EQ-5D.

Regression analysis demonstrated that "the gain in QALY after 1 year of biological therapy increased with increasing baseline patient global score and number of swollen joints, and patients with two or more extraarticular manifestations gained more QALY compared with those without such manifestations," the investigators wrote.

"This finding may reflect the likely scenario that patients with very active or severe disease have more room for improvement. This does not imply, however that such patients will have a more favorable final status than those with less active or less severe disease at baseline, a conclusion not supported by our observational data," they noted.

The mean age of the patients in this study was 55 years. They were recruited from 17 routine care sites between November 2005 and July 2007. Clinical and patient-reported data were collected at baseline and after 3, 6, and 12 months of therapy. Clinical data were obtained via the Danish DANBIO registry, which includes 90% of Danish patients with RA who are receiving biological therapy. Collected clinical data included disease duration, 28 swollen and tender joint counts, CRP, patient global score on a visual analog scale, IgM-rheumatoid factor status, number of previous biological therapies, and concomitant use of methotrexate and glucocorticoids. Self-reported patient data included marital status, education, smoking behavior, body mass index, exercise habits, extra-articular features, joint surgery, and comorbidities.

In addition to the EQ-5D, participants also completed the validated Danish Health Assessment Questionnaire.

Though limited by the factors inherent in observational study design, the study is strengthened by the nationwide recruitment, the fact that is was carried out in a clinical setting, and the fact that the study population had similar baseline demographic, clinical, and patent-reported values as have been reported for other RA patients treated with biological therapies in routine care in several other registries.

"This result suggests that our findings may be generalizable to patients with RA treated in routine care with biologicals in countries with a public healthcare system similar to the Danish model," the investigators wrote.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Response-guided neoadjuvant chemotherapy may improve disease-free and overall survival in patients with early breast cancer, particularly in those patients with hormone receptor–positive tumors, findings from an exploratory analysis of data from the phase III GeparTrio trial suggest.

"Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy," Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, and his colleagues reported, noting that the findings must be tested prospectively but can be used to guide the design of future trials.

After treating 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), the researchers randomized 1,390 early responders to receive either four or six additional TAC cycles, and randomized 622 early nonresponders either to four additional TAC cycles or to non-cross-resistant treatment with vinorelbine and capecitabine (TAC-NX) before surgery. TAC cycles included 75 mg/m² of docetaxel, 50 mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide on day 1 every 3 weeks. NX included 25 mg/m² of vinorelbine on days 1 and 8 plus 1,000 mg/m² of capecitabine given orally twice daily on days 1-14 every 3 weeks. Sixty patients did not continue in the study after the initial TAC cycles.

Disease-free survival was better in the 686 early responders who received a total of eight TAC cycles, compared with the 704 patients who received six TAC cycles (hazard ratio, 0.78), and in 301 early nonresponders who received TAC-NX, compared with 321 early nonresponders who received six TAC cycles (HR, 0.59), the investigators reported online Sept. 3 in the Journal of Clinical Oncology.

An exploratory analysis demonstrated that both disease-free survival and overall survival were longer following either eight TAC cycles or TAC-NX, as compared with conventional chemotherapy with six TAC cycles (HRs, 0.71 and 0.79, respectively), the investigators reported (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2012.45.0940]).

"Treatment effects on overall survival were less pronounced. Responders receiving TAC x 8 showed only a trend toward longer overall survival compared with those receiving TAC x 6 (hazard ratio, 0.76), whereas nonresponders receiving TAC-NX showed no improvement in overall survival compared with those receiving TAC x 6 (hazard ratio, 0.85). Response-guided chemotherapy provided significant but marginal overall survival benefit over conventional chemotherapy (hazard ratio, 0.79)," they said.

Of note, the effects of response-guided therapy on disease-free survival were apparent in all hormone receptor–positive tumors but not in hormone receptor–negative tumors, they noted (HRs for luminal A, luminal B HER2-negative, and luminal B HER2-positive tumors were 0.55, 0.40, and 0.56, respectively; HRs for nonluminal HER2-positive and triple-negative tumors were 1.01 and 0.87, respectively).

Pathological complete response (pCR) did not predict long-term outcomes; a comparison of pCR rates based on treatment strategy showed that "survival in patients with hormone receptor–positive tumors did not depend on pCR but was improved by response-guided therapy, whereas survival in patients with hormone receptor–negative tumors did depend on pCR but was not improved by response-guided therapy," they said. pCR predicted improved disease-free survival in triple-negative, nonluminal HER2-positive, and luminal B HER2-negative tumors (HRs, 6.67, 5.24, and 3.74, respectively), they reported.

