From Medscape Medical News
Caroline Cassels
March 25, 2010 — An interactive, Internet-based cognitive screening tool is superior to standard tests used to detect cognitive impairment and may provide clinicians with a simple, accurate, early screening tool that can be used in the primary care setting, new research suggests.
Developed by investigators at the University of Tennessee Medical Center, Knoxville, the computer self test (CST) was substantially more accurate than the Mini Mental Status Examination (MMSE) and the Mini-Cog in classifying cognitively impaired individuals vs control participants, with an accuracy rate of 96% vs 71% and 69%, respectively.
"Not only [was the CST] able to distinguish people who did and did not have cognitive impairment, but it was able to distinguish between the various stages of [Alzheimer's disease (AD)] with superior accuracy," study investigator Rex L. Cannon, PhD, CPA, BCN, told Medscape Psychiatry.
Led by John H. Dougherty, MD, the study was published online March 11 and will appear in the April issue of the Journal of Alzheimer's Disease.
Most AD Patients Not Diagnosed by General Practitioners
The investigators note that up to 60% of patients with AD are not diagnosed in the primary care setting — a situation that suggests there are a significant number of missed opportunities to slow disease progression with early intervention, using agents approved by the US Food and Drug Administration for mild AD including donepezil (Aricept, Eisai Co, Ltd), galantamine (Razadyne, Ortho-McNeil Neurologics), and rivastigmine (Exelon, Novartis).
Tacrine (Cognex), the first approved cholinesterase inhibitor for mild AD, is another treatment option but is rarely prescribed because of possible hepatotoxic effects.
"By the time patients reach a specialist clinic where the majority of cognitive testing is done, their overall cognitive function has dropped significantly. It is our hope that the development of a simple, accurate, user-friendly test that can be administered relatively quickly in the primary care setting will facilitate earlier diagnosis of cognitive impairment so that we can direct treatment more efficiently," said Dr. Cannon.
The CST, he added, assesses 6 cognitive domains including memory, verbal fluency, orientation, visuospatial organization, executive function, and attention, as well as processing speed, in approximately 15 minutes and is designed to detect early deficits in 1 or more specific cognitive domains.
The investigators hypothesized that CST would accurately identify patients who were cognitively normal or who had mild cognitive impairment, early AD, mild to moderate AD, moderate to severe AD, or severe AD.
Extending Quality of Life
The study included 215 participants with a mean age of 75.24 years. Of these individuals, 84 had a diagnosis of AD and 27 had mild cognitive impairment. The remainder of the study participants were cognitively intact age-matched controls.
The CST was administered to all participants before routine neurocognitive testing in a memory disorders clinic. Using laptop computers, participants completed the test. If subjects had little or no computer experience, a caregiver or technician could help administer the test by assisting with manipulation of the mouse or arrows or facilitating typing and entering subjects' responses.
Study participants then underwent traditional neurocognitive testing including the MMSE and Mini-Cog.
Using discriminant analysis, the investigators compared the accuracy of the CST, MMSE, and Mini-Cog in classifying cognitively impaired and control groups and in distinguishing between the different types of cognitive impairment.
The results showed that the CST correctly classified 91% of the 6 potential diagnostic groups and 96% of cognitively impaired individuals and control participants.
In comparison, the authors report, the MMSE correctly classified 54% of the 6 groups and 71% of cognitively impaired subjects and control participants. Similarly, the Mini-Cog correctly classified 48% of the 6 groups and 69% of cognitively impaired patients and control participants.
"We need further validation of these results, but we are open to using the CST in all areas, in the primary care as well as the specialist settings. This test...offers promise in a novel direction for testing, and we just need to optimize the primary care setting, particularly for the geriatric population, so that we can flag people with early [AD] or [mild cognitive impairment] and try to extend their quality of life," said Dr. Cannon.
Clinicians interested in the CST for clinical or research purposes can contact the investigators by visiting www.medinteract.com
Dr. Cannon reports he has received consulting or advisory board fees from Medical Interactive Education. Dr. Dougherty has received lecture fees from, and is a member of, the Speakers Bureau for Eisai, Forest, Novartis, and Pfizer. He also reports he has equity ownership/stock options in Medical Interactive Education.
J Alzheimers Dis. Published online March 11, 2010.
Friday, March 26, 2010
Infertility and Prostate Cancer May Have Common Cause
From Medscape Medical News
Janis C. Kelly
March 25, 2010 — Infertile men could be at increased risk of developing high-grade prostate cancer, but more work is needed before recommending early screening, according to a new study published online March 22 in Cancer.
"I think the key point is that this study clearly has generated more questions than it has answered," lead author Thomas J. Walsh, MD, from the University of Washington in Seattle, told Medscape Oncology. "We need to keep in mind that one of the greatest concerns with prostate cancer is overdiagnosis and overtreatment of low-grade indolent cancer. Our goal should be to identify the most aggressive cancer in the youngest men — and to that end, our findings may prove insightful."
First Study of Men With Proven Infertility
Previous studies using the number of offspring sired as a surrogate marker for male fertility have produced conflicting results related to this association. Dr. Walsh and colleagues examined prostate cancer rates in men with proven male-factor infertility.
The study examined data from 22,562 men evaluated for infertility from 1967 to 1998 in 15 California infertility centers. The incidence of prostate cancer in these men was compared with that in a sample of men in the general population who were of similar ages and from similar geographic locations.
The researchers identified 168 cases of prostate cancer in the men who had been evaluated for infertility, a rate not significantly different from that expected in the general population (185 cases).
Two-Fold Higher Risk
However, men who had been evaluated and found to be infertile were 2.6 times more likely to be diagnosed with high-grade prostate cancer than men who had been evaluated but were found not to be infertile.
According to Dr. Walsh, "this suggests that we may want to search for common etiologies that underlie both male-factor infertility and prostate cancer."
Dr. Walsh suggested that the most clarity will come from studies that identify risk factors for male infertility. "Subjects assembled for such a study could then be followed longitudinally, with standardized prostate cancer screening, to determine whether or not they develop prostate cancer," he said.
"We were surprised to find significant risk only for high-grade cancers," Dr. Walsh added. "This fact alone raises many questions. . . . What are the etiologies that may lead some men to have poor sperm production early in life and high-grade cancer later in life? Could this association be translated into a tool to identify men who are at greatest risk for dangerous cancer?"
Questions About Ethnic Composition of Study Population
Aleksander Giwercman, MD, professor of andrology at Malmö University Hospital's Scanian Andrology Center in Sweden, was asked by Medscape Oncology to comment on this study. "I think that the study has some limitations," he said "First of all, the use of a white population as the control group is questionable for me. The risk of prostate cancer is highly race-dependent, and it is also likely that testicular function — and therefore semen quality — may differ between races. Therefore, not strictly controlling for race in matching the cases and the controls may introduce a serious bias that, theoretically, could affect the risk-ratio estimates in both directions."
Dr. Giwercman also pointed out that the researchers had complete data on less than 50% of all subjects. "This could also be a source of serious bias, as cancer data were, apparently, not available for half of the men," he said. Dr. Giwercman reported in an earlier study a reduced risk for prostate cancer in men who are childless (Int J Cancer. 2005;115:994-997).
"From a biological point of view, it is not easy to understand why men with infertility problems should have a higher risk of prostate cancer/high-grade disease. The authors propose a mechanism related to the ability to repair DNA, but this needs to be explored further," Dr. Giwercman said. "I think that we need further studies elucidating the risk of prostate cancer in men with testicular dysfunction. It seems plausible that testicular failure leads to a lower risk of prostate cancer — a disease considered to be androgen-dependent. However, it needs to be confirmed — or [refuted] — if the results presented by Walsh et al hold in additional studies."
Is Undiagnosed Prostate Cancer Causing Infertility?
Kristian Tore Jørgensen, MSc, from the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, Denmark, was also asked to comment on the study. Mr. Jørgensen has studied fatherhood status and prostate cancer risk (Cancer. 2008;112:919-923).
"The authors suggest that gene defects on the Y chromosome or faulty DNA repair might be at play in the association between male-factor infertility and high-grade prostate cancer risk," he said. "However, there are a number of important factors that have to be considered as perhaps more likely explanations for the findings in this study. Prostate cancer development normally takes decades to cause clinical symptoms, so some cases of male-factor infertility might actually have been caused by an undiagnosed prostate cancer interfering with normal prostate gland function, a situation of reverse causality."
"Even though the authors excluded men diagnosed with prostate cancer in the year after infertility evaluation, a possible biological explanation for the study findings could be that the association between male-factor infertility and high-grade prostate cancer is related to impaired prostate function in men with yet undiagnosed prostate cancer," he added.
Mr. Jørgensen is also concerned about the racial composition of the cohort. "It was assumed that men in the cohort were predominantly white, even though ethnic data were not available. The rate of prostate cancer in the cohort was therefore compared with the rate in whites in California. The incidence of prostate cancer among black men is approximately 60% higher than it is in white men. So this simplification might have led to an overestimation of the risk of prostate cancer in the group of male-factor infertile men."
Mr. Jørgensen echoed Dr. Walsh's caution about rushing to early screening, pointing out that the observed 2-fold risk for prostate cancer was based on only 19 cases of high-grade prostate cancer in male-factor infertile men.
The study was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the California Urology Foundation. Dr. Walsh has disclosed no relevant financial relationships.
Cancer. Published online March 22, 2010. Abstract
Janis C. Kelly
March 25, 2010 — Infertile men could be at increased risk of developing high-grade prostate cancer, but more work is needed before recommending early screening, according to a new study published online March 22 in Cancer.
"I think the key point is that this study clearly has generated more questions than it has answered," lead author Thomas J. Walsh, MD, from the University of Washington in Seattle, told Medscape Oncology. "We need to keep in mind that one of the greatest concerns with prostate cancer is overdiagnosis and overtreatment of low-grade indolent cancer. Our goal should be to identify the most aggressive cancer in the youngest men — and to that end, our findings may prove insightful."
First Study of Men With Proven Infertility
Previous studies using the number of offspring sired as a surrogate marker for male fertility have produced conflicting results related to this association. Dr. Walsh and colleagues examined prostate cancer rates in men with proven male-factor infertility.
The study examined data from 22,562 men evaluated for infertility from 1967 to 1998 in 15 California infertility centers. The incidence of prostate cancer in these men was compared with that in a sample of men in the general population who were of similar ages and from similar geographic locations.
The researchers identified 168 cases of prostate cancer in the men who had been evaluated for infertility, a rate not significantly different from that expected in the general population (185 cases).
Two-Fold Higher Risk
However, men who had been evaluated and found to be infertile were 2.6 times more likely to be diagnosed with high-grade prostate cancer than men who had been evaluated but were found not to be infertile.
According to Dr. Walsh, "this suggests that we may want to search for common etiologies that underlie both male-factor infertility and prostate cancer."
Dr. Walsh suggested that the most clarity will come from studies that identify risk factors for male infertility. "Subjects assembled for such a study could then be followed longitudinally, with standardized prostate cancer screening, to determine whether or not they develop prostate cancer," he said.
"We were surprised to find significant risk only for high-grade cancers," Dr. Walsh added. "This fact alone raises many questions. . . . What are the etiologies that may lead some men to have poor sperm production early in life and high-grade cancer later in life? Could this association be translated into a tool to identify men who are at greatest risk for dangerous cancer?"
Questions About Ethnic Composition of Study Population
Aleksander Giwercman, MD, professor of andrology at Malmö University Hospital's Scanian Andrology Center in Sweden, was asked by Medscape Oncology to comment on this study. "I think that the study has some limitations," he said "First of all, the use of a white population as the control group is questionable for me. The risk of prostate cancer is highly race-dependent, and it is also likely that testicular function — and therefore semen quality — may differ between races. Therefore, not strictly controlling for race in matching the cases and the controls may introduce a serious bias that, theoretically, could affect the risk-ratio estimates in both directions."
Dr. Giwercman also pointed out that the researchers had complete data on less than 50% of all subjects. "This could also be a source of serious bias, as cancer data were, apparently, not available for half of the men," he said. Dr. Giwercman reported in an earlier study a reduced risk for prostate cancer in men who are childless (Int J Cancer. 2005;115:994-997).
"From a biological point of view, it is not easy to understand why men with infertility problems should have a higher risk of prostate cancer/high-grade disease. The authors propose a mechanism related to the ability to repair DNA, but this needs to be explored further," Dr. Giwercman said. "I think that we need further studies elucidating the risk of prostate cancer in men with testicular dysfunction. It seems plausible that testicular failure leads to a lower risk of prostate cancer — a disease considered to be androgen-dependent. However, it needs to be confirmed — or [refuted] — if the results presented by Walsh et al hold in additional studies."
Is Undiagnosed Prostate Cancer Causing Infertility?
Kristian Tore Jørgensen, MSc, from the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, Denmark, was also asked to comment on the study. Mr. Jørgensen has studied fatherhood status and prostate cancer risk (Cancer. 2008;112:919-923).
"The authors suggest that gene defects on the Y chromosome or faulty DNA repair might be at play in the association between male-factor infertility and high-grade prostate cancer risk," he said. "However, there are a number of important factors that have to be considered as perhaps more likely explanations for the findings in this study. Prostate cancer development normally takes decades to cause clinical symptoms, so some cases of male-factor infertility might actually have been caused by an undiagnosed prostate cancer interfering with normal prostate gland function, a situation of reverse causality."
"Even though the authors excluded men diagnosed with prostate cancer in the year after infertility evaluation, a possible biological explanation for the study findings could be that the association between male-factor infertility and high-grade prostate cancer is related to impaired prostate function in men with yet undiagnosed prostate cancer," he added.
Mr. Jørgensen is also concerned about the racial composition of the cohort. "It was assumed that men in the cohort were predominantly white, even though ethnic data were not available. The rate of prostate cancer in the cohort was therefore compared with the rate in whites in California. The incidence of prostate cancer among black men is approximately 60% higher than it is in white men. So this simplification might have led to an overestimation of the risk of prostate cancer in the group of male-factor infertile men."
Mr. Jørgensen echoed Dr. Walsh's caution about rushing to early screening, pointing out that the observed 2-fold risk for prostate cancer was based on only 19 cases of high-grade prostate cancer in male-factor infertile men.
The study was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the California Urology Foundation. Dr. Walsh has disclosed no relevant financial relationships.
Cancer. Published online March 22, 2010. Abstract
Thursday, March 25, 2010
New Drug Eases Menstrual Cramps
From WebMD Health News
Jennifer Warner
March 25, 2010 — An experimental new drug may ease menstrual cramps by targeting the cause rather than the symptom of the pain.
Researchers say the drug, now in phase II clinical trials in the U.K. and U.S., works by blocking the hormone vasopressin, which is involved in contractions of the uterus. Increased levels of this hormone are believed to cause the pain associated with menstrual cramps.
Menstrual cramps, known in medical terms as dysmenorrhea, affect more than 50% of women of childbearing age. They occur when the smooth muscles of the uterus contract with increasing frequency. The most common symptoms are abdominal and back pain, but dysmenorrhea may also cause nausea, vomiting, sweating, and dizziness.
Treatments for dysmenorrhea include pain relievers, anti-inflammatory drugs, and contraceptives that stop menstruation. But researchers say these only relieve the symptoms of the condition rather than the underlying cause and may have unwanted side effects.
"We hope that the drug will provide a more effective treatment option for millions of women worldwide with this painful condition," researcher Andrzej R. Batt of Vantia Ltd., the U.K.-based pharmaceutical company that is developing and testing the drug, says in a news release. "Dysmenorrhea not only diminishes the quality of life for millions of women, but also has a hidden, society-wide economic cost that involves an enormous number of days lost from work and school."
Batt presented new information about the molecular structure of the drug, known as VA111913, today at the annual meeting of the American Chemical Society in San Francisco.
Last year, the drug passed the first stage of clinical trials by showing it was safe for further research in humans. The drug has been modified to allow it to be taken as a pill rather than as an injection.
Phase II clinical trials are under way at sites in the U.K. and the U.S., which are evaluating the drug’s effectiveness in women with dysmenorrhea.
Results of the phase II clinical trials are expected to be released later this year. If those results confirm the initial findings and phase III clinical trial findings are positive, the drug could be FDA approved and available for use in about four years.
SOURCES:
American Chemical Society 239th National Meeting, San Francisco, March 21-25, 2010.
News release, American Chemical Society.
Jennifer Warner
March 25, 2010 — An experimental new drug may ease menstrual cramps by targeting the cause rather than the symptom of the pain.
Researchers say the drug, now in phase II clinical trials in the U.K. and U.S., works by blocking the hormone vasopressin, which is involved in contractions of the uterus. Increased levels of this hormone are believed to cause the pain associated with menstrual cramps.
Menstrual cramps, known in medical terms as dysmenorrhea, affect more than 50% of women of childbearing age. They occur when the smooth muscles of the uterus contract with increasing frequency. The most common symptoms are abdominal and back pain, but dysmenorrhea may also cause nausea, vomiting, sweating, and dizziness.
Treatments for dysmenorrhea include pain relievers, anti-inflammatory drugs, and contraceptives that stop menstruation. But researchers say these only relieve the symptoms of the condition rather than the underlying cause and may have unwanted side effects.
"We hope that the drug will provide a more effective treatment option for millions of women worldwide with this painful condition," researcher Andrzej R. Batt of Vantia Ltd., the U.K.-based pharmaceutical company that is developing and testing the drug, says in a news release. "Dysmenorrhea not only diminishes the quality of life for millions of women, but also has a hidden, society-wide economic cost that involves an enormous number of days lost from work and school."
Batt presented new information about the molecular structure of the drug, known as VA111913, today at the annual meeting of the American Chemical Society in San Francisco.
Last year, the drug passed the first stage of clinical trials by showing it was safe for further research in humans. The drug has been modified to allow it to be taken as a pill rather than as an injection.
Phase II clinical trials are under way at sites in the U.K. and the U.S., which are evaluating the drug’s effectiveness in women with dysmenorrhea.
Results of the phase II clinical trials are expected to be released later this year. If those results confirm the initial findings and phase III clinical trial findings are positive, the drug could be FDA approved and available for use in about four years.
SOURCES:
American Chemical Society 239th National Meeting, San Francisco, March 21-25, 2010.
News release, American Chemical Society.
Tuesday, March 23, 2010
Prostate Cancer Screening Guideline Updated by ACS
From MedscapeCME Clinical Briefs
News Author: Nick Mulcahy
CME Author: Penny Murata, MD
03/09/2010
The most commonly diagnosed cancer in men in the United States and the second leading cause of cancer death in men is prostate cancer, as reported by Jemal and colleagues in the July-August 2009 issue of CA: A Cancer Journal for Clinicians.
However, the benefits and harms of early detection of prostate cancer are not clear. The European Randomized Study of Screening for Prostate Cancer, described by Schroder and colleagues in the March 26, 2009, issue of the New England Journal of Medicine, found that men randomly assigned to screening had a 20% reduction in prostate cancer-specific mortality rates. However, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial in the United States, described by Andriole and colleagues in the March 26, 2009, issue of the New England Journal of Medicine, reported no reduction in mortality rates.
This ACS guideline for prostate cancer screening updates the previous 2001 guideline.
Study Highlights
The ACS Prostate Cancer Advisory Committee evaluated systematic reviews, and identified studies from 1950 to June 2009 by Medline search.
The guidelines were approved by the ACS Mission Outcomes Committee and the ACS Board of Directors.
The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer prospective randomized studies of screening had different efficacy results.
Asymptomatic men with at least a 10-year life expectancy should be offered informed decision making about prostate cancer screening.
Information provided should cover uncertainties, risks, and benefits of screening.
Information source should be the healthcare provider or a reliable and culturally appropriate source.
Community-based screening programs are not recommended unless adequate informed decision making and appropriate follow-up care are available.
Patient decision aids improve patients' knowledge, but there is no evidence about
For men who cannot decide, the healthcare provider should consider the patients' general health preferences and values.
The age to begin screening is linked to risk:
At age 50 years for average-risk men
At age 45 years for higher-risk men (African American ethnicity or first-degree relative with prostate cancer before age 65 years)
At age 40 years for appreciably higher-risk men (multiple family members diagnosed with prostate cancer before age 65 years)
Prostate cancer screening is not recommended in men with a life expectancy of less than 10 years based on age and health status because of low benefit relative to the
The recommendations for follow-up depend on PSA level.
If PSA level is less than 2.5 ng/mL, screening is recommended every 2 years; for levels of 2.5 ng/mL or higher, screening is recommended every year.
If PSA level is between 2.5 to 4.0 ng/mL, individualized decision making is recommended:
Biopsy is recommended for high-risk patients (African American, family history of prostate cancer, increasing age, and an abnormal DRE result).
Previous negative biopsy result confers lower risk.
The traditional PSA threshold level of 4.0 ng/mL is considered reasonable for biopsy, although a true cutoff level has not been determined.
Screening harms from phlebotomy and DRE are not significant.
Weak evidence exists of low anxiety linked with screening process and slightly greater anxiety linked with awaiting biopsy.
Stronger evidence exists that false-positive PSA results are linked with cancer worry and more subsequent tests and visits.
Estimated overdiagnosis rates range from 23% to 42% of screen-detected cancers.
Adverse effects of radical prostatectomy include bleeding, 30-day complication rates of approximately 22%, death in 0.1% to 0.2%, anastomotic stricture of the bladder and urethra in 5% to 14%, urinary incontinence in 12% to 16%, and sexual dysfunction in 19% to 27%.
Adverse effects of radiation therapy include acute toxicities in 50% and late toxicities (erectile dysfunction in up to 50%).
Adverse effects of hormonal therapy are reported briefly because hormonal treatment is chiefly for advanced disease.
The harms of watchful waiting or active surveillance are obstructive symptoms and subsequent biopsy, but the quality-of-life effect is not known.
PSA velocity should not be routinely included in screening.
DRE has an unclear role in screening but can be useful if PSA level is between 2.5 and 4.0 ng/mL.
Clinical Implications
Prostate cancer screening by PSA with or without DRE is recommended after informed decision making beginning at age 50 years for asymptomatic men at average risk with at least a 10-year life expectancy, beginning at age 45 years in African American men and in men with a first-degree relative diagnosed with prostate cancer younger than 65 years, and beginning at age 40 years in men with multiple first-degree relatives diagnosed with prostate cancer younger than 65 years.
In men who undergo prostate cancer screening with PSA levels less than 2.5 ng/mL, screening is recommended every 2 years. If PSA level is between 2.5 and 4.0 ng/mL, annual screening is recommended with possible biopsy in African American men and in men with a family history of prostate cancer, increasing age, or abnormal DRE result. If PSA level is 4.0 ng/mL or more, referral for evaluation or biopsy is recommended.
News Author: Nick Mulcahy
CME Author: Penny Murata, MD
03/09/2010
The most commonly diagnosed cancer in men in the United States and the second leading cause of cancer death in men is prostate cancer, as reported by Jemal and colleagues in the July-August 2009 issue of CA: A Cancer Journal for Clinicians.
However, the benefits and harms of early detection of prostate cancer are not clear. The European Randomized Study of Screening for Prostate Cancer, described by Schroder and colleagues in the March 26, 2009, issue of the New England Journal of Medicine, found that men randomly assigned to screening had a 20% reduction in prostate cancer-specific mortality rates. However, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial in the United States, described by Andriole and colleagues in the March 26, 2009, issue of the New England Journal of Medicine, reported no reduction in mortality rates.
This ACS guideline for prostate cancer screening updates the previous 2001 guideline.
Study Highlights
The ACS Prostate Cancer Advisory Committee evaluated systematic reviews, and identified studies from 1950 to June 2009 by Medline search.
The guidelines were approved by the ACS Mission Outcomes Committee and the ACS Board of Directors.
The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer prospective randomized studies of screening had different efficacy results.
Asymptomatic men with at least a 10-year life expectancy should be offered informed decision making about prostate cancer screening.
Information provided should cover uncertainties, risks, and benefits of screening.
Information source should be the healthcare provider or a reliable and culturally appropriate source.
Community-based screening programs are not recommended unless adequate informed decision making and appropriate follow-up care are available.
Patient decision aids improve patients' knowledge, but there is no evidence about
For men who cannot decide, the healthcare provider should consider the patients' general health preferences and values.
The age to begin screening is linked to risk:
At age 50 years for average-risk men
At age 45 years for higher-risk men (African American ethnicity or first-degree relative with prostate cancer before age 65 years)
At age 40 years for appreciably higher-risk men (multiple family members diagnosed with prostate cancer before age 65 years)
Prostate cancer screening is not recommended in men with a life expectancy of less than 10 years based on age and health status because of low benefit relative to the
The recommendations for follow-up depend on PSA level.
If PSA level is less than 2.5 ng/mL, screening is recommended every 2 years; for levels of 2.5 ng/mL or higher, screening is recommended every year.
If PSA level is between 2.5 to 4.0 ng/mL, individualized decision making is recommended:
Biopsy is recommended for high-risk patients (African American, family history of prostate cancer, increasing age, and an abnormal DRE result).
Previous negative biopsy result confers lower risk.
The traditional PSA threshold level of 4.0 ng/mL is considered reasonable for biopsy, although a true cutoff level has not been determined.
Screening harms from phlebotomy and DRE are not significant.
Weak evidence exists of low anxiety linked with screening process and slightly greater anxiety linked with awaiting biopsy.
Stronger evidence exists that false-positive PSA results are linked with cancer worry and more subsequent tests and visits.
Estimated overdiagnosis rates range from 23% to 42% of screen-detected cancers.
Adverse effects of radical prostatectomy include bleeding, 30-day complication rates of approximately 22%, death in 0.1% to 0.2%, anastomotic stricture of the bladder and urethra in 5% to 14%, urinary incontinence in 12% to 16%, and sexual dysfunction in 19% to 27%.
Adverse effects of radiation therapy include acute toxicities in 50% and late toxicities (erectile dysfunction in up to 50%).
Adverse effects of hormonal therapy are reported briefly because hormonal treatment is chiefly for advanced disease.
The harms of watchful waiting or active surveillance are obstructive symptoms and subsequent biopsy, but the quality-of-life effect is not known.
PSA velocity should not be routinely included in screening.
DRE has an unclear role in screening but can be useful if PSA level is between 2.5 and 4.0 ng/mL.
Clinical Implications
Prostate cancer screening by PSA with or without DRE is recommended after informed decision making beginning at age 50 years for asymptomatic men at average risk with at least a 10-year life expectancy, beginning at age 45 years in African American men and in men with a first-degree relative diagnosed with prostate cancer younger than 65 years, and beginning at age 40 years in men with multiple first-degree relatives diagnosed with prostate cancer younger than 65 years.
In men who undergo prostate cancer screening with PSA levels less than 2.5 ng/mL, screening is recommended every 2 years. If PSA level is between 2.5 and 4.0 ng/mL, annual screening is recommended with possible biopsy in African American men and in men with a family history of prostate cancer, increasing age, or abnormal DRE result. If PSA level is 4.0 ng/mL or more, referral for evaluation or biopsy is recommended.
Physical Exercise and Brain Health
Jun 26, 2008
By: Dr. Pascale Michelon
According to Harvard Psychiatry Professor John Ratey nothing beats exercise for promoting brain heath.
I am sure you have also heard that exercising your mind promotes brain health.
What is the connection between physical and mental exercises? Do they have additive effects on brain health? Are they redundant?
Let’s start by reviewing what we know about the effects of physical exercise on the brain.
The effect of physical exercise on cognitive performance
Early studies compared groups of people who exercised to groups of people who did not exercise much. Results showed that people who exercised usually had better performance in a range of cognitive tasks compared to non-exercisers.
Laurin and colleagues (2001) even suggested that moderate and high levels of physical activity were associated with lower risk for Alzheimer’s disease and other dementias.
The problem with these studies is that the exercisers and the non-exercisers may differ on other factors than just exercise. The advantage that exerciser show may not come from exercising but from other factors such as more resources, better brain health to start with, better diet, etc.
The solution to this problem is to randomly assigned people to either an aerobic training group or a control group. If the exerciser group and the non-exerciser group are very similar to start with and if the exerciser group shows less decline or better performance over time than the non-exerciser group, then one can conclude that physical exercise is beneficial for brain health.
In 2003, Colcombe and Kramer, analyzed the results of 18 scientific studies published between 2000 and 2001 that were conducted in the way described above.
The results of this meta-analysis clearly showed that fitness training increases cognitive performance in healthy adults between the ages of 55 and 80.
Another meta-analysis published in 2004 by Heyn and colleagues shows similar beneficial effects of fitness training on people over 65 years old who had cognitive impairment or dementia.
What is the effect of fitness training on the brain itself?
Research with animals has shown that in mice, increased aerobic fitness (running) can increase the number of new cells formed in the hippocampus (the hippocampus is crucial for learning and memory). Increased exercise also has a beneficial effect on mice’s vascular system.
Only one study has used brain imaging to look at the effect of fitness on the human brain. In 2006, Colcombe and colleagues randomly assigned 59 older adults to either a cardiovascular exercise group, or a nonaerobic exercise control group (stretching and toning exercise). Participants exercised 3h per week for 6 months. Colcombe et al. scanned the participants’ brains before and after the training period.
After 6 months, the brain volume of the aerobic exercising group increased in several areas compared to the other group. Volume increase occurred principally in frontal and temporal areas of the brain involved in executive control and memory processes. The authors do not know what underlying cellular changes might have caused these volume changes. However they suspect, based on animal research, that volume changes may be due to an increased number of blood vessels and an increased number of connections between neurons.
How does physical exercise compare to mental exercise?
Very few studies have tried to compare the effect of physical exercise and mental exercise on cognitive performance.
When looking at each domain of research one notices the following differences:
- The effects of cognitive or mental exercise on performance seem to be very task specific, that is trained tasks benefit from training but the benefits do not transfer very well to tasks in which one was not trained.
- The effects of physical exercise on performance seem broader. However they do not generalize to all tasks. They benefit mostly tasks that involve executive-control components (that is, tasks that require planning, working memory, multitasking, resistance to distraction).
To my knowledge only one study tried to directly compare cognitive and fitness training:
Fabre and colleagues, in 1999, randomly assigned subjects to 4 groups: an aerobic training group (walking or running for 2 h per week for 2 months), a memory training group (one 90 min session a week for 2 months), a combined aerobic and mental training group, or a control group (no training).
Results showed that compared to the control group, the memory performance of all 3 groups increased. The combined group showed greater increase than the other 2 training groups.
This suggests that the effects of cognitive and fitness training may be additive… However this study involved only 8 participants per group! More research is clearly needed before anything can be safely concluded.
In the meantime let’s play it safe and combine fitness and cognitive training for better brain health…!
By: Dr. Pascale Michelon
According to Harvard Psychiatry Professor John Ratey nothing beats exercise for promoting brain heath.
I am sure you have also heard that exercising your mind promotes brain health.
What is the connection between physical and mental exercises? Do they have additive effects on brain health? Are they redundant?
Let’s start by reviewing what we know about the effects of physical exercise on the brain.
The effect of physical exercise on cognitive performance
Early studies compared groups of people who exercised to groups of people who did not exercise much. Results showed that people who exercised usually had better performance in a range of cognitive tasks compared to non-exercisers.
Laurin and colleagues (2001) even suggested that moderate and high levels of physical activity were associated with lower risk for Alzheimer’s disease and other dementias.
The problem with these studies is that the exercisers and the non-exercisers may differ on other factors than just exercise. The advantage that exerciser show may not come from exercising but from other factors such as more resources, better brain health to start with, better diet, etc.
The solution to this problem is to randomly assigned people to either an aerobic training group or a control group. If the exerciser group and the non-exerciser group are very similar to start with and if the exerciser group shows less decline or better performance over time than the non-exerciser group, then one can conclude that physical exercise is beneficial for brain health.
In 2003, Colcombe and Kramer, analyzed the results of 18 scientific studies published between 2000 and 2001 that were conducted in the way described above.
The results of this meta-analysis clearly showed that fitness training increases cognitive performance in healthy adults between the ages of 55 and 80.
Another meta-analysis published in 2004 by Heyn and colleagues shows similar beneficial effects of fitness training on people over 65 years old who had cognitive impairment or dementia.
What is the effect of fitness training on the brain itself?
Research with animals has shown that in mice, increased aerobic fitness (running) can increase the number of new cells formed in the hippocampus (the hippocampus is crucial for learning and memory). Increased exercise also has a beneficial effect on mice’s vascular system.
Only one study has used brain imaging to look at the effect of fitness on the human brain. In 2006, Colcombe and colleagues randomly assigned 59 older adults to either a cardiovascular exercise group, or a nonaerobic exercise control group (stretching and toning exercise). Participants exercised 3h per week for 6 months. Colcombe et al. scanned the participants’ brains before and after the training period.
After 6 months, the brain volume of the aerobic exercising group increased in several areas compared to the other group. Volume increase occurred principally in frontal and temporal areas of the brain involved in executive control and memory processes. The authors do not know what underlying cellular changes might have caused these volume changes. However they suspect, based on animal research, that volume changes may be due to an increased number of blood vessels and an increased number of connections between neurons.
How does physical exercise compare to mental exercise?
Very few studies have tried to compare the effect of physical exercise and mental exercise on cognitive performance.
When looking at each domain of research one notices the following differences:
- The effects of cognitive or mental exercise on performance seem to be very task specific, that is trained tasks benefit from training but the benefits do not transfer very well to tasks in which one was not trained.
- The effects of physical exercise on performance seem broader. However they do not generalize to all tasks. They benefit mostly tasks that involve executive-control components (that is, tasks that require planning, working memory, multitasking, resistance to distraction).
To my knowledge only one study tried to directly compare cognitive and fitness training:
Fabre and colleagues, in 1999, randomly assigned subjects to 4 groups: an aerobic training group (walking or running for 2 h per week for 2 months), a memory training group (one 90 min session a week for 2 months), a combined aerobic and mental training group, or a control group (no training).
Results showed that compared to the control group, the memory performance of all 3 groups increased. The combined group showed greater increase than the other 2 training groups.
This suggests that the effects of cognitive and fitness training may be additive… However this study involved only 8 participants per group! More research is clearly needed before anything can be safely concluded.
In the meantime let’s play it safe and combine fitness and cognitive training for better brain health…!
Friday, March 19, 2010
Recommended Adult Immunization Schedule — United States, 2010
From Morbidity & Mortality Weekly Report
Department of Health and Human Services; Centers for Disease Control and Prevention
Posted: 03/09/2010; Morbidity & Mortality Weekly Report. 2010;59(1):1-4. © 2010 Centers for Disease Control and Prevention (CDC)
Introduction
The Advisory Committee on Immunization Practices (ACIP) annually reviews the recommended Adult Immunization Schedule to ensure that the schedule reflects current recommendations for the licensed vaccines.
In October 2009, ACIP approved the Adult Immunization Schedule for 2010, which includes several changes.
A bivalent human papillomavirus vaccine (HPV2) was licensed for use in females in October 2009. ACIP recommends vaccination of females with either HPV2 or the quadrivalent human papillomavirus vaccine (HPV4).
HPV4 was licensed for use in males in October 2009, and ACIP issued a permissive recommendation for use in males.
Introductory sentences were added to the footnotes for measles, mumps, rubella, influenza, pneumococcal, hepatitis A, hepatitis B, and meningococcal vaccines. Clarifications were made to the footnotes for measles, mumps, rubella, influenza, hepatitis A, meningococcal, and Haemophilus influenza type b vaccines, and schedule information was added to the hepatitis B vaccine footnote.
The human papillomavirus (HPV) footnote (#2) includes language that a bivalent HPV vaccine (HPV2) has been licensed for use in females. Either HPV2 or the quadrivalent human papillomavirus vaccine (HPV4) can be used for vaccination of females aged 19 through 26 years. In addition, language has been added to indicate that ACIP issued a permissive recommendation for use of HPV4 in males.
The measles, mumps, rubella (MMR) footnote (#5) has language added to clarify which adults born during or after 1957 do not need 1 or more doses of MMR vaccine for the measles and mumps components, and clarifies which women should receive a dose of MMR vaccine. Also, interval dosing information has been added to indicate when a second dose of MMR vaccine should be administered. Language has been added to highlight recommendations for vaccinating health-care personnel born before 1957 routinely and during outbreaks.
The term "seasonal" has been added to the influenza footnote (#6).
The hepatitis A footnote (#9) has language added to indicate that unvaccinated persons who anticipate close contact with an international adoptee should consider vaccination.
The hepatitis B footnote (#10) has language added to include schedule information for the 3-dose hepatitis B vaccine.
The meningococcal vaccine footnote (#11) clarifies which vaccine formulations are preferred for adults aged ≤55 years and ≥56 years, and which vaccine formulation can be used for revaccination. New examples have been added to demonstrate who should and should not be considered for revaccination.
The selected conditions for Haemophilus influenza type b (Hib) footnote (#13) clarifies which high-risk persons may receive 1 dose of Hib vaccine.