Patients included in the study had unilateral or bilateral primary breast cancer confirmed by core biopsy, and had at least one additional risk factor, including age under 36, clinical tumor size more than 5 cm, estrogen receptor and progesterone receptor negativity, clinical axillary node involvement, or undifferentiated tumor grade.

The findings from the GeparTrio study demonstrate the advantage of neoadjuvant versus adjuvant chemotherapy. Response-guided treatment can only be conducted when the tumor is available for the monitoring of response, the investigators noted.

This study was supported by Amgen, Chugai, Roche, and Sanofi-Aventis. Dr. von Minckwitz and multiple coauthors reported serving as a consultant or advisor for, owning stock in, and/or receiving honoraria or research funding from Amgen, Roche, Sanofi-Aventis, and other companies.

Response-guided neoadjuvant chemotherapy may improve disease-free and overall survival in patients with early breast cancer, particularly in those patients with hormone receptor–positive tumors, findings from an exploratory analysis of data from the phase III GeparTrio trial suggest.

"Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy," Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, and his colleagues reported, noting that the findings must be tested prospectively but can be used to guide the design of future trials.

After treating 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), the researchers randomized 1,390 early responders to receive either four or six additional TAC cycles, and randomized 622 early nonresponders either to four additional TAC cycles or to non-cross-resistant treatment with vinorelbine and capecitabine (TAC-NX) before surgery. TAC cycles included 75 mg/m² of docetaxel, 50 mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide on day 1 every 3 weeks. NX included 25 mg/m² of vinorelbine on days 1 and 8 plus 1,000 mg/m² of capecitabine given orally twice daily on days 1-14 every 3 weeks. Sixty patients did not continue in the study after the initial TAC cycles.

Disease-free survival was better in the 686 early responders who received a total of eight TAC cycles, compared with the 704 patients who received six TAC cycles (hazard ratio, 0.78), and in 301 early nonresponders who received TAC-NX, compared with 321 early nonresponders who received six TAC cycles (HR, 0.59), the investigators reported online Sept. 3 in the Journal of Clinical Oncology.

An exploratory analysis demonstrated that both disease-free survival and overall survival were longer following either eight TAC cycles or TAC-NX, as compared with conventional chemotherapy with six TAC cycles (HRs, 0.71 and 0.79, respectively), the investigators reported (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2012.45.0940]).

"Treatment effects on overall survival were less pronounced. Responders receiving TAC x 8 showed only a trend toward longer overall survival compared with those receiving TAC x 6 (hazard ratio, 0.76), whereas nonresponders receiving TAC-NX showed no improvement in overall survival compared with those receiving TAC x 6 (hazard ratio, 0.85). Response-guided chemotherapy provided significant but marginal overall survival benefit over conventional chemotherapy (hazard ratio, 0.79)," they said.

Of note, the effects of response-guided therapy on disease-free survival were apparent in all hormone receptor–positive tumors but not in hormone receptor–negative tumors, they noted (HRs for luminal A, luminal B HER2-negative, and luminal B HER2-positive tumors were 0.55, 0.40, and 0.56, respectively; HRs for nonluminal HER2-positive and triple-negative tumors were 1.01 and 0.87, respectively).

Pathological complete response (pCR) did not predict long-term outcomes; a comparison of pCR rates based on treatment strategy showed that "survival in patients with hormone receptor–positive tumors did not depend on pCR but was improved by response-guided therapy, whereas survival in patients with hormone receptor–negative tumors did depend on pCR but was not improved by response-guided therapy," they said. pCR predicted improved disease-free survival in triple-negative, nonluminal HER2-positive, and luminal B HER2-negative tumors (HRs, 6.67, 5.24, and 3.74, respectively), they reported.

Patients included in the study had unilateral or bilateral primary breast cancer confirmed by core biopsy, and had at least one additional risk factor, including age under 36, clinical tumor size more than 5 cm, estrogen receptor and progesterone receptor negativity, clinical axillary node involvement, or undifferentiated tumor grade.

The findings from the GeparTrio study demonstrate the advantage of neoadjuvant versus adjuvant chemotherapy. Response-guided treatment can only be conducted when the tumor is available for the monitoring of response, the investigators noted.

This study was supported by Amgen, Chugai, Roche, and Sanofi-Aventis. Dr. von Minckwitz and multiple coauthors reported serving as a consultant or advisor for, owning stock in, and/or receiving honoraria or research funding from Amgen, Roche, Sanofi-Aventis, and other companies.