The Recommended Adult Immunization Schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians.
http://www.medscape.com/viewarticle/716419_2
Department of Health and Human Services; Centers for Disease Control and Prevention
Posted: 03/09/2010; Morbidity & Mortality Weekly Report. 2010;59(1):1-4. © 2010 Centers for Disease Control and Prevention (CDC)
Introduction
The Advisory Committee on Immunization Practices (ACIP) annually reviews the recommended Adult Immunization Schedule to ensure that the schedule reflects current recommendations for the licensed vaccines.
In October 2009, ACIP approved the Adult Immunization Schedule for 2010, which includes several changes.
A bivalent human papillomavirus vaccine (HPV2) was licensed for use in females in October 2009. ACIP recommends vaccination of females with either HPV2 or the quadrivalent human papillomavirus vaccine (HPV4).
HPV4 was licensed for use in males in October 2009, and ACIP issued a permissive recommendation for use in males.
Introductory sentences were added to the footnotes for measles, mumps, rubella, influenza, pneumococcal, hepatitis A, hepatitis B, and meningococcal vaccines. Clarifications were made to the footnotes for measles, mumps, rubella, influenza, hepatitis A, meningococcal, and Haemophilus influenza type b vaccines, and schedule information was added to the hepatitis B vaccine footnote.
The human papillomavirus (HPV) footnote (#2) includes language that a bivalent HPV vaccine (HPV2) has been licensed for use in females. Either HPV2 or the quadrivalent human papillomavirus vaccine (HPV4) can be used for vaccination of females aged 19 through 26 years. In addition, language has been added to indicate that ACIP issued a permissive recommendation for use of HPV4 in males.
The measles, mumps, rubella (MMR) footnote (#5) has language added to clarify which adults born during or after 1957 do not need 1 or more doses of MMR vaccine for the measles and mumps components, and clarifies which women should receive a dose of MMR vaccine. Also, interval dosing information has been added to indicate when a second dose of MMR vaccine should be administered. Language has been added to highlight recommendations for vaccinating health-care personnel born before 1957 routinely and during outbreaks.
The term "seasonal" has been added to the influenza footnote (#6).
The hepatitis A footnote (#9) has language added to indicate that unvaccinated persons who anticipate close contact with an international adoptee should consider vaccination.
The hepatitis B footnote (#10) has language added to include schedule information for the 3-dose hepatitis B vaccine.
The meningococcal vaccine footnote (#11) clarifies which vaccine formulations are preferred for adults aged ≤55 years and ≥56 years, and which vaccine formulation can be used for revaccination. New examples have been added to demonstrate who should and should not be considered for revaccination.
The selected conditions for Haemophilus influenza type b (Hib) footnote (#13) clarifies which high-risk persons may receive 1 dose of Hib vaccine.
The Recommended Adult Immunization Schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians.
http://www.medscape.com/viewarticle/716419_2
Older Patients Less Likely to Get Adjuvant Chemo for Colorectal Cancer
From Medscape Medical News
Maria Sgambati, MD
March 18, 2010 (Washington, DC) — Older patients who undergo surgery for colon cancer are less likely to receive adjuvant chemotherapy, according to a new study published in the March 17 issue of Journal of the American Medical Association. The findings were reported here at a special press briefing to highlight this issue of the journal, which focuses on cancer.
Investigators analyzed the use of adjuvant chemotherapy in 675 patients diagnosed with stage 3 colon cancer who had already undergone surgical removal of part of the colon as their initial treatment.
Chemotherapy in this setting has demonstrated benefit in reducing disease recurrence and improving survival, regardless of age.
Of these 675 patients, 513 received supplemental chemotherapy, with a large difference based on age; 87% percent of patients younger than 75 years received chemotherapy, compared with 50% of patients older than 75 years.
"Our study shows what others have shown — that older patients in the community are less likely to get chemotherapy, despite evidence-based recommendations," said Robert Fletcher, MD, MSc, an author on the study and professor emeritus of ambulatory care and prevention at Harvard Medical School in Boston, Massachusetts. "It's not clear why they aren't getting it as often as younger patients." Dr. Fletcher speculated that part of the reason might be that physicians are less likely to offer chemotherapy and older patients might be more likely to refuse it, but it's hard to get at that information, he said.
Despite that fact that many patients who get cancer are older, there is a limited but growing body of data on the effectiveness and toxicity of chemotherapy in older patients.
"While we know that older patients can often have the same benefit from chemotherapy as younger patients, most of this information comes from clinical trials where patients are highly selected," said Nancy Keating, MD, associate professor of medicine and healthcare policy at Harvard Medical School and an associate physician at Brigham and Women's Hospital in Boston. "What we don't know is how clinical trial data translate into what's happening in the community. This study is important in that it evaluates what is happening in populations of patients in the community who often have other illnesses."
To conduct this study, Dr. Fletcher and his colleagues examined data gathered as part of the Cancer Care Outcomes Research and Surveillance (CanCORS) project, a consortium supported by the National Institutes of Health and the Department of Veterans Affairs that is looking at outcomes in a cohort of newly diagnosed patients with lung and colorectal cancer.
Older Patients More Likely to Discontinue
Medical record and survey data were used to gather information on chemotherapy regimens, adverse events experienced while on chemotherapy, burden of illness of the patient — that is, other health issues such as diabetes, hypertension, pulmonary disease, and other demographic factors (including income and ethnicity). Patients were drawn from communities across 5 different geographic regions of the United States, from 5 integrated healthcare delivery systems and 15 Veteran's Affairs hospitals.
The study also found that older patients were more likely than younger patients to stop taking chemotherapy, which, in this setting, is often given for at least 6 months, depending on the type of regimen used. After 150 days, 40% of patients older than 65 had discontinued chemotherapy, compared with 25% of patients younger than 65. Stopping treatment early or using lower doses can be problematic. "We don't know whether a shorter duration of treatment or lower doses are as effective," notes Dr. Fletcher.
One possibility for this pattern of discontinuation is that older patients might be more likely to experience toxic effects from chemotherapy. However, data from this study doesn't bear that out. Dr. Fletcher and his colleagues explored this issue in their study and found that 1 in 3 patients receiving chemotherapy experienced an adverse event. Although patients older than 75 had a higher rate of early clinical adverse events — events that might be more related to surgery — after controlling or adjusting for a number of factors, including dose received, older patients were no more likely than younger patients to have late adverse events, they report. This finding might be related to differences that were seen in the type of chemotherapy given or to the health of patients. "Regardless of age, we also found that chemotherapy was given to healthier patients overall, right or wrong," noted Dr. Fletcher. "This may partly explain our findings on adverse events."
Until recently, clinical trials often had upper age limits for patients. Many trials still have very restrictive eligibility criteria, which often exclude patients with comorbidities. However, that is changing, and there does seem to be an emerging opinion that trials are needed to reflect "real-world" scenarios. "I think these trials with older patients only and those that have comorbidities are the way to go," observed Dr. Keating. "While they may be difficult to do, they will provide very important information we need to help patients, particularly as the population ages."
Maria Sgambati, MD
March 18, 2010 (Washington, DC) — Older patients who undergo surgery for colon cancer are less likely to receive adjuvant chemotherapy, according to a new study published in the March 17 issue of Journal of the American Medical Association. The findings were reported here at a special press briefing to highlight this issue of the journal, which focuses on cancer.
Investigators analyzed the use of adjuvant chemotherapy in 675 patients diagnosed with stage 3 colon cancer who had already undergone surgical removal of part of the colon as their initial treatment.
Chemotherapy in this setting has demonstrated benefit in reducing disease recurrence and improving survival, regardless of age.
Of these 675 patients, 513 received supplemental chemotherapy, with a large difference based on age; 87% percent of patients younger than 75 years received chemotherapy, compared with 50% of patients older than 75 years.
"Our study shows what others have shown — that older patients in the community are less likely to get chemotherapy, despite evidence-based recommendations," said Robert Fletcher, MD, MSc, an author on the study and professor emeritus of ambulatory care and prevention at Harvard Medical School in Boston, Massachusetts. "It's not clear why they aren't getting it as often as younger patients." Dr. Fletcher speculated that part of the reason might be that physicians are less likely to offer chemotherapy and older patients might be more likely to refuse it, but it's hard to get at that information, he said.
Despite that fact that many patients who get cancer are older, there is a limited but growing body of data on the effectiveness and toxicity of chemotherapy in older patients.
"While we know that older patients can often have the same benefit from chemotherapy as younger patients, most of this information comes from clinical trials where patients are highly selected," said Nancy Keating, MD, associate professor of medicine and healthcare policy at Harvard Medical School and an associate physician at Brigham and Women's Hospital in Boston. "What we don't know is how clinical trial data translate into what's happening in the community. This study is important in that it evaluates what is happening in populations of patients in the community who often have other illnesses."
To conduct this study, Dr. Fletcher and his colleagues examined data gathered as part of the Cancer Care Outcomes Research and Surveillance (CanCORS) project, a consortium supported by the National Institutes of Health and the Department of Veterans Affairs that is looking at outcomes in a cohort of newly diagnosed patients with lung and colorectal cancer.
Older Patients More Likely to Discontinue
Medical record and survey data were used to gather information on chemotherapy regimens, adverse events experienced while on chemotherapy, burden of illness of the patient — that is, other health issues such as diabetes, hypertension, pulmonary disease, and other demographic factors (including income and ethnicity). Patients were drawn from communities across 5 different geographic regions of the United States, from 5 integrated healthcare delivery systems and 15 Veteran's Affairs hospitals.
The study also found that older patients were more likely than younger patients to stop taking chemotherapy, which, in this setting, is often given for at least 6 months, depending on the type of regimen used. After 150 days, 40% of patients older than 65 had discontinued chemotherapy, compared with 25% of patients younger than 65. Stopping treatment early or using lower doses can be problematic. "We don't know whether a shorter duration of treatment or lower doses are as effective," notes Dr. Fletcher.
One possibility for this pattern of discontinuation is that older patients might be more likely to experience toxic effects from chemotherapy. However, data from this study doesn't bear that out. Dr. Fletcher and his colleagues explored this issue in their study and found that 1 in 3 patients receiving chemotherapy experienced an adverse event. Although patients older than 75 had a higher rate of early clinical adverse events — events that might be more related to surgery — after controlling or adjusting for a number of factors, including dose received, older patients were no more likely than younger patients to have late adverse events, they report. This finding might be related to differences that were seen in the type of chemotherapy given or to the health of patients. "Regardless of age, we also found that chemotherapy was given to healthier patients overall, right or wrong," noted Dr. Fletcher. "This may partly explain our findings on adverse events."
Until recently, clinical trials often had upper age limits for patients. Many trials still have very restrictive eligibility criteria, which often exclude patients with comorbidities. However, that is changing, and there does seem to be an emerging opinion that trials are needed to reflect "real-world" scenarios. "I think these trials with older patients only and those that have comorbidities are the way to go," observed Dr. Keating. "While they may be difficult to do, they will provide very important information we need to help patients, particularly as the population ages."
FDA Drug Safety Communication: Ongoing safety review of high-dose Zocor* (simvastatin) and increased risk of muscle injury
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm
In March 2010,
FDA approved a labeling revision for simvastatin based on interim results from an ongoing clinical trial – the Heart Protection Study 2 (HPS2).
The revised label states that patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products. Further, the revised label recommends caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products.
The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients not of Chinese descent (0.03%) taking 40 mg simvastatin plus cholesterol-modifying doses (≥1 g/day) of a niacin-containing product.
It is not known if the increased risk for myopathy observed in these patients applies to other patients of Asian descent.
Simvastatin Dose Limitations
These limitations apply to ALL patients taking simvastatin.
Do not use simvastatin with these medications:
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Do not use more than 10mg of simvastatin with these medications:
Gemfibrozil
Cyclosporine
Danazol
Do not use more than 20mg of simvastatin with these medications:
Amiodarone
Verapamil
Do not use more than 40mg of simvastatin with this medication:
Diltiazem
In March 2010,
FDA approved a labeling revision for simvastatin based on interim results from an ongoing clinical trial – the Heart Protection Study 2 (HPS2).
The revised label states that patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products. Further, the revised label recommends caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products.
The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients not of Chinese descent (0.03%) taking 40 mg simvastatin plus cholesterol-modifying doses (≥1 g/day) of a niacin-containing product.
It is not known if the increased risk for myopathy observed in these patients applies to other patients of Asian descent.
Simvastatin Dose Limitations
These limitations apply to ALL patients taking simvastatin.
Do not use simvastatin with these medications:
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Do not use more than 10mg of simvastatin with these medications:
Gemfibrozil
Cyclosporine
Danazol
Do not use more than 20mg of simvastatin with these medications:
Amiodarone
Verapamil
Do not use more than 40mg of simvastatin with this medication:
Diltiazem
Information on Simvastatin/Amiodarone
FDA ALERT [08/08/2008]:
The FDA is notifying the public of the risk of a rare condition of muscle injury called rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone.
This risk is dose-related and increases when a dose of simvastatin greater than 20 mg per day is given with amiodarone.
A revision of the simvastatin labeling in 2002 described an increased risk of rhabdomyolysis when amiodarone is taken with simvastatin doses greater than 20 mg daily.
However, the FDA continues to receive reports of rhabdomyolysis in patients treated concurrently with amiodarone and simvastatin, particularly with simvastatin doses greater than 20 mg daily.
Prescribers should be aware of the increased risk of rhabdomyolysis when simvastatin is prescribed with amiodarone, and they should avoid doses of simvastatin greater than 20 mg per day in patients taking amiodarone.
The FDA is notifying the public of the risk of a rare condition of muscle injury called rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone.
This risk is dose-related and increases when a dose of simvastatin greater than 20 mg per day is given with amiodarone.
A revision of the simvastatin labeling in 2002 described an increased risk of rhabdomyolysis when amiodarone is taken with simvastatin doses greater than 20 mg daily.
However, the FDA continues to receive reports of rhabdomyolysis in patients treated concurrently with amiodarone and simvastatin, particularly with simvastatin doses greater than 20 mg daily.
Prescribers should be aware of the increased risk of rhabdomyolysis when simvastatin is prescribed with amiodarone, and they should avoid doses of simvastatin greater than 20 mg per day in patients taking amiodarone.
High-Dose Simvastatin Associated With Increased Risk for Myopathy, FDA Warns
From Medscape Medical News > Alerts, Approvals and Safety Changes > Medscape Alerts
Emma Hitt, PhD
March 19, 2010 — Simvastatin (Zocor, Merck/Schering-Plough Pharmaceuticals), used at the highest approved dose of 80 mg, is associated with an increased risk for myopathy, including rhabdomyolysis, according to the US Food and Drug Administration (FDA).
The alert sent today from MedWatch, the FDA's safety information and adverse event reporting program, was based on a review of data from the large clinical Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial. Other sources, including data from clinical trials, observational studies, and adverse event reports, as well as data on prescription use of simvastatin, are under review.
The SEARCH trial evaluated the number of major cardiovascular events (heart attack, revascularization, and cardiovascular death) in 6031 patients with a history of myocardial infarction taking 80 mg of simvastatin and compared that number with that from 6033 patients taking 20 mg of simvastatin. The study included 6.7 years of follow-up.
According to preliminary results, more patients in the simvastatin 80-mg group developed myopathy compared with patients in the simvastatin 20-mg group (52 cases [0.9%] vs 1 case [0.02%]). In addition, 11 patients in the simvastatin 80-mg group (0.02%) developed rhabdomyolysis compared with no patients in the simvastatin 20-mg group.
"Review of simvastatin is part of an ongoing FDA effort to evaluate the risk of statin-associated muscle injury and to provide that information to the public as it becomes available," noted Eric Colman, MD, deputy director of the FDA's Division of Metabolism and Endocrinology Products, in a news release.
According to the FDA, healthcare professionals should consider the following when prescribing simvastatin:
1.Rhabdomyolysis is a rare class effect associated with statins
The increased risk for muscle injury with the 80-mg dose of simvastatin is compared with the use of lower doses of simvastatin and possibly other statin drugs
2.Whether simvastatin is clinically appropriate
3.Discuss with patients the benefits and risks of simvastatin
4.Potential drug–drug interactions can occur with simvastatin
Last month, simvastatin was one of 27 drugs or drug categories that was included on an FDA watch list, based on potential signs of serious risks or new safety information identified in the agency's Adverse Event Reporting System last year.
Risk for myopathy may be linked to genetic heterogeneity in statin users. A study published in the October 20, 2009, issue of the Journal of American College of Cardiology found that carriers of the reduced-function single nucleotide polymorphism of the SLCO1B1 gene were at increased risk of developing mild statin-induced adverse effects, including myopathy and myalgia.
The risk for adverse events was greatest among those treated with simvastatin, but minimal in those receiving pravastatin.
Previous FDA safety communications on the increased risk for muscle injury with simvastatin in patients who concurrently take other medications is also available on the FDA's Web site.
Simvastatin is sold as a single agent and also in combination with ezetimibe (Vytorin, Merck/Schering-Plough Pharmaceuticals) and in combination with niacin (Simcor, Abbott Laboratories).
Rhabdomyolysis is the most serious form of myopathy and is associated with severe renal toxicity and failure, and occasional fatalities.
Adverse events related to simvastatin should be communicated to MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787
[.
Emma Hitt, PhD
March 19, 2010 — Simvastatin (Zocor, Merck/Schering-Plough Pharmaceuticals), used at the highest approved dose of 80 mg, is associated with an increased risk for myopathy, including rhabdomyolysis, according to the US Food and Drug Administration (FDA).
The alert sent today from MedWatch, the FDA's safety information and adverse event reporting program, was based on a review of data from the large clinical Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial. Other sources, including data from clinical trials, observational studies, and adverse event reports, as well as data on prescription use of simvastatin, are under review.
The SEARCH trial evaluated the number of major cardiovascular events (heart attack, revascularization, and cardiovascular death) in 6031 patients with a history of myocardial infarction taking 80 mg of simvastatin and compared that number with that from 6033 patients taking 20 mg of simvastatin. The study included 6.7 years of follow-up.
According to preliminary results, more patients in the simvastatin 80-mg group developed myopathy compared with patients in the simvastatin 20-mg group (52 cases [0.9%] vs 1 case [0.02%]). In addition, 11 patients in the simvastatin 80-mg group (0.02%) developed rhabdomyolysis compared with no patients in the simvastatin 20-mg group.
"Review of simvastatin is part of an ongoing FDA effort to evaluate the risk of statin-associated muscle injury and to provide that information to the public as it becomes available," noted Eric Colman, MD, deputy director of the FDA's Division of Metabolism and Endocrinology Products, in a news release.
According to the FDA, healthcare professionals should consider the following when prescribing simvastatin:
1.Rhabdomyolysis is a rare class effect associated with statins
The increased risk for muscle injury with the 80-mg dose of simvastatin is compared with the use of lower doses of simvastatin and possibly other statin drugs
2.Whether simvastatin is clinically appropriate
3.Discuss with patients the benefits and risks of simvastatin
4.Potential drug–drug interactions can occur with simvastatin
Last month, simvastatin was one of 27 drugs or drug categories that was included on an FDA watch list, based on potential signs of serious risks or new safety information identified in the agency's Adverse Event Reporting System last year.
Risk for myopathy may be linked to genetic heterogeneity in statin users. A study published in the October 20, 2009, issue of the Journal of American College of Cardiology found that carriers of the reduced-function single nucleotide polymorphism of the SLCO1B1 gene were at increased risk of developing mild statin-induced adverse effects, including myopathy and myalgia.
The risk for adverse events was greatest among those treated with simvastatin, but minimal in those receiving pravastatin.
Previous FDA safety communications on the increased risk for muscle injury with simvastatin in patients who concurrently take other medications is also available on the FDA's Web site.
Simvastatin is sold as a single agent and also in combination with ezetimibe (Vytorin, Merck/Schering-Plough Pharmaceuticals) and in combination with niacin (Simcor, Abbott Laboratories).
Rhabdomyolysis is the most serious form of myopathy and is associated with severe renal toxicity and failure, and occasional fatalities.
Adverse events related to simvastatin should be communicated to MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787
[.
Genetic Variant Again Linked With Statin Side Effects
From Heartwire
Michael O’Riordan
October 13, 2009 (Durham, North Carolina) — Carriers of the reduced-function single nucleotide polymorphism (SNP) of the SLCO1B1 gene are at an increased risk of developing mild statin-induced side effects, including myopathy and myalgia, a new study has shown [1].
The risk of adverse events, however, was greatest among those treated with simvastatin and negligible in those assigned to pravastatin.
"We report that carriers of the SLCO1B1*5 allele are at a twofold relative risk of mild statin-induced side effects, the majority of which had normal [creatine kinase] CK levels," according to lead investigator Dr Deepak Voora (Duke University Medical Center, Durham, NC) and colleagues in the October 20, 2009 issue of the Journal of American College of Cardiology. "These results could have potential implications for clinical practice, because the vast majority of patients who are intolerant of statins have mild symptoms without associated CK elevations."
The results confirm a recent genomewide-association study by the SEARCH Collaborative Group, a study reported by heartwire . The SEARCH group identified a strong association between simvastatin-induced myopathy and two tightly linked variants in SLCO1B1, a gene that encodes for a protein involved in the transport of statins and other drugs from the blood into the liver.
In this most recent study, known as the Statin Response Examined by Genetic Haplotype Markers (STRENGTH) trial, 509 patients were randomized to treatment with atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg, with each increased to doses of 80 mg, 80 mg, and 40 mg, respectively. After 16 weeks of follow-up, 99 patients developed an adverse event, a composite end point that included 54 patients who discontinued therapy, 49 who developed myalgias, and nine who had CK elevations greater than three times the upper limit of normal.
The SLCO1B1*5 allele was associated with drug discontinuation, myalgia, and CK elevations. Importantly, statin-induced myalgia side effects also occurred in patients without CK elevations. The study also showed an association between female sex and adverse events among those receiving statin therapy.
In an editorial accompanying the study [2], Drs Joseph Rossi and Howard McLeod (Duke University Medical Center, Durham, NC) are optimistic that "genetic testing may someday become an important adjunct to risk stratification," but in the meantime it is reasonable to pick a statin based on drug interactions, particularly CYP450 interactions, and treatment goals. If a patient develops myalgias or CK elevation with simvastatin, changing agents may provide relief of symptoms, they add.
Michael O’Riordan
October 13, 2009 (Durham, North Carolina) — Carriers of the reduced-function single nucleotide polymorphism (SNP) of the SLCO1B1 gene are at an increased risk of developing mild statin-induced side effects, including myopathy and myalgia, a new study has shown [1].
The risk of adverse events, however, was greatest among those treated with simvastatin and negligible in those assigned to pravastatin.
"We report that carriers of the SLCO1B1*5 allele are at a twofold relative risk of mild statin-induced side effects, the majority of which had normal [creatine kinase] CK levels," according to lead investigator Dr Deepak Voora (Duke University Medical Center, Durham, NC) and colleagues in the October 20, 2009 issue of the Journal of American College of Cardiology. "These results could have potential implications for clinical practice, because the vast majority of patients who are intolerant of statins have mild symptoms without associated CK elevations."
The results confirm a recent genomewide-association study by the SEARCH Collaborative Group, a study reported by heartwire . The SEARCH group identified a strong association between simvastatin-induced myopathy and two tightly linked variants in SLCO1B1, a gene that encodes for a protein involved in the transport of statins and other drugs from the blood into the liver.
In this most recent study, known as the Statin Response Examined by Genetic Haplotype Markers (STRENGTH) trial, 509 patients were randomized to treatment with atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg, with each increased to doses of 80 mg, 80 mg, and 40 mg, respectively. After 16 weeks of follow-up, 99 patients developed an adverse event, a composite end point that included 54 patients who discontinued therapy, 49 who developed myalgias, and nine who had CK elevations greater than three times the upper limit of normal.
The SLCO1B1*5 allele was associated with drug discontinuation, myalgia, and CK elevations. Importantly, statin-induced myalgia side effects also occurred in patients without CK elevations. The study also showed an association between female sex and adverse events among those receiving statin therapy.
In an editorial accompanying the study [2], Drs Joseph Rossi and Howard McLeod (Duke University Medical Center, Durham, NC) are optimistic that "genetic testing may someday become an important adjunct to risk stratification," but in the meantime it is reasonable to pick a statin based on drug interactions, particularly CYP450 interactions, and treatment goals. If a patient develops myalgias or CK elevation with simvastatin, changing agents may provide relief of symptoms, they add.
Friday, March 12, 2010
NCCN Breast Cancer Guidelines Updated: SLNB and PET/CT Are Highlights
Medscape Medical News from the:
National Comprehensive Cancer Network (NCCN) 15th Annual Conference
Nick Mulcahy
March 12, 2010 (Hollywood, Florida) — In women with stage I/II breast cancer who have clinically negative axilla, "sentinel lymph node biopsy [SLNB] is now the standard of care" in staging these nodes, said Robert Carlson, MD, during the breast cancer guideline update here at the National Comprehensive Cancer Network (NCCN) 15th Annual Conference.
Not only is SNLB the standard of care, but full axillary lymph node dissection has been removed as an option for women with clinically negative axilla, noted Dr. Carlson, who is from the Stanford Comprehensive Cancer Center in Palo Alto, California.
The alterations represent the most significant new change in this year's NCCN breast cancer guideline, Dr. Carlson told reporters after making his presentation.
Randomized clinical trials indicate that there is a lower risk for morbidity associated with sentinel node mapping and excision than with level I/II axillary dissection, he said.
The change to the guideline also reflects current practice, suggested Dr. Carlson, who is also chair of NCCN's Breast Cancer Panel.
Between 1998 and 2005, SLNB in breast cancer increased to about 65% of all stage I/II cases, he said, adding that SLNB training is now standard in American surgery programs, and is widely available.
Only an "experienced sentinel lymph node team" should perform the SLNB, Dr. Carlson added. Otherwise, the NCCN's guideline calls for a patient to be referred to such a team, which would include a surgeon, a radiologist, a nuclear medicine physician, and a pathologist.
"In an experienced surgeon's hands, the sentinel lymph node is identified 95% of the time," Dr. Carlson told the NCCN audience. "The false-negative rate is less than 10%, and axillary recurrence is less than 1% if the sentinel lymph node is negative."
Lymph edema is about 7% with this approach, said Dr. Carlson. This compares favorably with the 10% to 20% rate of edema seen with axillary dissection.
SLNB has only been in practice for "about 10 years," and so not all surgeons know how to perform it. Thus, there might be limited access in some part of the United States, he told the audience while listing the "cons" associated with this new staging directive.
Dr. Carlson warned that some surgeons might feel forced to do SLNB, "despite lack of skill," because it is now the standard. "This could promote adoption by providers with limited opportunity to apply sentinel lymph node biopsy," he cautioned.
There was one other axillary lymph-node-related change to the breast cancer guideline.
A complete axillary dissection should not be performed in women with "apparent pure" ductal carcinoma in situ (DCIS), and thus an absence of invasive cancer or proven metastatic disease.
However, as Dr. Carlson noted, a small proportion of patients will be found to have invasive cancer at the time of their definitive surgical procedure.
"Therefore, the performance of a [sentinel lymph node] procedure may be considered if the patient with apparent pure DCIS is to be treated with mastectomy or with excision in an anatomic location compromising the performance of a future sentinel lymph node procedure," according to the guideline.
No Longer Silent About PET/CT
Previous NCCN breast cancer guidelines were "silent" about positron emission tomography (PET)/computed tomography (CT), said Dr. Carlson. But not any longer, because Dr. Carlson and his colleagues felt compelled to make a number of recommendations about the imaging technology in the current update.
"PET/CT is overused in breast cancer," opined Dr. Carlson, providing an overview of the recommendations for reporters.
PET/CT should not be used at all in early breast cancer, he said.
The use of PET or the combined PET/CT is not indicated in the staging of clinical stage I, II, or operable stage III breast cancer, according to a footnote added to the invasive breast cancer workup section.
The reasons for the exclusion include one of the "major problems" with PET/CT, said Dr. Carlson. "There is a remarkably high frequency of false positives" with the technology, he explained.
Dr. Carlson cited a breast cancer staging study from the University of Kansas as part of the evidence. Fifteen of the 83 women in the retrospective study had a "suspicious" FDG-PET/CT. Of those 15 women, 2 (13%) had confirmed metastatic disease, but the other 13 (87%) had false-positive scans.
Dr. Carlson also cited a set of studies that indicated that PET/CT was "not sensitive" in detecting nodal disease in early breast cancer. "The sensitivity is very poor," he said, referring to 5 studies in which the sensitivity of the technology was as low as 20% and no higher than 61% in research that used SLNB as the comparator, mostly.
However, PET/CT does have a role to play in locally advance disease.
It is cited as an "additional study" to bone scan and CT scan in the optional workup section of the guideline for locally advanced (stage III) disease.
"FDG-PET/CT is most helpful where standard staging studies are equivocal or suspicious, especially in locally advanced or metastatic disease" said Dr. Carlson, reading aloud the guideline. In various studies, the technology has identified distant metastases in 10% to 21% of patients, and might be able to identify extra-axial nodes, he said.
Even when PET or PET/CT scanning is encouraged in the case of metastatic disease with equivocal or suspicious standard staging results, the guideline is not enthusiastic. "Even in these situations, biopsy of equivocal or suspicious sites is more likely to provide useful information," it states.
"A positive result on a PET is just as likely to mislead you as help you," said Dr. Carlson, in reference to staging recurrent/metastatic disease when other results were equivocal/suspicious.
Joan S. McClure, MS, senior vice president of clinical information and publications for the NCCN, agreed with Dr. Carlson's summary assessment of PET/CT. "Overall, it's been used excessively," she told Medscape Oncology in an interview.
Dr. Carlson said that PET/CT has benefited from being a "new technology."
"Everybody likes to do the new thing," Dr. Carlson said. It is also simple to order, provides financial rewards for clinicians who order it, and is irrationally overvalued because of its "high price tag," he added.
Another Change for Genetic Counseling
Last year at NCCN, genetic counseling was highlighted after being added to the optional additional studies section for breast cancer patients who are found to be, with genetic testing, at high risk for hereditary breast cancer.
This year, the NCCN has bumped counseling up the ladder of importance.
Now, counseling is part of the general workup and has been added to all the workup sections, from DCIS onward. "We want to make sure people do it," explained Dr. Carlson.
National Comprehensive Cancer Network (NCCN) 15th Annual Conference. Presented March 11, 2010
National Comprehensive Cancer Network (NCCN) 15th Annual Conference
Nick Mulcahy
March 12, 2010 (Hollywood, Florida) — In women with stage I/II breast cancer who have clinically negative axilla, "sentinel lymph node biopsy [SLNB] is now the standard of care" in staging these nodes, said Robert Carlson, MD, during the breast cancer guideline update here at the National Comprehensive Cancer Network (NCCN) 15th Annual Conference.
Not only is SNLB the standard of care, but full axillary lymph node dissection has been removed as an option for women with clinically negative axilla, noted Dr. Carlson, who is from the Stanford Comprehensive Cancer Center in Palo Alto, California.
The alterations represent the most significant new change in this year's NCCN breast cancer guideline, Dr. Carlson told reporters after making his presentation.
Randomized clinical trials indicate that there is a lower risk for morbidity associated with sentinel node mapping and excision than with level I/II axillary dissection, he said.
The change to the guideline also reflects current practice, suggested Dr. Carlson, who is also chair of NCCN's Breast Cancer Panel.
Between 1998 and 2005, SLNB in breast cancer increased to about 65% of all stage I/II cases, he said, adding that SLNB training is now standard in American surgery programs, and is widely available.
Only an "experienced sentinel lymph node team" should perform the SLNB, Dr. Carlson added. Otherwise, the NCCN's guideline calls for a patient to be referred to such a team, which would include a surgeon, a radiologist, a nuclear medicine physician, and a pathologist.
"In an experienced surgeon's hands, the sentinel lymph node is identified 95% of the time," Dr. Carlson told the NCCN audience. "The false-negative rate is less than 10%, and axillary recurrence is less than 1% if the sentinel lymph node is negative."
Lymph edema is about 7% with this approach, said Dr. Carlson. This compares favorably with the 10% to 20% rate of edema seen with axillary dissection.
SLNB has only been in practice for "about 10 years," and so not all surgeons know how to perform it. Thus, there might be limited access in some part of the United States, he told the audience while listing the "cons" associated with this new staging directive.
Dr. Carlson warned that some surgeons might feel forced to do SLNB, "despite lack of skill," because it is now the standard. "This could promote adoption by providers with limited opportunity to apply sentinel lymph node biopsy," he cautioned.
There was one other axillary lymph-node-related change to the breast cancer guideline.
A complete axillary dissection should not be performed in women with "apparent pure" ductal carcinoma in situ (DCIS), and thus an absence of invasive cancer or proven metastatic disease.
However, as Dr. Carlson noted, a small proportion of patients will be found to have invasive cancer at the time of their definitive surgical procedure.
"Therefore, the performance of a [sentinel lymph node] procedure may be considered if the patient with apparent pure DCIS is to be treated with mastectomy or with excision in an anatomic location compromising the performance of a future sentinel lymph node procedure," according to the guideline.
No Longer Silent About PET/CT
Previous NCCN breast cancer guidelines were "silent" about positron emission tomography (PET)/computed tomography (CT), said Dr. Carlson. But not any longer, because Dr. Carlson and his colleagues felt compelled to make a number of recommendations about the imaging technology in the current update.
"PET/CT is overused in breast cancer," opined Dr. Carlson, providing an overview of the recommendations for reporters.
PET/CT should not be used at all in early breast cancer, he said.
The use of PET or the combined PET/CT is not indicated in the staging of clinical stage I, II, or operable stage III breast cancer, according to a footnote added to the invasive breast cancer workup section.
The reasons for the exclusion include one of the "major problems" with PET/CT, said Dr. Carlson. "There is a remarkably high frequency of false positives" with the technology, he explained.
Dr. Carlson cited a breast cancer staging study from the University of Kansas as part of the evidence. Fifteen of the 83 women in the retrospective study had a "suspicious" FDG-PET/CT. Of those 15 women, 2 (13%) had confirmed metastatic disease, but the other 13 (87%) had false-positive scans.
Dr. Carlson also cited a set of studies that indicated that PET/CT was "not sensitive" in detecting nodal disease in early breast cancer. "The sensitivity is very poor," he said, referring to 5 studies in which the sensitivity of the technology was as low as 20% and no higher than 61% in research that used SLNB as the comparator, mostly.
However, PET/CT does have a role to play in locally advance disease.
It is cited as an "additional study" to bone scan and CT scan in the optional workup section of the guideline for locally advanced (stage III) disease.
"FDG-PET/CT is most helpful where standard staging studies are equivocal or suspicious, especially in locally advanced or metastatic disease" said Dr. Carlson, reading aloud the guideline. In various studies, the technology has identified distant metastases in 10% to 21% of patients, and might be able to identify extra-axial nodes, he said.
Even when PET or PET/CT scanning is encouraged in the case of metastatic disease with equivocal or suspicious standard staging results, the guideline is not enthusiastic. "Even in these situations, biopsy of equivocal or suspicious sites is more likely to provide useful information," it states.
"A positive result on a PET is just as likely to mislead you as help you," said Dr. Carlson, in reference to staging recurrent/metastatic disease when other results were equivocal/suspicious.
Joan S. McClure, MS, senior vice president of clinical information and publications for the NCCN, agreed with Dr. Carlson's summary assessment of PET/CT. "Overall, it's been used excessively," she told Medscape Oncology in an interview.
Dr. Carlson said that PET/CT has benefited from being a "new technology."
"Everybody likes to do the new thing," Dr. Carlson said. It is also simple to order, provides financial rewards for clinicians who order it, and is irrationally overvalued because of its "high price tag," he added.
Another Change for Genetic Counseling
Last year at NCCN, genetic counseling was highlighted after being added to the optional additional studies section for breast cancer patients who are found to be, with genetic testing, at high risk for hereditary breast cancer.
This year, the NCCN has bumped counseling up the ladder of importance.
Now, counseling is part of the general workup and has been added to all the workup sections, from DCIS onward. "We want to make sure people do it," explained Dr. Carlson.
National Comprehensive Cancer Network (NCCN) 15th Annual Conference. Presented March 11, 2010
Smoking May Be an Independent Risk Factor for Suicidality
From Medscape Medical News
Crina Frincu-Mallos, PhD
March 11, 2010 (Baltimore, Maryland) — Smoking may be an independent risk factor for suicidality, new research suggests.
A longitudinal study presented here at the Anxiety Disorders Association of America 30th Annual Conference shows a strong association between smoking and suicidality in a cohort of 3021 adolescents and young adults aged 14 to 24 years at baseline.
The Early Developmental Stages of Psychopathology study, a prospective, longitudinal study, showed that prior occasional, regular smoking and nicotine dependence were associated with an increased risk for the onset of suicidal ideation, with odds ratios (ORs) ranging from 1.5 to 2.7.
Prior regular smoking and nicotine dependence were also associated with the subsequent first onset of suicide attempts (ORs, 3.1-4.5). According to the investigators led by Roselind Lieb, PhD, preexisting suicidality was not associated with subsequent smoking or nicotine dependence.
"Smoking increases the risk for subsequent suicidality. We have found it is a risk factor independent of other psychopathologies or other drug use,” Dr. Lieb, professor of epidemiology and health psychology, University of Basel, Switzerland, told Medscape Psychiatry.