Response-guided neoadjuvant chemotherapy may improve disease-free and overall survival in patients with early breast cancer, particularly in those patients with hormone receptor–positive tumors, findings from an exploratory analysis of data from the phase III GeparTrio trial suggest.

"Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy," Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, and his colleagues reported, noting that the findings must be tested prospectively but can be used to guide the design of future trials.

After treating 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), the researchers randomized 1,390 early responders to receive either four or six additional TAC cycles, and randomized 622 early nonresponders either to four additional TAC cycles or to non-cross-resistant treatment with vinorelbine and capecitabine (TAC-NX) before surgery. TAC cycles included 75 mg/m² of docetaxel, 50 mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide on day 1 every 3 weeks. NX included 25 mg/m² of vinorelbine on days 1 and 8 plus 1,000 mg/m² of capecitabine given orally twice daily on days 1-14 every 3 weeks. Sixty patients did not continue in the study after the initial TAC cycles.

Disease-free survival was better in the 686 early responders who received a total of eight TAC cycles, compared with the 704 patients who received six TAC cycles (hazard ratio, 0.78), and in 301 early nonresponders who received TAC-NX, compared with 321 early nonresponders who received six TAC cycles (HR, 0.59), the investigators reported online Sept. 3 in the Journal of Clinical Oncology.

An exploratory analysis demonstrated that both disease-free survival and overall survival were longer following either eight TAC cycles or TAC-NX, as compared with conventional chemotherapy with six TAC cycles (HRs, 0.71 and 0.79, respectively), the investigators reported (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2012.45.0940]).

"Treatment effects on overall survival were less pronounced. Responders receiving TAC x 8 showed only a trend toward longer overall survival compared with those receiving TAC x 6 (hazard ratio, 0.76), whereas nonresponders receiving TAC-NX showed no improvement in overall survival compared with those receiving TAC x 6 (hazard ratio, 0.85). Response-guided chemotherapy provided significant but marginal overall survival benefit over conventional chemotherapy (hazard ratio, 0.79)," they said.

Of note, the effects of response-guided therapy on disease-free survival were apparent in all hormone receptor–positive tumors but not in hormone receptor–negative tumors, they noted (HRs for luminal A, luminal B HER2-negative, and luminal B HER2-positive tumors were 0.55, 0.40, and 0.56, respectively; HRs for nonluminal HER2-positive and triple-negative tumors were 1.01 and 0.87, respectively).

Pathological complete response (pCR) did not predict long-term outcomes; a comparison of pCR rates based on treatment strategy showed that "survival in patients with hormone receptor–positive tumors did not depend on pCR but was improved by response-guided therapy, whereas survival in patients with hormone receptor–negative tumors did depend on pCR but was not improved by response-guided therapy," they said. pCR predicted improved disease-free survival in triple-negative, nonluminal HER2-positive, and luminal B HER2-negative tumors (HRs, 6.67, 5.24, and 3.74, respectively), they reported.

Patients included in the study had unilateral or bilateral primary breast cancer confirmed by core biopsy, and had at least one additional risk factor, including age under 36, clinical tumor size more than 5 cm, estrogen receptor and progesterone receptor negativity, clinical axillary node involvement, or undifferentiated tumor grade.

The findings from the GeparTrio study demonstrate the advantage of neoadjuvant versus adjuvant chemotherapy. Response-guided treatment can only be conducted when the tumor is available for the monitoring of response, the investigators noted.

This study was supported by Amgen, Chugai, Roche, and Sanofi-Aventis. Dr. von Minckwitz and multiple coauthors reported serving as a consultant or advisor for, owning stock in, and/or receiving honoraria or research funding from Amgen, Roche, Sanofi-Aventis, and other companies.

Low-dose computed tomography reduces lung cancer mortality and all-cause mortality when used as a screening tool in asymptomatic adults at high risk for the disease, according to the results of a systematic review conducted for the U.S. Preventive Services Task Force.

In 2004, the USPSTF deemed the evidence insufficient for recommending for or against low-dose computed tomography (LDCT) for lung cancer screening in asymptomatic individuals, but the current review suggests screening has a definite benefit for most patients, Dr. Linda L. Humphrey, of Oregon Health and Science University and the Portland Veterans Affairs Medical Center, and her colleagues reported.