The study appears to confirm results from a previous 10-year, longitudinal study published in 2005 that showed that current daily smoking, but not past smoking, predicted the subsequent occurrence of suicidal thoughts or attempts independent of major depression, prior substance use, and suicidal predisposition (Arch Gen Psychiatry. 2005;62:328-334).
The analyses of the 10-year follow-up data indicate that there is a dose-response relationship between the duration of smoking and suicidality.
However, he added, “it’s not clear whether smoking may be some attempt to cope with the conditions which later on lead to suicidality,” he told Medscape Psychiatry.
Anxiety Disorders Association of America (ADAA) 30th Annual Conference: Abstract 183. Presented March 5, 2010.
Crina Frincu-Mallos, PhD
March 11, 2010 (Baltimore, Maryland) — Smoking may be an independent risk factor for suicidality, new research suggests.
A longitudinal study presented here at the Anxiety Disorders Association of America 30th Annual Conference shows a strong association between smoking and suicidality in a cohort of 3021 adolescents and young adults aged 14 to 24 years at baseline.
The Early Developmental Stages of Psychopathology study, a prospective, longitudinal study, showed that prior occasional, regular smoking and nicotine dependence were associated with an increased risk for the onset of suicidal ideation, with odds ratios (ORs) ranging from 1.5 to 2.7.
Prior regular smoking and nicotine dependence were also associated with the subsequent first onset of suicide attempts (ORs, 3.1-4.5). According to the investigators led by Roselind Lieb, PhD, preexisting suicidality was not associated with subsequent smoking or nicotine dependence.
"Smoking increases the risk for subsequent suicidality. We have found it is a risk factor independent of other psychopathologies or other drug use,” Dr. Lieb, professor of epidemiology and health psychology, University of Basel, Switzerland, told Medscape Psychiatry.
The study appears to confirm results from a previous 10-year, longitudinal study published in 2005 that showed that current daily smoking, but not past smoking, predicted the subsequent occurrence of suicidal thoughts or attempts independent of major depression, prior substance use, and suicidal predisposition (Arch Gen Psychiatry. 2005;62:328-334).
The analyses of the 10-year follow-up data indicate that there is a dose-response relationship between the duration of smoking and suicidality.
However, he added, “it’s not clear whether smoking may be some attempt to cope with the conditions which later on lead to suicidality,” he told Medscape Psychiatry.
Anxiety Disorders Association of America (ADAA) 30th Annual Conference: Abstract 183. Presented March 5, 2010.
Men Who Have Sex With Men Have a 40-Fold Higher Risk for HIV, Syphilis
Medscape Medical News from the:
2010 National STD Prevention Conference (NSTDP)
Emma Hitt, PhD
March 11, 2010 (Atlanta, Georgia) — Approximately 7% of the American male population reports that they have ever had sex with another male, according to an analysis by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.
The finding enables the calculation of HIV and syphilis rates for this risk group and suggests that rates of these sexually transmitted infections among men who have sex with men (MSM) are at least 40 times higher than among other men or women.
David W. Purcell, JD, PhD, from the CDC's Division of HIV/AIDS Prevention, reported the findings at a late-breaking session here at the 2010 National STD Prevention Conference.
"This first-of-its-kind CDC analysis provides a new look at the stark disparities in HIV and syphilis rates among men who have sex with men, compared with other men and women," Dr. Purcell told Medscape Infectious Diseases. "While we've known that MSM make up the majority of the HIV epidemic, the new analysis allows us to put numbers to the disproportionate impact of HIV and syphilis in the gay community," he added.
The CDC first estimated the population size of MSM in the United States, then estimated HIV and syphilis rates in this group, and then compared these rates with those of other men and women.
The researchers searched the literature and identified 7 surveys involving nationwide American samples. Data were pooled based on recall period and then applied to census data to generate a population-sized estimate.
The CDC estimates that MSM comprise 2.0% (range, 1.4% to 2.7%) of the overall population in the United States aged 13 and older, or 4% of American men (range, 2.8% to 5.3%).
The data differed by recall year, however. The proportion of males who had engaged in same-sex behavior within the previous year was 2.6% (95% confidence interval [CI], 2.2 - 2.9), and within the previous 5 years was 4.0% (95% CI, 2.8 - 5.3); 7.0% of men stated that they had ever had sex with another male.
Using the 5-year recall period rate of 4%, Dr. Purcell and colleagues estimated that the rate of new HIV diagnoses among MSM was more than 44 times that of other men and more than 40 times that of women. The range was 522 to 989 cases of new HIV diagnoses per 100,000 MSM, compared with 12 per 100,000 other men and 13 per 100,000 women.
Similarly, the rate of primary and secondary syphilis among MSM was more than 46 times that of other men and more than 71 times that of women. The range was 91 to 173 cases per 100,000 MSM, compared with 2 per 100,000 other men and 1 per 100,000 women.
"This analysis is just a first step," Dr. Purcell said. "CDC is developing further breakdowns of MSM rates by race and age, as well as estimates for other populations significantly affected by HIV, such as injection drug users."
According to a related written release, CDC is implementing an updated National Syphilis Elimination Plan in cities where MSM have been hardest hit by the disease, and will release an updated HIV prevention strategic plan within the next year to support the President's upcoming National HIV/AIDS Strategy.
"These findings are very much what I would expect and are very credible," said Willi McFarland, MD, PhD, MPH, from the San Francisco Department of Public Health, and associate professor of epidemiology and biostatistics at the University of California, San Francisco. "There is a global conventional wisdom that the proportion of adult MSM falls between 2% and 5% when speaking of nations and large areas as a whole," he told Medscape Infectious Diseases.
"It is reaffirming to see that a synthesis of surveys produces estimates that fall within this range, and it may even explain some of the variation based on the time frame," he said.
However, Dr. McFarland points out that the nature of the calculation may be "one dimensional" when it comes to human sexuality and dealing with behavior alone.
"In addition to same-sex behavior, there is also same-sex attraction and sexual identity," he said. "A simple single number may belie the complexities of human sexuality and how we all fall on some spectrum of these factors, and may move in between them. Estimates of 2.6% to 7.0% understate all this."
Dr. McFarland added that it is important that clinicians and their patients strive to be comfortable discussing sexual orientation, sexual behavior, and their related health implications.
The study was supported solely by the CDC. Dr. Purcell and Dr. McFarland have disclosed no relevant financial relationships.
2010 National STD Prevention Conference (NSTDP): Abstract LBc. Presented March 10, 2010.
2010 National STD Prevention Conference (NSTDP)
Emma Hitt, PhD
March 11, 2010 (Atlanta, Georgia) — Approximately 7% of the American male population reports that they have ever had sex with another male, according to an analysis by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.
The finding enables the calculation of HIV and syphilis rates for this risk group and suggests that rates of these sexually transmitted infections among men who have sex with men (MSM) are at least 40 times higher than among other men or women.
David W. Purcell, JD, PhD, from the CDC's Division of HIV/AIDS Prevention, reported the findings at a late-breaking session here at the 2010 National STD Prevention Conference.
"This first-of-its-kind CDC analysis provides a new look at the stark disparities in HIV and syphilis rates among men who have sex with men, compared with other men and women," Dr. Purcell told Medscape Infectious Diseases. "While we've known that MSM make up the majority of the HIV epidemic, the new analysis allows us to put numbers to the disproportionate impact of HIV and syphilis in the gay community," he added.
The CDC first estimated the population size of MSM in the United States, then estimated HIV and syphilis rates in this group, and then compared these rates with those of other men and women.
The researchers searched the literature and identified 7 surveys involving nationwide American samples. Data were pooled based on recall period and then applied to census data to generate a population-sized estimate.
The CDC estimates that MSM comprise 2.0% (range, 1.4% to 2.7%) of the overall population in the United States aged 13 and older, or 4% of American men (range, 2.8% to 5.3%).
The data differed by recall year, however. The proportion of males who had engaged in same-sex behavior within the previous year was 2.6% (95% confidence interval [CI], 2.2 - 2.9), and within the previous 5 years was 4.0% (95% CI, 2.8 - 5.3); 7.0% of men stated that they had ever had sex with another male.
Using the 5-year recall period rate of 4%, Dr. Purcell and colleagues estimated that the rate of new HIV diagnoses among MSM was more than 44 times that of other men and more than 40 times that of women. The range was 522 to 989 cases of new HIV diagnoses per 100,000 MSM, compared with 12 per 100,000 other men and 13 per 100,000 women.
Similarly, the rate of primary and secondary syphilis among MSM was more than 46 times that of other men and more than 71 times that of women. The range was 91 to 173 cases per 100,000 MSM, compared with 2 per 100,000 other men and 1 per 100,000 women.
"This analysis is just a first step," Dr. Purcell said. "CDC is developing further breakdowns of MSM rates by race and age, as well as estimates for other populations significantly affected by HIV, such as injection drug users."
According to a related written release, CDC is implementing an updated National Syphilis Elimination Plan in cities where MSM have been hardest hit by the disease, and will release an updated HIV prevention strategic plan within the next year to support the President's upcoming National HIV/AIDS Strategy.
"These findings are very much what I would expect and are very credible," said Willi McFarland, MD, PhD, MPH, from the San Francisco Department of Public Health, and associate professor of epidemiology and biostatistics at the University of California, San Francisco. "There is a global conventional wisdom that the proportion of adult MSM falls between 2% and 5% when speaking of nations and large areas as a whole," he told Medscape Infectious Diseases.
"It is reaffirming to see that a synthesis of surveys produces estimates that fall within this range, and it may even explain some of the variation based on the time frame," he said.
However, Dr. McFarland points out that the nature of the calculation may be "one dimensional" when it comes to human sexuality and dealing with behavior alone.
"In addition to same-sex behavior, there is also same-sex attraction and sexual identity," he said. "A simple single number may belie the complexities of human sexuality and how we all fall on some spectrum of these factors, and may move in between them. Estimates of 2.6% to 7.0% understate all this."
Dr. McFarland added that it is important that clinicians and their patients strive to be comfortable discussing sexual orientation, sexual behavior, and their related health implications.
The study was supported solely by the CDC. Dr. Purcell and Dr. McFarland have disclosed no relevant financial relationships.
2010 National STD Prevention Conference (NSTDP): Abstract LBc. Presented March 10, 2010.
Regular Analgesic Use May Increase Risk for Hearing Loss
From Medscape Medical News
Fran Lowry
March 11, 2010 – Regular use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetaminophen may increase the risk for hearing loss in men, and the impact is larger on those younger than 60 years, according to a prospective study published in the March issue of the American Journal of Medicine.
"Aspirin, acetaminophen, and ibuprofen are the 3 most commonly used drugs in the US," write Sharon G. Curhan, MD, ScM, from Brigham and Women's Hospital, Boston, Massachusetts, and colleagues. "Given that analgesic use might result in pathophysiologic changes in the cochlea and that regular use of these analgesics is so common, the relation of these medications and hearing loss might be an important public health issue."
However, Curhan and colleagues point out several study limitations that may affect the results of their study. Two independent commentators interviewed by Medscape Family Medicine reiterate these limitations and emphasize that causality cannot be determined from the study results. Yet, both agree that the study focuses on an important issue.
Findings of the Study
The aim of this study was to determine if there was an association between regular analgesic use and the risk for hearing loss.
The study subjects were participants in the Health Professionals Follow-up Study, which enrolled 51,529 male dentists, optometrists, osteopathic physicians, pharmacists, podiatrists, and veterinarians aged 40 to 75 years at baseline in 1986. The participants filled out detailed questionnaires about their diet, medical history, and medication use, including their use of aspirin, NSAIDs, and acetaminophen, at baseline and every 2 years thereafter. Regular analgesic use was defined as 2 or more times per week.
In 2004, the questionnaire asked participants if they had been professionally diagnosed with hearing loss and, if so, the year of their diagnosis. Incident cases were defined as hearing loss diagnosed after 1986.
The authors analyzed 26,917 men from the original cohort. They excluded men who were diagnosed with hearing loss before 1986; those who had been exposed to ototoxic chemotherapeutic agents; and, because age is such a strong risk factor and the prevalence of hearing loss is so high among the elderly population, those who had reached age 75 years during follow-up.
During 369,079 person-years of follow-up, 3488 cases of hearing loss were reported. Regular analgesic use was independently associated with an increased risk for hearing loss for all 3 types of analgesics.
After controlling for age, race, profession, body mass index, alcohol intake, folate intake, physical activity, smoking, hypertension, diabetes, and the use of other classes of analgesics, the hazard ratios of hearing loss in regular users vs those who used aspirin, NSAIDs, or acetaminophen less than twice per week were 1.12 (95% confidence interval [CI], 1.04 - 1.20) for aspirin, 1.21 (95% CI, 1.11 - 1.33) for NSAIDs, and 1.22 (95% CI, 1.07 - 1.39) for acetaminophen.
These results were further adjusted for a history of elevated cholesterol, cardiovascular disease, use of furosemide, rheumatoid arthritis, and osteoarthritis, and remained the same, the study authors report.
The risk for hearing loss also increased with longer duration of regular use. Men who used aspirin regularly for 1 to 4 years were 28% (95% CI, 17% - 40%) more likely to develop hearing loss than those who did not, although this risk did not increase with longer duration of use, the study authors report.
Men who used NSAIDs for 4 or more years were 33% (95% CI, 18% - 49%) more likely to develop hearing loss, and men who used acetaminophen for 4 or more years were also 33% (95% CI, 14% - 56%) more likely to develop hearing loss.
The study authors also report that the magnitude of the association between analgesic use and hearing loss was substantially higher in younger men. For men younger than 50 years, the hazard ratio (HR) for hearing loss was 1.33 for regular aspirin use, 1.61 for NSAIDs, and 1.99 for acetaminophen. No such association was observed in men 60 years and older.
Combining 2 classes of analgesics also increased the risk for hearing loss, the study authors report. The risk was highest when NSAIDs and acetaminophen were combined (HR, 1.58; 95% CI, 1.16 - 2.16).
Study Limitations
That the diagnosis of hearing loss was self-reported is a limitation of this study. Another is the lack of information on lifetime noise exposure, which is a known risk factor for hearing loss.
In addition, the study population consisted of predominantly white men; therefore, the results may not be generalizable to other racial groups. Other studies in women, younger men, and other racial groups are needed to examine whether similar associations between analgesic use and hearing loss exist in these groups, the study authors write.
Hearing loss because of regular use of analgesics represents an important public health issue, "given the high prevalence of regular analgesic use and health and social implications of hearing impairment," the study authors conclude.
Can Definitive Conclusions Be Made From the Study?
Commenting on the study in an interview with Medscape Family Medicine, Pamela Roehm, MD, PhD, of the New York University School of Medicine, New York, NY, said it was potentially interesting but had certain limitations that make it difficult to draw any definite conclusions.
Dr. Roehm comments on the limitations cited by the study authors: "The study was not designed to look at the link between hearing loss and analgesic use. They don't have any measures of noise exposure, and this is a huge issue, especially with sensory neural hearing loss in men."
The issue of familial hearing loss was not addressed, and neither was the type of hearing loss. "The genetic predilection for hearing loss was not taken into account. Also, this was a study of professional men, mainly Caucasian. There are going to be some genetic tendencies for hearing loss that have not been taken into account by the study," she said.
She agreed that the association between NSAID use and hearing loss has yet to be explained. However, the association between aspirin and hearing loss is well known to be reversible and therefore a problem that is easily remedied.
With regard to the link between acetaminophen and hearing loss, Dr. Roehm said she would have liked to know if codeine was also involved.
"There is not a lot of literature on acetaminophen on its own being linked to hearing loss. In fact, I couldn't find any at all. But there is quite a bit of recent literature on acetaminophen plus codeine and sensory neural hearing loss. This study brings up interesting associations, but a lot of avenues still need to be explored further," she said.
Medscape Family Medicine also interviewed John K. Niparko, MD, director of otolaryngology at Johns Hopkins Medicine in Baltimore, Maryland, for an independent comment on the study. Dr. Niparko told Medscape Family Medicine that the fact that there is no information about noise exposure is a very serious limitation of the study.
"This is a study of observation and association and does not prove that these medicines caused the hearing loss," he said. "These are very valuable medications for a variety of disorders, so we have to be cautious in interpreting results that show an association but do not prove causality."
However, he congratulated the study authors for investigating the potential causes of hearing loss, which "has become a major public health concern in the US."
This study was supported by the National Institutes of Health and the Massachusetts Eye and Ear Infirmary Foundation, Boston. Drs. Curhan, Roehm, and Niparko have have disclosed no relevant financial relationships.
Am J Med. 2010;123:231-237. Abstract
Fran Lowry
March 11, 2010 – Regular use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetaminophen may increase the risk for hearing loss in men, and the impact is larger on those younger than 60 years, according to a prospective study published in the March issue of the American Journal of Medicine.
"Aspirin, acetaminophen, and ibuprofen are the 3 most commonly used drugs in the US," write Sharon G. Curhan, MD, ScM, from Brigham and Women's Hospital, Boston, Massachusetts, and colleagues. "Given that analgesic use might result in pathophysiologic changes in the cochlea and that regular use of these analgesics is so common, the relation of these medications and hearing loss might be an important public health issue."
However, Curhan and colleagues point out several study limitations that may affect the results of their study. Two independent commentators interviewed by Medscape Family Medicine reiterate these limitations and emphasize that causality cannot be determined from the study results. Yet, both agree that the study focuses on an important issue.
Findings of the Study
The aim of this study was to determine if there was an association between regular analgesic use and the risk for hearing loss.
The study subjects were participants in the Health Professionals Follow-up Study, which enrolled 51,529 male dentists, optometrists, osteopathic physicians, pharmacists, podiatrists, and veterinarians aged 40 to 75 years at baseline in 1986. The participants filled out detailed questionnaires about their diet, medical history, and medication use, including their use of aspirin, NSAIDs, and acetaminophen, at baseline and every 2 years thereafter. Regular analgesic use was defined as 2 or more times per week.
In 2004, the questionnaire asked participants if they had been professionally diagnosed with hearing loss and, if so, the year of their diagnosis. Incident cases were defined as hearing loss diagnosed after 1986.
The authors analyzed 26,917 men from the original cohort. They excluded men who were diagnosed with hearing loss before 1986; those who had been exposed to ototoxic chemotherapeutic agents; and, because age is such a strong risk factor and the prevalence of hearing loss is so high among the elderly population, those who had reached age 75 years during follow-up.
During 369,079 person-years of follow-up, 3488 cases of hearing loss were reported. Regular analgesic use was independently associated with an increased risk for hearing loss for all 3 types of analgesics.
After controlling for age, race, profession, body mass index, alcohol intake, folate intake, physical activity, smoking, hypertension, diabetes, and the use of other classes of analgesics, the hazard ratios of hearing loss in regular users vs those who used aspirin, NSAIDs, or acetaminophen less than twice per week were 1.12 (95% confidence interval [CI], 1.04 - 1.20) for aspirin, 1.21 (95% CI, 1.11 - 1.33) for NSAIDs, and 1.22 (95% CI, 1.07 - 1.39) for acetaminophen.
These results were further adjusted for a history of elevated cholesterol, cardiovascular disease, use of furosemide, rheumatoid arthritis, and osteoarthritis, and remained the same, the study authors report.
The risk for hearing loss also increased with longer duration of regular use. Men who used aspirin regularly for 1 to 4 years were 28% (95% CI, 17% - 40%) more likely to develop hearing loss than those who did not, although this risk did not increase with longer duration of use, the study authors report.
Men who used NSAIDs for 4 or more years were 33% (95% CI, 18% - 49%) more likely to develop hearing loss, and men who used acetaminophen for 4 or more years were also 33% (95% CI, 14% - 56%) more likely to develop hearing loss.
The study authors also report that the magnitude of the association between analgesic use and hearing loss was substantially higher in younger men. For men younger than 50 years, the hazard ratio (HR) for hearing loss was 1.33 for regular aspirin use, 1.61 for NSAIDs, and 1.99 for acetaminophen. No such association was observed in men 60 years and older.
Combining 2 classes of analgesics also increased the risk for hearing loss, the study authors report. The risk was highest when NSAIDs and acetaminophen were combined (HR, 1.58; 95% CI, 1.16 - 2.16).
Study Limitations
That the diagnosis of hearing loss was self-reported is a limitation of this study. Another is the lack of information on lifetime noise exposure, which is a known risk factor for hearing loss.
In addition, the study population consisted of predominantly white men; therefore, the results may not be generalizable to other racial groups. Other studies in women, younger men, and other racial groups are needed to examine whether similar associations between analgesic use and hearing loss exist in these groups, the study authors write.
Hearing loss because of regular use of analgesics represents an important public health issue, "given the high prevalence of regular analgesic use and health and social implications of hearing impairment," the study authors conclude.
Can Definitive Conclusions Be Made From the Study?
Commenting on the study in an interview with Medscape Family Medicine, Pamela Roehm, MD, PhD, of the New York University School of Medicine, New York, NY, said it was potentially interesting but had certain limitations that make it difficult to draw any definite conclusions.
Dr. Roehm comments on the limitations cited by the study authors: "The study was not designed to look at the link between hearing loss and analgesic use. They don't have any measures of noise exposure, and this is a huge issue, especially with sensory neural hearing loss in men."
The issue of familial hearing loss was not addressed, and neither was the type of hearing loss. "The genetic predilection for hearing loss was not taken into account. Also, this was a study of professional men, mainly Caucasian. There are going to be some genetic tendencies for hearing loss that have not been taken into account by the study," she said.
She agreed that the association between NSAID use and hearing loss has yet to be explained. However, the association between aspirin and hearing loss is well known to be reversible and therefore a problem that is easily remedied.
With regard to the link between acetaminophen and hearing loss, Dr. Roehm said she would have liked to know if codeine was also involved.
"There is not a lot of literature on acetaminophen on its own being linked to hearing loss. In fact, I couldn't find any at all. But there is quite a bit of recent literature on acetaminophen plus codeine and sensory neural hearing loss. This study brings up interesting associations, but a lot of avenues still need to be explored further," she said.
Medscape Family Medicine also interviewed John K. Niparko, MD, director of otolaryngology at Johns Hopkins Medicine in Baltimore, Maryland, for an independent comment on the study. Dr. Niparko told Medscape Family Medicine that the fact that there is no information about noise exposure is a very serious limitation of the study.
"This is a study of observation and association and does not prove that these medicines caused the hearing loss," he said. "These are very valuable medications for a variety of disorders, so we have to be cautious in interpreting results that show an association but do not prove causality."
However, he congratulated the study authors for investigating the potential causes of hearing loss, which "has become a major public health concern in the US."
This study was supported by the National Institutes of Health and the Massachusetts Eye and Ear Infirmary Foundation, Boston. Drs. Curhan, Roehm, and Niparko have have disclosed no relevant financial relationships.
Am J Med. 2010;123:231-237. Abstract
Thursday, March 11, 2010
Adding ECG Picks up Abnormalities Not Detected by Physical Exam and Medical History
From Heartwire
Michael O'Riordan
March 2, 2010 (Boston, Massachusetts) — Adding electrocardiography (ECG) to a physical examination and medical history significantly improves the sensitivity of screening programs designed to detect abnormalities that would restrict participation in sports, a new study has shown
In a prospective study designed to test the current preparticipation screening program standard of care with a program that includes a 12-lead ECG, researchers showed that screening limited to medical history and physical examination missed a significant percentage of athletes at increased risk for adverse cardiac events. When the ECG was added to screening, there was an improved sensitivity for detecting diseases responsible for sports-related sudden death.
Speaking with heartwire , lead investigator Dr Aaron Baggish (Massachusetts General Hospital, Boston) said that the physical examination, medical history, and 12-lead ECG were "complementary," with the exam and history detecting individuals with valvular disease, while "the strength of the ECG was in its ability to detect myocardial abnormalities."
To heartwire , Baggish said that he agrees with most of the conclusions reached by Maron and that adding 12-lead ECG as part of a mandate for improved public health is "probably not possible at this point."
Instead, he sees the addition of 12-lead ECG to screening programs already in place, such as those around the US for high-school and collegiate sports, as well as other competitive athletic programs.
"If screening with medical history and a physical exam is already in place, then adding the ECG to pick up cardiomyopathies is something that could be done."
The study and editorial are published in the March 2, 2010 issue of the Annals of Internal Medicine.
Data From Collegiate Athletes
In this study, Baggish and colleagues performed a prospective analysis of preparticipation screening with medical history and a physical examination--the current recommended approach in the US--with an approach that includes medical history and physical examination along with a 12-lead ECG. Included in the analysis were 508 Harvard University collegiate athletes, all of whom received standard screening and who then underwent resting 12-lead ECG and transthoracic echocardiography (TTE).
Of the participants screened with TTE, the imaging gold standard, 76% had normal hearts, while another 22% had mildly abnormal findings that were consistent with physiologic remodeling. Abnormalities were detected in 11 patients, or in 2.2%, and of these, three had an abnormality that met current restrictions for permanent or temporary restriction of sports, including one individual with pulmonary stenosis, one with hypertrophic cardiomyopathy, and one with myocarditis.
When using medical history and physical examination alone, clinicians blinded to the TTE results identified five of the 11 abnormalities, all valvular heart disease. Screening with medical history and physical examination failed to identify the one patient with hypertrophic cardiomyopathy and the other with myocarditis.
When ECG screening was added, 10 of the 11 athletes with TTE-detected abnormalities were identified, including all patients who met criteria for restriction from sports.
The combined screening with medical history, physical exam, and ECG had a sensitivity of 90.9%, a specificity of 82.7%, a positive predictive value of 10.4%, and a negative predictive value of 99.8%. Screening with the ECG increased the false-positive rate to 17%, reported investigators.
Baggish said the high false-positive rate has the potential to exclude healthy athletes from sports but believes the high rate is caused by the abnormality criteria used in the study. "The adoption of ECG-based screening only makes sense if there are refined 'abnormality' criteria that account for the normal variations that are common in athletes," he commented.
Michael O'Riordan
March 2, 2010 (Boston, Massachusetts) — Adding electrocardiography (ECG) to a physical examination and medical history significantly improves the sensitivity of screening programs designed to detect abnormalities that would restrict participation in sports, a new study has shown
In a prospective study designed to test the current preparticipation screening program standard of care with a program that includes a 12-lead ECG, researchers showed that screening limited to medical history and physical examination missed a significant percentage of athletes at increased risk for adverse cardiac events. When the ECG was added to screening, there was an improved sensitivity for detecting diseases responsible for sports-related sudden death.
Speaking with heartwire , lead investigator Dr Aaron Baggish (Massachusetts General Hospital, Boston) said that the physical examination, medical history, and 12-lead ECG were "complementary," with the exam and history detecting individuals with valvular disease, while "the strength of the ECG was in its ability to detect myocardial abnormalities."
To heartwire , Baggish said that he agrees with most of the conclusions reached by Maron and that adding 12-lead ECG as part of a mandate for improved public health is "probably not possible at this point."
Instead, he sees the addition of 12-lead ECG to screening programs already in place, such as those around the US for high-school and collegiate sports, as well as other competitive athletic programs.
"If screening with medical history and a physical exam is already in place, then adding the ECG to pick up cardiomyopathies is something that could be done."
The study and editorial are published in the March 2, 2010 issue of the Annals of Internal Medicine.
Data From Collegiate Athletes
In this study, Baggish and colleagues performed a prospective analysis of preparticipation screening with medical history and a physical examination--the current recommended approach in the US--with an approach that includes medical history and physical examination along with a 12-lead ECG. Included in the analysis were 508 Harvard University collegiate athletes, all of whom received standard screening and who then underwent resting 12-lead ECG and transthoracic echocardiography (TTE).
Of the participants screened with TTE, the imaging gold standard, 76% had normal hearts, while another 22% had mildly abnormal findings that were consistent with physiologic remodeling. Abnormalities were detected in 11 patients, or in 2.2%, and of these, three had an abnormality that met current restrictions for permanent or temporary restriction of sports, including one individual with pulmonary stenosis, one with hypertrophic cardiomyopathy, and one with myocarditis.
When using medical history and physical examination alone, clinicians blinded to the TTE results identified five of the 11 abnormalities, all valvular heart disease. Screening with medical history and physical examination failed to identify the one patient with hypertrophic cardiomyopathy and the other with myocarditis.
When ECG screening was added, 10 of the 11 athletes with TTE-detected abnormalities were identified, including all patients who met criteria for restriction from sports.
The combined screening with medical history, physical exam, and ECG had a sensitivity of 90.9%, a specificity of 82.7%, a positive predictive value of 10.4%, and a negative predictive value of 99.8%. Screening with the ECG increased the false-positive rate to 17%, reported investigators.
Baggish said the high false-positive rate has the potential to exclude healthy athletes from sports but believes the high rate is caused by the abnormality criteria used in the study. "The adoption of ECG-based screening only makes sense if there are refined 'abnormality' criteria that account for the normal variations that are common in athletes," he commented.
FDA Says No "Clear Connection" Between Bisphosphonate Use and Femur Fracture Risk
From Medscape Medical News
Robert Lowes
March 11, 2010 — The US Food and Drug Administration (FDA) announced yesterday that patient taking bisphosphonates should continue to do so, barring any recommendation from their physician, as the agency had no evidence to conclude that the drugs increased the risk for femur fractures just below the hip joint.
The FDA advisory came a day after ABC News cited "mounting evidence" allegedly showing that long-term use of alendronate (Fosamax, Merck), a popular bisphosphonate, or its generic versions could cause spontaneous femur fractures in some women.
"At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures," the FDA stated, adding that it has been working closely with outside experts to investigate the issue. The FDA began their ongoing investigation on this topic in June 2008.
The FDA notes that healthcare professionals should follow the recommendations on the drug label when prescribing bisphosphonates, and adverse events potentially associated with bisphosphonates should be reported to MedWatch, the FDA's safety information and adverse event reporting program.
More information is available on the FDA Web site.
To report adverse events related to bisphosphonates, contact MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.
Robert Lowes
March 11, 2010 — The US Food and Drug Administration (FDA) announced yesterday that patient taking bisphosphonates should continue to do so, barring any recommendation from their physician, as the agency had no evidence to conclude that the drugs increased the risk for femur fractures just below the hip joint.
The FDA advisory came a day after ABC News cited "mounting evidence" allegedly showing that long-term use of alendronate (Fosamax, Merck), a popular bisphosphonate, or its generic versions could cause spontaneous femur fractures in some women.
"At this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures," the FDA stated, adding that it has been working closely with outside experts to investigate the issue. The FDA began their ongoing investigation on this topic in June 2008.
The FDA notes that healthcare professionals should follow the recommendations on the drug label when prescribing bisphosphonates, and adverse events potentially associated with bisphosphonates should be reported to MedWatch, the FDA's safety information and adverse event reporting program.
More information is available on the FDA Web site.
To report adverse events related to bisphosphonates, contact MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.
Rescue Breathing Improves CPR Outcomes in Kids
From Heartwire
Reed Miller
March 10, 2010 (Kyoto, Japan) — A large population-based study of pediatric cardiac-arrest patients shows that conventional cardiopulmonary resuscitation (CPR)--with rescue breathing ventilations--is the best approach to resuscitating children outside the hospital [1].
In a study supported by the All-Japan Utstein Registry of the Fire and Disaster Management Agency, Dr Tetsuhisa Kitamura (Kyoto University Health Service, Japan) and colleagues collected data from 5170 children 17 and under with an out-of-hospital cardiac arrest. According to the authors, it is the first study powered to measure the benefits of CPR in pediatric patients.
The results, published online March 3, 2010 in the Lancet, show that bystander CPR without rescue breathing had a much higher rate of favorable neurological outcomes than children who received no CPR. Favorable neurological outcome was defined as a Glasgow-Pittsburgh cerebral performance category of 1 or 2 one month after the arrest.
The study also found that, in children older than one year suffering cardiac arrest from a noncardiac cause such as drug overdose, hanging, drowning, or trauma (71% of the children in the study), CPR with rescue-breathing yielded better results than compression-only CPR. In children in cardiac arrest due to cardiac causes, both types of CPR yielded similar success rates.
Outcomes were uniformly poor in infants younger than one year regardless of resuscitation. Neurologically intact survival rates were around 2% with cardiac arrest of noncardiac origin and about 1% for cardiac arrest of cardiac origins in this population.
Based on the results, Kitamura et al "strongly recommend that conventional CPR, including rescue breathing, continue to be the standard treatment for children who have out-of-hospital cardiac arrests with presumed noncardiac causes."
However, previous research shows that bystanders are more willing to do CPR with chest compressions only, without the ventilations, and the American Heart Association's Hands-Only CPR public-education program tells people to just call 911 and begin chest compressions on a person who has collapsed.
Therefore, since the study showed that compression-only CPR was better than no CPR at all, Kitamura et al recommend that the hands-only approach be taught to the general public to increase the overall rate of bystander CPR.
People who are likely to witness children in cardiac arrest--teachers, parents, lifeguards--should receive additional training to perform conventional CPR with rescue breathing, they recommend.
"Citizens would be increasingly taught compression-only CPR--a simpler technique that is easier to learn, remember, and undertake than is conventional CPR.
If a bystander has learned chest-compression–only CPR, or if a member of the emergency-telephone dispatcher system prefers to teach chest-compression-only CPR rather than conventional CPR because conventional CPR is difficult, the bystander should be encouraged to provide compression-only CPR rather than no bystander CPR."
But Dr Jesus López-Herce and Dr Angel Carrillo Alvarez (Hospital General Universitario Gregorio Marañón, Madrid, Spain) argue, in an accompanying editorial, that the "double-training" strategy advocated by Kitamura and colleagues "could mean that most children would be resuscitated with compression-only CPR, reducing their possibility of survival" .
They suggest teaching everyone conventional CPR with ventilations, with the caveat that compression-only CPR is the best approach in adults suspected of cardiac arrest of cardiac origin, but concede that further research is needed to assess the merits of that approach. And, until further research on the best approach to teaching CPR to the whole population can be completed, chest compression plus ventilation should continue to be taught to the whole population, and no changes should be made to the recommendations for pediatric bystander-initiated CPR, López-Herce and Alvarez maintain.
Reed Miller
March 10, 2010 (Kyoto, Japan) — A large population-based study of pediatric cardiac-arrest patients shows that conventional cardiopulmonary resuscitation (CPR)--with rescue breathing ventilations--is the best approach to resuscitating children outside the hospital [1].
In a study supported by the All-Japan Utstein Registry of the Fire and Disaster Management Agency, Dr Tetsuhisa Kitamura (Kyoto University Health Service, Japan) and colleagues collected data from 5170 children 17 and under with an out-of-hospital cardiac arrest. According to the authors, it is the first study powered to measure the benefits of CPR in pediatric patients.
The results, published online March 3, 2010 in the Lancet, show that bystander CPR without rescue breathing had a much higher rate of favorable neurological outcomes than children who received no CPR. Favorable neurological outcome was defined as a Glasgow-Pittsburgh cerebral performance category of 1 or 2 one month after the arrest.
The study also found that, in children older than one year suffering cardiac arrest from a noncardiac cause such as drug overdose, hanging, drowning, or trauma (71% of the children in the study), CPR with rescue-breathing yielded better results than compression-only CPR. In children in cardiac arrest due to cardiac causes, both types of CPR yielded similar success rates.
Outcomes were uniformly poor in infants younger than one year regardless of resuscitation. Neurologically intact survival rates were around 2% with cardiac arrest of noncardiac origin and about 1% for cardiac arrest of cardiac origins in this population.
Based on the results, Kitamura et al "strongly recommend that conventional CPR, including rescue breathing, continue to be the standard treatment for children who have out-of-hospital cardiac arrests with presumed noncardiac causes."
However, previous research shows that bystanders are more willing to do CPR with chest compressions only, without the ventilations, and the American Heart Association's Hands-Only CPR public-education program tells people to just call 911 and begin chest compressions on a person who has collapsed.
Therefore, since the study showed that compression-only CPR was better than no CPR at all, Kitamura et al recommend that the hands-only approach be taught to the general public to increase the overall rate of bystander CPR.
People who are likely to witness children in cardiac arrest--teachers, parents, lifeguards--should receive additional training to perform conventional CPR with rescue breathing, they recommend.
"Citizens would be increasingly taught compression-only CPR--a simpler technique that is easier to learn, remember, and undertake than is conventional CPR.
If a bystander has learned chest-compression–only CPR, or if a member of the emergency-telephone dispatcher system prefers to teach chest-compression-only CPR rather than conventional CPR because conventional CPR is difficult, the bystander should be encouraged to provide compression-only CPR rather than no bystander CPR."
But Dr Jesus López-Herce and Dr Angel Carrillo Alvarez (Hospital General Universitario Gregorio Marañón, Madrid, Spain) argue, in an accompanying editorial, that the "double-training" strategy advocated by Kitamura and colleagues "could mean that most children would be resuscitated with compression-only CPR, reducing their possibility of survival" .