A draft recommendation based on the findings, published online in the Annals of Internal Medicine (2013 July 29 [doi: 10.7326/0003-4819-159-6-201309170-00690]), is available on the USPSTF website for comment.

©kutay tanir/iStockphoto.com

The researchers reviewed the literature published between 2000 and May 2013 and identified four trials that reported findings on the efficacy of LDCT screening in patients with smoking exposure for both intervention and control groups. Three small trials showed varying degrees of benefit with screening, but were underpowered; one large trial – the National Lung Screening Trial (NLST) – showed a significant 20% reduction in lung cancer mortality among those screened, as well as a 6.7% reduction in all-cause mortality.

The randomized multicenter NLST compared annual LDCT scans with annual single-view posterior-anterior chest radiographs for 3 years in more than 53,000 current or former smokers aged 55-74 years with at least a 30–pack-year history of smoking (N. Engl. J. Med. 2013;368:1980-91). One cancer death was prevented for every 320 patients who completed one screening, and one death from any cause was prevented for every 219 patients screened in that study; the trial was stopped early after 6.5 years of follow-up based on the findings.

The benefits of LDCT for lung cancer screening in this population outweighed the risks, they noted.

Harms associated with LDCT, according to findings from 7 trials and 13 cohort studies that reported on such outcomes, included radiation exposure, overdiagnosis, and a high rate of false-positive findings that were resolved by further imaging in most cases. False negatives were reported in six studies, and the rates ranged from 0% to 20%, but none of the studies evaluated the harm of false reassurance, the investigators noted. Screening benefits must be weighed against these potential harms.

Lung cancer is the leading cause of cancer-related deaths, accounting for nearly 27%. Furthermore, about 85% of U.S. lung cancer cases are attributable to smoking, and since about 20% of Americans currently smoke – and many more are former smokers who remain at increased risk because of their smoking history – "lung cancer will remain a major public health problem in this country for decades," the investigators wrote.

The studies included in this review were conducted in patients at high risk for lung cancer based on current or former smoking. However, patients at an increased risk for lung cancer, including older adults and those with a family history of lung cancer, chronic obstructive pulmonary disease, pulmonary fibrosis, and certain environmental and occupational exposures, may also benefit from LDCT screening.

"Future research to identify methods for focusing LDCT screening on persons at highest risk for disease, to improve discrimination between benign and malignant pulmonary nodules, and to find early indicators of aggressive disease is warranted," the investigators noted.

"If LDCT screening becomes routine, the risk for harms should be measured and methods to limit them identified."

The review was funded by grants from the Agency for Healthcare Research and Quality and the Portland Veterans Affairs Medical Center.

Low-dose computed tomography reduces lung cancer mortality and all-cause mortality when used as a screening tool in asymptomatic adults at high risk for the disease, according to the results of a systematic review conducted for the U.S. Preventive Services Task Force.

In 2004, the USPSTF deemed the evidence insufficient for recommending for or against low-dose computed tomography (LDCT) for lung cancer screening in asymptomatic individuals, but the current review suggests screening has a definite benefit for most patients, Dr. Linda L. Humphrey, of Oregon Health and Science University and the Portland Veterans Affairs Medical Center, and her colleagues reported.

A draft recommendation based on the findings, published online in the Annals of Internal Medicine (2013 July 29 [doi: 10.7326/0003-4819-159-6-201309170-00690]), is available on the USPSTF website for comment.

©kutay tanir/iStockphoto.com

The researchers reviewed the literature published between 2000 and May 2013 and identified four trials that reported findings on the efficacy of LDCT screening in patients with smoking exposure for both intervention and control groups. Three small trials showed varying degrees of benefit with screening, but were underpowered; one large trial – the National Lung Screening Trial (NLST) – showed a significant 20% reduction in lung cancer mortality among those screened, as well as a 6.7% reduction in all-cause mortality.

The randomized multicenter NLST compared annual LDCT scans with annual single-view posterior-anterior chest radiographs for 3 years in more than 53,000 current or former smokers aged 55-74 years with at least a 30–pack-year history of smoking (N. Engl. J. Med. 2013;368:1980-91). One cancer death was prevented for every 320 patients who completed one screening, and one death from any cause was prevented for every 219 patients screened in that study; the trial was stopped early after 6.5 years of follow-up based on the findings.

The benefits of LDCT for lung cancer screening in this population outweighed the risks, they noted.