They suggest teaching everyone conventional CPR with ventilations, with the caveat that compression-only CPR is the best approach in adults suspected of cardiac arrest of cardiac origin, but concede that further research is needed to assess the merits of that approach. And, until further research on the best approach to teaching CPR to the whole population can be completed, chest compression plus ventilation should continue to be taught to the whole population, and no changes should be made to the recommendations for pediatric bystander-initiated CPR, López-Herce and Alvarez maintain.
Should Women Receive Androgen Replacement Therapy, and If So, How?
From Clinical Endocrinology
Susan R. Davis
Posted: 03/01/2010; Clin Endocrinol. 2010;72(2):149-150.
Abstract
The available clinical evidence supports efficacy of testosterone therapy for the treatment of postmenopausal women with hypoactive sexual desire disorder (HSDD) who have undergone a comprehensive clinical evaluation.
Although few preparations designed to deliver an appropriate dose of testosterone for women are available, use of testosterone by women for the management of HSDD is widespread.
Issues that continue to simulate debate in this therapeutic area include whether HSDD is a condition that merits pharmacotherapy, how effective is such treatment and whether testosterone therapy is safe. Hence the question, should women receive androgen replacement therapy, and if so, how?
Introduction
Circulating levels of testosterone and the major pre-androgens, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and androstenedione decline with age in women, with the maximal rate of decline occurring in the premenopausal years (Fig. 1).
However, there is no diagnostic lower limit for any of these circulating steroids which can be used to classify a woman as androgen deficient.
Thus the use of testosterone therapy for women is not based on an established link between symptoms and biochemistry, but rather clinical evidence that exogenous testosterone improves specific parameters of sexual function in women.
Figure 1.
Relationship between age and individual androgens for the reference group.
The most commonly reported sexual problems in women relate to sexual desire and interest, pleasure and global satisfaction.
The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition provides major classifications for female sexual dysfunction (FSD): hypoactive sexual desire disorder (HSDD), sexual arousal disorder, orgasmic disorder, dyspareunia and other (such as aversion).
HSDD is diagnosed when a woman presents with loss of sexual desire in association with personal distress.
The prevalence of HSDD amongst postmenopausal women is in the order of 9 to 14%, with no differences between natural in surgically menopausal women.
Most studies evaluating the efficacy of testosterone for the treatment of FSD have required women to fulfil the diagnostic criteria of HSDD.
The controversies regarding the use of testosterone to treat HSDD appear to be firstly whether this is a condition that merits pharmacological intervention and secondly whether testosterone as a pharmacological intervention is sufficiently effective and safe.
The views expressed in this manuscript differ from the more conservative recommendations by the Endocrine Society Clinical practice guidelines published in 2006 which stated that 'Although there is evidence for short-term efficacy of testosterone in selected populations, such as surgically menopausal women, we recommend against the generalized use of testosterone by women because the indications are inadequate and evidence of safety in long-term studies is lacking'
Since that time several large studies of the efficacy and safety of testosterone and DHEA use in women which have been of longer duration have been published providing more outcome data.
Treatment Options
Presently there is a lack of approved preparations of testosterone specifically suitable for use in women. Use of preparations designed to deliver a dose of testosterone to men cannot be condoned.
In several countries, testosterone therapy is commonly initiated with testosterone pellets implanted under local anaesthetic subcutaneously. Most commonly a dose of 50 mg is used.[43] These implants remain effective for periods of 4 to 6 months. Repeat implantation should not be undertaken without confirmation that total testosterone corrected for SHBG, or free testosterone has fallen back into the lower quartile of the normal female range.
Testosterone transdermal patches have been shown to be effective and have a good short-term safety profile when used by naturally or surgically postmenopausal women with and without concurrent oestrogen therapy.[11,42] The Intrinsa® patch which delivers 300 μg of testosterone daily has been approved for use by surgically menopausal women using concurrent systemic oestrogen therapy in European Union countries. A transdermal testosterone cream for women, marketed as Androfeme1%®, is available in Australia[28] and testosterone gels for women and a transdermal spray are in development.
Various pharmacists prepare testosterone for buccal administration in the form of troches, or as creams, but there are no published pharmacokinetic or safety data or efficacy studies to validate this method of administration.
Some clinicians undertake a clinical trial of intramuscular injections of testosterone esters 50 to 100 mg. This may or may not result in a clinical response over 1–2 weeks or more. A positive response supports the initiation of longer term therapy. However, as peak levels are supraphysiological, testosterone esters should not be considered a long-term treatment option.
Another agent which can be conceived as having androgenic effects (in addition to having properties as an oestrogen and a progestin) is tibolone. In a dose of 2·5 mg daily, it improves sexual function in postmenopausal women.[44] DHEA therapy has not been covered in this article. There are little data to support the use of DHEA for the treatment of sexual dysfunction and safety data are limited.
Conclusion
Taken together, the available clinical evidence supports the efficacy of testosterone therapy for the treatment of postmenopausal women with HSDD who have undergone a comprehensive clinical evaluation. Data for use in women in their late reproductive years remain limited. Available data do not demonstrate serious safety concerns; however, further studies are required to determine the long-term safety of testosterone in women.
http://www.medscape.com/viewarticle/716443_6
Susan R. Davis
Posted: 03/01/2010; Clin Endocrinol. 2010;72(2):149-150.
Abstract
The available clinical evidence supports efficacy of testosterone therapy for the treatment of postmenopausal women with hypoactive sexual desire disorder (HSDD) who have undergone a comprehensive clinical evaluation.
Although few preparations designed to deliver an appropriate dose of testosterone for women are available, use of testosterone by women for the management of HSDD is widespread.
Issues that continue to simulate debate in this therapeutic area include whether HSDD is a condition that merits pharmacotherapy, how effective is such treatment and whether testosterone therapy is safe. Hence the question, should women receive androgen replacement therapy, and if so, how?
Introduction
Circulating levels of testosterone and the major pre-androgens, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and androstenedione decline with age in women, with the maximal rate of decline occurring in the premenopausal years (Fig. 1).
However, there is no diagnostic lower limit for any of these circulating steroids which can be used to classify a woman as androgen deficient.
Thus the use of testosterone therapy for women is not based on an established link between symptoms and biochemistry, but rather clinical evidence that exogenous testosterone improves specific parameters of sexual function in women.
Figure 1.
Relationship between age and individual androgens for the reference group.
The most commonly reported sexual problems in women relate to sexual desire and interest, pleasure and global satisfaction.
The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition provides major classifications for female sexual dysfunction (FSD): hypoactive sexual desire disorder (HSDD), sexual arousal disorder, orgasmic disorder, dyspareunia and other (such as aversion).
HSDD is diagnosed when a woman presents with loss of sexual desire in association with personal distress.
The prevalence of HSDD amongst postmenopausal women is in the order of 9 to 14%, with no differences between natural in surgically menopausal women.
Most studies evaluating the efficacy of testosterone for the treatment of FSD have required women to fulfil the diagnostic criteria of HSDD.
The controversies regarding the use of testosterone to treat HSDD appear to be firstly whether this is a condition that merits pharmacological intervention and secondly whether testosterone as a pharmacological intervention is sufficiently effective and safe.
The views expressed in this manuscript differ from the more conservative recommendations by the Endocrine Society Clinical practice guidelines published in 2006 which stated that 'Although there is evidence for short-term efficacy of testosterone in selected populations, such as surgically menopausal women, we recommend against the generalized use of testosterone by women because the indications are inadequate and evidence of safety in long-term studies is lacking'
Since that time several large studies of the efficacy and safety of testosterone and DHEA use in women which have been of longer duration have been published providing more outcome data.
Treatment Options
Presently there is a lack of approved preparations of testosterone specifically suitable for use in women. Use of preparations designed to deliver a dose of testosterone to men cannot be condoned.
In several countries, testosterone therapy is commonly initiated with testosterone pellets implanted under local anaesthetic subcutaneously. Most commonly a dose of 50 mg is used.[43] These implants remain effective for periods of 4 to 6 months. Repeat implantation should not be undertaken without confirmation that total testosterone corrected for SHBG, or free testosterone has fallen back into the lower quartile of the normal female range.
Testosterone transdermal patches have been shown to be effective and have a good short-term safety profile when used by naturally or surgically postmenopausal women with and without concurrent oestrogen therapy.[11,42] The Intrinsa® patch which delivers 300 μg of testosterone daily has been approved for use by surgically menopausal women using concurrent systemic oestrogen therapy in European Union countries. A transdermal testosterone cream for women, marketed as Androfeme1%®, is available in Australia[28] and testosterone gels for women and a transdermal spray are in development.
Various pharmacists prepare testosterone for buccal administration in the form of troches, or as creams, but there are no published pharmacokinetic or safety data or efficacy studies to validate this method of administration.
Some clinicians undertake a clinical trial of intramuscular injections of testosterone esters 50 to 100 mg. This may or may not result in a clinical response over 1–2 weeks or more. A positive response supports the initiation of longer term therapy. However, as peak levels are supraphysiological, testosterone esters should not be considered a long-term treatment option.
Another agent which can be conceived as having androgenic effects (in addition to having properties as an oestrogen and a progestin) is tibolone. In a dose of 2·5 mg daily, it improves sexual function in postmenopausal women.[44] DHEA therapy has not been covered in this article. There are little data to support the use of DHEA for the treatment of sexual dysfunction and safety data are limited.
Conclusion
Taken together, the available clinical evidence supports the efficacy of testosterone therapy for the treatment of postmenopausal women with HSDD who have undergone a comprehensive clinical evaluation. Data for use in women in their late reproductive years remain limited. Available data do not demonstrate serious safety concerns; however, further studies are required to determine the long-term safety of testosterone in women.
http://www.medscape.com/viewarticle/716443_6
Wednesday, March 10, 2010
Role of Infection in the Development and Exacerbation of Asthma
From Expert Review of Respiratory Medicine
Theresa W Guilbert; Loren C Denlinger
Posted: 03/02/2010; Expert Rev Resp Med. 2010;4(1):71-83. © 2010 Expert Reviews Ltd.
Abstract
Respiratory infections are associated with wheezing illnesses in all ages and may also impact the development and severity of asthma.
Respiratory tract infections caused by viruses, Chlamydophila or Mycoplasma have been hypothesized to have significant roles in the pathogenesis of asthma.
Progress is being made toward establishing the mechanisms by which these agents can cause acute wheezing and impact the pathophysiology of asthma.
Host factors probably contribute to the risk of asthma inception and exacerbation, and these contributions may also vary with respect to early- versus adult-onset disease. This review discusses these various associations as they pertain to the development and exacerbation of asthma.
Introduction
Respiratory infections are associated with wheezing illnesses at all ages and may also impact the development and severity of asthma. Respiratory tract infections caused by viruses, Chlamydophila or Mycoplasma have been hypothesized to have significant roles in the pathogenesis of asthma.
Of these respiratory pathogens, viruses have been shown to be epidemiologically associated with asthma in several ways.
First, particular viruses associated with infantile wheezing have been theorized to lead to the inception of the asthmatic phenotype.
Second, children who experience severe viral respiratory infections in early life are more likely to have asthma later in childhood.
Furthermore, in children and adults with established asthma, viral upper respiratory tract infections (URIs) play a key role in producing acute exacerbations that may lead to healthcare utilization.
Several host factors, such as allergic sensitization and virus-induced interferon responses, modify the risk of virus-induced wheezing.
For infections with other microbes, interest has focused on Chlamydophila and Mycoplasma as possible contributors to both acute exacerbations and the severity of chronic asthma.
Finally, colonization of the upper airways in infancy with common bacterial pathogens has been demonstrated to increase the risk of subsequent asthma. We review these various associations as they pertain to the development and exacerbation of asthma.
Theresa W Guilbert; Loren C Denlinger
Posted: 03/02/2010; Expert Rev Resp Med. 2010;4(1):71-83. © 2010 Expert Reviews Ltd.
Abstract
Respiratory infections are associated with wheezing illnesses in all ages and may also impact the development and severity of asthma.
Respiratory tract infections caused by viruses, Chlamydophila or Mycoplasma have been hypothesized to have significant roles in the pathogenesis of asthma.
Progress is being made toward establishing the mechanisms by which these agents can cause acute wheezing and impact the pathophysiology of asthma.
Host factors probably contribute to the risk of asthma inception and exacerbation, and these contributions may also vary with respect to early- versus adult-onset disease. This review discusses these various associations as they pertain to the development and exacerbation of asthma.
Introduction
Respiratory infections are associated with wheezing illnesses at all ages and may also impact the development and severity of asthma. Respiratory tract infections caused by viruses, Chlamydophila or Mycoplasma have been hypothesized to have significant roles in the pathogenesis of asthma.
Of these respiratory pathogens, viruses have been shown to be epidemiologically associated with asthma in several ways.
First, particular viruses associated with infantile wheezing have been theorized to lead to the inception of the asthmatic phenotype.
Second, children who experience severe viral respiratory infections in early life are more likely to have asthma later in childhood.
Furthermore, in children and adults with established asthma, viral upper respiratory tract infections (URIs) play a key role in producing acute exacerbations that may lead to healthcare utilization.
Several host factors, such as allergic sensitization and virus-induced interferon responses, modify the risk of virus-induced wheezing.
For infections with other microbes, interest has focused on Chlamydophila and Mycoplasma as possible contributors to both acute exacerbations and the severity of chronic asthma.
Finally, colonization of the upper airways in infancy with common bacterial pathogens has been demonstrated to increase the risk of subsequent asthma. We review these various associations as they pertain to the development and exacerbation of asthma.
The Effects of Tobacco on the Fetal Brain - makes it smaller?
From Medscape Pediatrics > Viewpoints
William T. Basco, Jr., MD
J Pediatr. 2010;156:185-190
Study Summary
In the introduction to this report, the investigators review the multiple clinical effects attributed to intrauterine exposure to maternal smoking, but little is known about how fetal tobacco and nicotine exposure affect actual brain development.
This study evaluated a cohort of children born in Finland at a single hospital from 2001 to 2006. The patients were all very-low-birthweight or born < 32 weeks gestational age (very-low gestational age). This analysis included 232 infants. The maternal information was collected at enrollment, or at birth of the infant.
The infants underwent head ultrasound at predetermined points, and cranial magnetic resonance imaging when the infants were at term (by corrected age). The investigators used computer programming to determine volume measurements. Analyses determined the contribution of smoke exposure to brain volume, controlling for multiple prenatal and postnatal clinical features, including gestational age, presence of intraventricular hemorrhage, other clinical complications of prematurity, and maternal factors including alcohol use during pregnancy.
Of the 232 mothers, 42 had smoked during their pregnancy (18.1%), and they smoked a median of 10 cigarettes per day. Of those infants exposed prenatally via maternal smoking, 13% were exposed to more than 20 cigarettes per day. Boys comprised 66.7% of the exposed infants but only 54.2% of the nonexposed infants. The mean gestational age was 29 weeks. Clinical conditions of the infants did not differ between groups, including neonatal inflammatory diseases (septicemia, lung disease, etc), rates of patent ductus arteriosi, or intraventricular hemorrhage.
Mothers who smoked during pregnancy were more likely to drink alcohol during pregnancy (16.7% vs 5.8% of those who didn't smoke). They were also more likely to use illicit drugs during pregnancy, but this difference did not quite reach statistical significance (4.8% of moms who smoked used illicit drugs, compared to 0.5% of those who did not smoke, P = .08).
Although the mean total brain volume did not differ between the 2 groups (390.8 mL in exposed infants, compared with 398.4 mL in nonexposed infants, P = .09), the infants exposed to prenatal smoking had smaller frontal lobe volumes and cerebellar volumes.
The mean frontal lobe volume among infants exposed to prenatal smoking was 117.9 mL compared with 127.3 mL in nonexposed infants, and the cerebellar volume was 23.1 mL compared with 24.5 mL. The differences between frontal lobe and cerebellar volumes remained significant after adjusting for all confounding variables.
Maternal smoking was not associated with different head circumference at birth or at later time points. The authors conclude that prenatal smoking exposure is associated with a smaller frontal lobe and cerebellar volumes.
Viewpoint
I doubt that the results of this study will surprise many practitioners, most of whom (I assume) believe prenatal smoke exposure to be detrimental to a developing fetus, but actually finding brain volume associations is really eye-opening. Sadly, even these striking findings may not be enough to persuade women with nicotine addiction to not smoke during pregnancy, but it is always nice to have those discussions take place from a basis of data.
The investigators caution that it is unclear what clinical implications can be drawn from lower frontal lobe or cerebellar volumes, because this study did not report on development or functioning of the children as they aged. However, the discussion section reviews other studies that show lower frontal lobe or cerebellar volume in children and adults with behavioral problems, including attention-deficit/hyperactivity disorder, suggesting that intrauterine smoke exposure might be related to attention-deficit/hyperactivity disorder. Again, this study could raise
Because of the degree to which mothers who smoked in this study were also more likely to use alcohol during pregnancy, and have a higher rate of illicit drug use, this study points out the importance of statistically controlling for other factors that occur along with smoking, because several of these variables would also be hypothesized to have adverse effects on the developing brain.
William T. Basco, Jr., MD
J Pediatr. 2010;156:185-190
Study Summary
In the introduction to this report, the investigators review the multiple clinical effects attributed to intrauterine exposure to maternal smoking, but little is known about how fetal tobacco and nicotine exposure affect actual brain development.
This study evaluated a cohort of children born in Finland at a single hospital from 2001 to 2006. The patients were all very-low-birthweight or born < 32 weeks gestational age (very-low gestational age). This analysis included 232 infants. The maternal information was collected at enrollment, or at birth of the infant.
The infants underwent head ultrasound at predetermined points, and cranial magnetic resonance imaging when the infants were at term (by corrected age). The investigators used computer programming to determine volume measurements. Analyses determined the contribution of smoke exposure to brain volume, controlling for multiple prenatal and postnatal clinical features, including gestational age, presence of intraventricular hemorrhage, other clinical complications of prematurity, and maternal factors including alcohol use during pregnancy.
Of the 232 mothers, 42 had smoked during their pregnancy (18.1%), and they smoked a median of 10 cigarettes per day. Of those infants exposed prenatally via maternal smoking, 13% were exposed to more than 20 cigarettes per day. Boys comprised 66.7% of the exposed infants but only 54.2% of the nonexposed infants. The mean gestational age was 29 weeks. Clinical conditions of the infants did not differ between groups, including neonatal inflammatory diseases (septicemia, lung disease, etc), rates of patent ductus arteriosi, or intraventricular hemorrhage.
Mothers who smoked during pregnancy were more likely to drink alcohol during pregnancy (16.7% vs 5.8% of those who didn't smoke). They were also more likely to use illicit drugs during pregnancy, but this difference did not quite reach statistical significance (4.8% of moms who smoked used illicit drugs, compared to 0.5% of those who did not smoke, P = .08).