Harms associated with LDCT, according to findings from 7 trials and 13 cohort studies that reported on such outcomes, included radiation exposure, overdiagnosis, and a high rate of false-positive findings that were resolved by further imaging in most cases. False negatives were reported in six studies, and the rates ranged from 0% to 20%, but none of the studies evaluated the harm of false reassurance, the investigators noted. Screening benefits must be weighed against these potential harms.

Lung cancer is the leading cause of cancer-related deaths, accounting for nearly 27%. Furthermore, about 85% of U.S. lung cancer cases are attributable to smoking, and since about 20% of Americans currently smoke – and many more are former smokers who remain at increased risk because of their smoking history – "lung cancer will remain a major public health problem in this country for decades," the investigators wrote.

The studies included in this review were conducted in patients at high risk for lung cancer based on current or former smoking. However, patients at an increased risk for lung cancer, including older adults and those with a family history of lung cancer, chronic obstructive pulmonary disease, pulmonary fibrosis, and certain environmental and occupational exposures, may also benefit from LDCT screening.

"Future research to identify methods for focusing LDCT screening on persons at highest risk for disease, to improve discrimination between benign and malignant pulmonary nodules, and to find early indicators of aggressive disease is warranted," the investigators noted.

"If LDCT screening becomes routine, the risk for harms should be measured and methods to limit them identified."

The review was funded by grants from the Agency for Healthcare Research and Quality and the Portland Veterans Affairs Medical Center.

Low-dose computed tomography reduces lung cancer mortality and all-cause mortality when used as a screening tool in asymptomatic adults at high risk for the disease, according to the results of a systematic review conducted for the U.S. Preventive Services Task Force.

In 2004, the USPSTF deemed the evidence insufficient for recommending for or against low-dose computed tomography (LDCT) for lung cancer screening in asymptomatic individuals, but the current review suggests screening has a definite benefit for most patients, Dr. Linda L. Humphrey, of Oregon Health and Science University and the Portland Veterans Affairs Medical Center, and her colleagues reported.

A draft recommendation based on the findings, published online in the Annals of Internal Medicine (2013 July 29 [doi: 10.7326/0003-4819-159-6-201309170-00690]), is available on the USPSTF website for comment.

©kutay tanir/iStockphoto.com

The researchers reviewed the literature published between 2000 and May 2013 and identified four trials that reported findings on the efficacy of LDCT screening in patients with smoking exposure for both intervention and control groups. Three small trials showed varying degrees of benefit with screening, but were underpowered; one large trial – the National Lung Screening Trial (NLST) – showed a significant 20% reduction in lung cancer mortality among those screened, as well as a 6.7% reduction in all-cause mortality.

The randomized multicenter NLST compared annual LDCT scans with annual single-view posterior-anterior chest radiographs for 3 years in more than 53,000 current or former smokers aged 55-74 years with at least a 30–pack-year history of smoking (N. Engl. J. Med. 2013;368:1980-91). One cancer death was prevented for every 320 patients who completed one screening, and one death from any cause was prevented for every 219 patients screened in that study; the trial was stopped early after 6.5 years of follow-up based on the findings.

The benefits of LDCT for lung cancer screening in this population outweighed the risks, they noted.

Harms associated with LDCT, according to findings from 7 trials and 13 cohort studies that reported on such outcomes, included radiation exposure, overdiagnosis, and a high rate of false-positive findings that were resolved by further imaging in most cases. False negatives were reported in six studies, and the rates ranged from 0% to 20%, but none of the studies evaluated the harm of false reassurance, the investigators noted. Screening benefits must be weighed against these potential harms.

Lung cancer is the leading cause of cancer-related deaths, accounting for nearly 27%. Furthermore, about 85% of U.S. lung cancer cases are attributable to smoking, and since about 20% of Americans currently smoke – and many more are former smokers who remain at increased risk because of their smoking history – "lung cancer will remain a major public health problem in this country for decades," the investigators wrote.

The studies included in this review were conducted in patients at high risk for lung cancer based on current or former smoking. However, patients at an increased risk for lung cancer, including older adults and those with a family history of lung cancer, chronic obstructive pulmonary disease, pulmonary fibrosis, and certain environmental and occupational exposures, may also benefit from LDCT screening.

"Future research to identify methods for focusing LDCT screening on persons at highest risk for disease, to improve discrimination between benign and malignant pulmonary nodules, and to find early indicators of aggressive disease is warranted," the investigators noted.

"If LDCT screening becomes routine, the risk for harms should be measured and methods to limit them identified."

The review was funded by grants from the Agency for Healthcare Research and Quality and the Portland Veterans Affairs Medical Center.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.