Although the mean total brain volume did not differ between the 2 groups (390.8 mL in exposed infants, compared with 398.4 mL in nonexposed infants, P = .09), the infants exposed to prenatal smoking had smaller frontal lobe volumes and cerebellar volumes.
The mean frontal lobe volume among infants exposed to prenatal smoking was 117.9 mL compared with 127.3 mL in nonexposed infants, and the cerebellar volume was 23.1 mL compared with 24.5 mL. The differences between frontal lobe and cerebellar volumes remained significant after adjusting for all confounding variables.
Maternal smoking was not associated with different head circumference at birth or at later time points. The authors conclude that prenatal smoking exposure is associated with a smaller frontal lobe and cerebellar volumes.
Viewpoint
I doubt that the results of this study will surprise many practitioners, most of whom (I assume) believe prenatal smoke exposure to be detrimental to a developing fetus, but actually finding brain volume associations is really eye-opening. Sadly, even these striking findings may not be enough to persuade women with nicotine addiction to not smoke during pregnancy, but it is always nice to have those discussions take place from a basis of data.
The investigators caution that it is unclear what clinical implications can be drawn from lower frontal lobe or cerebellar volumes, because this study did not report on development or functioning of the children as they aged. However, the discussion section reviews other studies that show lower frontal lobe or cerebellar volume in children and adults with behavioral problems, including attention-deficit/hyperactivity disorder, suggesting that intrauterine smoke exposure might be related to attention-deficit/hyperactivity disorder. Again, this study could raise
Because of the degree to which mothers who smoked in this study were also more likely to use alcohol during pregnancy, and have a higher rate of illicit drug use, this study points out the importance of statistically controlling for other factors that occur along with smoking, because several of these variables would also be hypothesized to have adverse effects on the developing brain.
Tuesday, March 9, 2010
FDA Mandates New Safety Controls for Long-Acting Beta Agonists
From MedscapeCME Clinical Briefs > FDA Approvals and Safety Changes for CME
News Author: Robert Lowes
CME Author: Yael Waknine
February 25, 2010 — The US Food and Drug Administration (FDA) announced on February 24 that manufacturers of long-acting beta agonists (LABAs) must now state on product labels that asthma patients must not take LABAs on a long-term basis unless their condition cannot be adequately controlled with other medications such as inhaled corticosteroids.
The labels also must state that the LABAs should never be used alone in the treatment of asthma in adults or children. Instead, they should be combined with an asthma "controller" medication.
Roughly 95% of asthma patients using a LABA receive it in combination with a corticosteroid in a single inhaled product such as Advair Diskus, Advair HFA, or Symbicort, according to the FDA.
Advair Diskus and Advair HFA both contain a LABA called salmeterol (Severent), and Symbicort contains the LABA formoterol (Foradil). These LABAs, along with arformoterol (Brovana), are also marketed as stand-alone medications.
Under the agency's new safety controls, LABA manufacturers must state on product labels that pediatric and adolescent patients who need a LABA in addition to a corticosteroid should be prescribed one of these combination products, as opposed to 2 separate drugs, to ensure medication compliance
Clinical Implications
Because of the increased risk for severe and potentially fatal exacerbations, patients with asthma must not take LABAs on a long-term basis unless their condition cannot be adequately controlled with other medications such as inhaled corticosteroids.
This limitation does not apply to patients receiving LABAs for chronic obstructive pulmonary disease.
LABAs should only be prescribed together with inhaled corticosteroids and other controller medications; pediatric and adolescent patients should receive a combination product to ensure compliance.
Treatment should be minimized to the shortest duration required to achieve control of asthma symptoms.
Clinical trial data have demonstrated that the addition of the LABA salmeterol to usual asthma therapy is linked to an increased risk for fatal asthma events. Salmeterol is linked to an increased risk for respiratory and asthma-related deaths relative to albuterol.
LABAs are associated with an increased risk for asthma-related death, intubation, and hospitalization, particularly in pediatric patients.
News Author: Robert Lowes
CME Author: Yael Waknine
February 25, 2010 — The US Food and Drug Administration (FDA) announced on February 24 that manufacturers of long-acting beta agonists (LABAs) must now state on product labels that asthma patients must not take LABAs on a long-term basis unless their condition cannot be adequately controlled with other medications such as inhaled corticosteroids.
The labels also must state that the LABAs should never be used alone in the treatment of asthma in adults or children. Instead, they should be combined with an asthma "controller" medication.
Roughly 95% of asthma patients using a LABA receive it in combination with a corticosteroid in a single inhaled product such as Advair Diskus, Advair HFA, or Symbicort, according to the FDA.
Advair Diskus and Advair HFA both contain a LABA called salmeterol (Severent), and Symbicort contains the LABA formoterol (Foradil). These LABAs, along with arformoterol (Brovana), are also marketed as stand-alone medications.
Under the agency's new safety controls, LABA manufacturers must state on product labels that pediatric and adolescent patients who need a LABA in addition to a corticosteroid should be prescribed one of these combination products, as opposed to 2 separate drugs, to ensure medication compliance
Clinical Implications
Because of the increased risk for severe and potentially fatal exacerbations, patients with asthma must not take LABAs on a long-term basis unless their condition cannot be adequately controlled with other medications such as inhaled corticosteroids.
This limitation does not apply to patients receiving LABAs for chronic obstructive pulmonary disease.
LABAs should only be prescribed together with inhaled corticosteroids and other controller medications; pediatric and adolescent patients should receive a combination product to ensure compliance.
Treatment should be minimized to the shortest duration required to achieve control of asthma symptoms.
Clinical trial data have demonstrated that the addition of the LABA salmeterol to usual asthma therapy is linked to an increased risk for fatal asthma events. Salmeterol is linked to an increased risk for respiratory and asthma-related deaths relative to albuterol.
LABAs are associated with an increased risk for asthma-related death, intubation, and hospitalization, particularly in pediatric patients.
Friday, March 5, 2010
New Alzheimer's Tool Predicts Disease Progression
From Medscape Medical News
Janis C. Kelly
March 4, 2010 — An Alzheimer's disease (AD) progression rate measure that can be calculated at the initial visit can reliably predict how quickly the individual patient will lose cognitive and other abilities.
Rachelle Doody, MD, PhD, and colleagues from Baylor College of Medicine in Houston, Texas, report initial results using the prognosis indicator with 597 patients followed up for 15 years published online February 23 in Alzheimer's Research & Therapy.
“Patients and families frequently ask clinicians to predict expected rates of cognitive and functional decline, and clinicians currently have little basis for making such decisions," Dr. Doody told Medscape Neurology.
"We’ve found that a simple, calculated progression rate at the initial visit gives reliable information regarding performance over time," she said. "The slowest progression group also survives longer."
Calculating AD Progression Rate
The preprogression rate is calculated using a standard assessment of symptom duration in years and the baseline Mini-Mental State Examination (MMSE) score. The estimate of duration includes a series of questions about the duration of specific symptoms that might be a sign of AD, medical records review, and informant interview.
The study authors explain, “Since a cognitively intact individual should obtain the maximum MMSE score of 30, the preprogression rate is given by the formula: (30 − baseline MMSE)/estimated duration of symptoms in years.”
Those with an MMSE score decrease of less than 2 points per year were classified as slow progressors. Intermediate progressors were defined as having a 2- to 4-point decrease per year and rapid progression as a 5 point or greater decrease per year in MMSE score.
Dr. Doody told Medscape Neurology, “The procedures for obtaining and using the information are not yet in common use, but they could be. With further refinement, physicians could use this work to tell patients whether they fall into a slow, intermediate, or rapidly progressing category with respect to the intrinsic progression of their AD. They might decide upon follow-up intervals and how aggressive to be with medications based upon the progression rate. Once started on therapy, it might be possible to alter the intrinsic rate, but this requires further study.”
The researchers examined outcomes for patients annually for up to 15 years using the MMSE, the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAScog), the Verbal Series Attention Test, the Clinical Dementia Rating Scale Sum of Boxes, and the Lawton and Brody Activities of Daily Living Scale, which combines the Physical Self-Maintenance Scale and the Instrumental Activities of Daily Living Scale.
Slow Progressors Also Live Longer
The investigators found that patients in the slow and intermediate groups maintained better performance on tests of cognitive function, global function, and complex activities of daily living than the rapid progressors. For example, slow progressors gained 0.6 fewer points per year on the ADAScog and intermediate progressors 0.8 fewer points per year than rapid progressors.
At study entry, the slow progressors also had a longer estimated duration of symptoms than intermediate or fast progressors, as well as higher IQ and education.
Slow progressors also lived longer. Median survival was 4.7 years for slow, 4.1 years for intermediate, and 2.5 years for rapid progressors, adjusted for age, sex, education, and baseline severity (hazard ratio, 0.62 for slow vs fast progressors).
“Our results suggest that prognostications based upon initial progression rate are most reliable for slow and fast progressors but that long duration reliability of an intermediate progression rate may depend upon the patient's age and life expectancy at diagnosis," the study authors conclude. "It would be safe to say that an intermediate progressor may remain so for several years, but that, if the patient lives for a long time after diagnosis, the rate may increase sufficiently to affect both abilities and survival."
Next Question: Can Drugs Alter Progression Rate?
Whether these “apparently intrinsic” progression rates can be modified by antidementia drug treatment is a key unanswered question that must be answered before the progression rate tool can be adopted for clinical use, the study authors say.
For now, Dr. Doody said, “Physicians could tell patients that people do not progress naturally at the same rate and that their individualized progression characteristics should be taken into account in planning their treatment and in monitoring their response to therapy. They could also say that the proposed rate requires some procedures that are not yet in everyday use (a standardized estimate of duration) and that they will decide over time whether or not to incorporate these procedures into what they do based upon continued studies of its utility.”
This study also has implications for AD clinical trial design. “Currently, parallel group studies count on randomization to yield comparable placebo and treatment groups," the study authors write. "Preprogression rates are not assessed, yet imbalances across the treatment groups in this important variable could obscure or create treatment differences. Future clinical trials may benefit from gathering systematic data regarding individual symptom onset in order to perform a formal estimate of duration and to calculate preprogression rates.”
Not Ready for Routine Use
Cognitive neurologist Alireza Atri, MD, PhD, agreed that this might be useful. Dr. Atri, who recently analyzed long-term effectiveness of combination therapy in AD (Alzheimer Dis Assoc Disord. 2008;11:209-221), is director of the Memory Disorders & Special Dementia Units at the Veterans' Affairs Geriatric Research Education and Clinical Center in Bedford, Massachusetts, and assistant in neurology at Massachusetts General Hospital/Harvard Medical School in Boston.
Asked by Medscape Neurology to comment on this study, Dr. Atri said, “I think this is an important study with several exceptional strengths, including utilization of a large, well-characterized longitudinal clinical cohort with useful measure and endpoints and analysis using sophisticated methods guided by good clinical and scientific knowledge from a leader in the field who has an uncommon perspective and expertise, working at the interface of clinical care and clinical trials and utilizing quantitative methodology to address important questions with great practical implications that, thus far, have been mostly neglected, overlooked, and/or underappreciated.”
Dr. Atri noted that although this model for predicting risk and prognosis in AD is not yet ready for routine use, it “provides a very good enhancement/upgrade from previous work and prognostication models, including some of Dr. Doody's own work, that integrate patient demographics and clinical characteristics and measures, including test scores, type and duration of symptoms, and physical exam findings, at a first clinical visit to a neurologist/physician in order to better predict the highly variable individual course we see in patients with Alzheimer's disease.”
Dr. Atri said that the study raises questions that need to be addressed further, including the effect of antidementia medications, vitamins and dietary supplements, vascular risk factors, behavioral symptoms, physical findings, especially parkinsonism and extrapyramidal signs, and genetic susceptibility factors, such as APOE-e4 status.
“We are a ways away still, but we desperately need to be wiser and more efficient in our approaches to gathering and using clinical data," Dr. Atri said. "I agree that clinical trials should heed Dr. Doody’s findings and incorporate more data and approaches like this to minimize risk of imbalances between or within treatment groups that can easily obscure signals of efficacy in Alzheimer's disease trials.”
The study was supported by the National Institutes of Health and by the Alzheimer's Association. Dr. Doody receives support from the Cain Foundation and from the Cynthia and George Mitchell Foundation. Dr. Atri has disclosed no relevant financial relationships.
Alzheimer Res Ther. Published online February 23, 2009.
Janis C. Kelly
March 4, 2010 — An Alzheimer's disease (AD) progression rate measure that can be calculated at the initial visit can reliably predict how quickly the individual patient will lose cognitive and other abilities.
Rachelle Doody, MD, PhD, and colleagues from Baylor College of Medicine in Houston, Texas, report initial results using the prognosis indicator with 597 patients followed up for 15 years published online February 23 in Alzheimer's Research & Therapy.
“Patients and families frequently ask clinicians to predict expected rates of cognitive and functional decline, and clinicians currently have little basis for making such decisions," Dr. Doody told Medscape Neurology.
"We’ve found that a simple, calculated progression rate at the initial visit gives reliable information regarding performance over time," she said. "The slowest progression group also survives longer."
Calculating AD Progression Rate
The preprogression rate is calculated using a standard assessment of symptom duration in years and the baseline Mini-Mental State Examination (MMSE) score. The estimate of duration includes a series of questions about the duration of specific symptoms that might be a sign of AD, medical records review, and informant interview.
The study authors explain, “Since a cognitively intact individual should obtain the maximum MMSE score of 30, the preprogression rate is given by the formula: (30 − baseline MMSE)/estimated duration of symptoms in years.”
Those with an MMSE score decrease of less than 2 points per year were classified as slow progressors. Intermediate progressors were defined as having a 2- to 4-point decrease per year and rapid progression as a 5 point or greater decrease per year in MMSE score.
Dr. Doody told Medscape Neurology, “The procedures for obtaining and using the information are not yet in common use, but they could be. With further refinement, physicians could use this work to tell patients whether they fall into a slow, intermediate, or rapidly progressing category with respect to the intrinsic progression of their AD. They might decide upon follow-up intervals and how aggressive to be with medications based upon the progression rate. Once started on therapy, it might be possible to alter the intrinsic rate, but this requires further study.”
The researchers examined outcomes for patients annually for up to 15 years using the MMSE, the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAScog), the Verbal Series Attention Test, the Clinical Dementia Rating Scale Sum of Boxes, and the Lawton and Brody Activities of Daily Living Scale, which combines the Physical Self-Maintenance Scale and the Instrumental Activities of Daily Living Scale.
Slow Progressors Also Live Longer
The investigators found that patients in the slow and intermediate groups maintained better performance on tests of cognitive function, global function, and complex activities of daily living than the rapid progressors. For example, slow progressors gained 0.6 fewer points per year on the ADAScog and intermediate progressors 0.8 fewer points per year than rapid progressors.
At study entry, the slow progressors also had a longer estimated duration of symptoms than intermediate or fast progressors, as well as higher IQ and education.
Slow progressors also lived longer. Median survival was 4.7 years for slow, 4.1 years for intermediate, and 2.5 years for rapid progressors, adjusted for age, sex, education, and baseline severity (hazard ratio, 0.62 for slow vs fast progressors).
“Our results suggest that prognostications based upon initial progression rate are most reliable for slow and fast progressors but that long duration reliability of an intermediate progression rate may depend upon the patient's age and life expectancy at diagnosis," the study authors conclude. "It would be safe to say that an intermediate progressor may remain so for several years, but that, if the patient lives for a long time after diagnosis, the rate may increase sufficiently to affect both abilities and survival."
Next Question: Can Drugs Alter Progression Rate?
Whether these “apparently intrinsic” progression rates can be modified by antidementia drug treatment is a key unanswered question that must be answered before the progression rate tool can be adopted for clinical use, the study authors say.
For now, Dr. Doody said, “Physicians could tell patients that people do not progress naturally at the same rate and that their individualized progression characteristics should be taken into account in planning their treatment and in monitoring their response to therapy. They could also say that the proposed rate requires some procedures that are not yet in everyday use (a standardized estimate of duration) and that they will decide over time whether or not to incorporate these procedures into what they do based upon continued studies of its utility.”
This study also has implications for AD clinical trial design. “Currently, parallel group studies count on randomization to yield comparable placebo and treatment groups," the study authors write. "Preprogression rates are not assessed, yet imbalances across the treatment groups in this important variable could obscure or create treatment differences. Future clinical trials may benefit from gathering systematic data regarding individual symptom onset in order to perform a formal estimate of duration and to calculate preprogression rates.”
Not Ready for Routine Use
Cognitive neurologist Alireza Atri, MD, PhD, agreed that this might be useful. Dr. Atri, who recently analyzed long-term effectiveness of combination therapy in AD (Alzheimer Dis Assoc Disord. 2008;11:209-221), is director of the Memory Disorders & Special Dementia Units at the Veterans' Affairs Geriatric Research Education and Clinical Center in Bedford, Massachusetts, and assistant in neurology at Massachusetts General Hospital/Harvard Medical School in Boston.
Asked by Medscape Neurology to comment on this study, Dr. Atri said, “I think this is an important study with several exceptional strengths, including utilization of a large, well-characterized longitudinal clinical cohort with useful measure and endpoints and analysis using sophisticated methods guided by good clinical and scientific knowledge from a leader in the field who has an uncommon perspective and expertise, working at the interface of clinical care and clinical trials and utilizing quantitative methodology to address important questions with great practical implications that, thus far, have been mostly neglected, overlooked, and/or underappreciated.”
Dr. Atri noted that although this model for predicting risk and prognosis in AD is not yet ready for routine use, it “provides a very good enhancement/upgrade from previous work and prognostication models, including some of Dr. Doody's own work, that integrate patient demographics and clinical characteristics and measures, including test scores, type and duration of symptoms, and physical exam findings, at a first clinical visit to a neurologist/physician in order to better predict the highly variable individual course we see in patients with Alzheimer's disease.”
Dr. Atri said that the study raises questions that need to be addressed further, including the effect of antidementia medications, vitamins and dietary supplements, vascular risk factors, behavioral symptoms, physical findings, especially parkinsonism and extrapyramidal signs, and genetic susceptibility factors, such as APOE-e4 status.
“We are a ways away still, but we desperately need to be wiser and more efficient in our approaches to gathering and using clinical data," Dr. Atri said. "I agree that clinical trials should heed Dr. Doody’s findings and incorporate more data and approaches like this to minimize risk of imbalances between or within treatment groups that can easily obscure signals of efficacy in Alzheimer's disease trials.”
The study was supported by the National Institutes of Health and by the Alzheimer's Association. Dr. Doody receives support from the Cain Foundation and from the Cynthia and George Mitchell Foundation. Dr. Atri has disclosed no relevant financial relationships.
Alzheimer Res Ther. Published online February 23, 2009.
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