Two Tests Added to Recommended List to Prevent or Detect Colorectal Cancer
By DENISE GRADY
The American Cancer Society and other health groups are recommending two tests they had not previously endorsed to prevent or detect colorectal cancer, the groups said Wednesday.
The new policy is based on evidence that the tests work well enough to recommend and applies to all adults 50 and older and to some younger people with symptoms or risk factors for colon cancer.
One test is virtual colonoscopy, which uses a CT scan to look for abnormal growths and, unlike the standard colonoscopy, does not require inserting a camera-tipped tube rectally.
The other test examines stool to find abnormal DNA associated with cancer and requires an entire bowel movement be packed in a kit and sent to a laboratory.
The tests are now part of a list of seven testing options from which people can choose. The medical groups are providing as many options as possible, they say, hoping patients find one acceptable.
Colorectal cancer is the second leading cause of cancer death in the United States, with 49,960 deaths and 148,810 new cases expected in 2008.
Many people are so squeamish about tests for the disease that they skip them entirely. It is one of the very few cancers that can be entirely prevented by removing polyps or other precancerous growths or can be cured if detected early.
“Fifty percent of the population gets no screening,” said Dr. Grace H. Elta, a gastroenterologist and professor at the University of Michigan who is president of the American Society for Gastrointestinal Endoscopy. “Any screening is better than that.”
The new guidelines organize the tests in two groups and specify the intervals to perform them.
The first group consists of tests that can detect cancer or prevent it by finding precancerous growths. It includes colonoscopy, which examines the entire colon; flexible sigmoidoscopy, which examines part of the colon; barium enemas; and virtual colonoscopy.
The second group primarily detects cancer, rather than preventing it. Two tests look for blood in the stool, and the third is the stool DNA test. Blood in the stool does not necessarily indicate cancer but requires follow-up.
“Prevention should be the primary goal,” said Dr. Robert Smith, director of screening for the cancer society.
That would mean that the first group of tests is preferable. But Dr. Smith said some people were unwilling to have them or unable to afford them.
Right now, Dr. Elta said, insurers do not cover virtual colonoscopy, which she said costs $1,200 to $1,500. It is uncertain whether the new guidelines will lead to coverage changes.
None of the tests are perfect. Doctors who perform colonoscopy, for instance, may fail to see precancerous lesions. Virtual colonoscopy will probably fail to detect lesions that are flat, a type that is especially risky and more common in the United States than previously realized, researchers reported Tuesday in The Journal of the American Medical Association.
Tests for blood in the stool generally miss polyps and detect just half of tumors. Sigmoidoscopy does not reach the upper stretches of the colon.
As for the stool DNA test, Dr. Elta said, “It’s really not ready for prime time.” The test is not accurate enough, she said, and in many instances not reimbursed by insurers.
“Most people are not using it right now,” she said. “The biggest hope of all is if it ever gets good enough to pick up polyps. It’s the test with the most promise, but right now it has no efficacy at picking up polyps.”
Thursday, March 06, 2008
Patients Accept Dementia Diagnosis with Composure
By Todd Neale
ST. LOUIS, March 5 -- A medical diagnosis of dementia is not necessarily the emotional roller-coaster it's cracked up to be, researchers here found. Indeed, many patients getting the news of dementia had less anxiety following the diagnosis and did not have major swings in depression, regardless of the level of impairment, Brian Carpenter, Ph.D., of Washington University, and colleagues reported in the March issue of the Journal of the American Geriatrics Society. Likewise, the patients' companions -- spouses, adult children, other family members, and friends -- kept their emotions under control after hearing a diagnosis, the investigators found.
Action Points --->
Explain to interested patients that this study found that learning whether a patient had dementia was not met with increases in depression or anxiety, regardless of diagnosis or dementia severity.
"Disclosure of a dementia diagnosis does not prompt a catastrophic emotional reaction in most people, even those who are only mildly impaired," the researchers said, "and may provide some relief once an explanation for symptoms is known and a treatment plan is developed."
Two recent literature reviews found that physicians are hesitant to disclose a suspected diagnosis of dementia to patients. Possible reasons include being uncomfortable making a diagnosis of dementia in its earliest stages, the thought that patients with cognitive impairment will fail to comprehend the diagnosis, and the lack of effective treatments.
Another reported concern is that the diagnosis will result in excessive emotional reactions, including depression or suicide.
To examine the validity of this last possibility, Dr. Carpenter and colleagues recruited 90 patients who were already involved with the Memory and Aging Project at Washington University's Alzheimer's Disease Research Center. A companion for each patient was enrolled to evaluate the effects of a diagnosis on caregivers.
Each participant completed a questionnaire that was used to rate levels of depression and anxiety prior to the patients receiving a physical and neurological examination.
Anxiety was assessed with the State-Trait Anxiety Inventory and depression was measured using the Geriatric Depression Scale.
Following the examination, patients and companions were brought in for the formal diagnosis.
Anxiety and depression were then reassessed by telephone interviews an average of 2.7 ± 2.0 days after diagnosis.
More than two-thirds (69%) of the patients were told they had dementia, with the rest receiving a diagnosis of no dementia.
More than a quarter (28%) of patients said they previously had been told by a physician that they might have dementia; 48% of companions said the patients had dementia, revealing a significant discrepancy in recollection (P<0.05), according to the researchers.
Compared with baseline, patients had a nonsignificant mean increase of 0.29 points on a depression scale of 15 after learning their dementia status (P=0.18), regardless of diagnosis or dementia severity.
Companions had a significant mean decrease of 0.43 points on the depression scale (P=0.03); however, "despite the statistical significance, this represents a clinically minor shift in depressive symptoms," the researchers said.
Patients with high levels of anxiety before diagnosis had a significant mean decrease of 12.60 points on an anxiety scale of 80 (P<0.001) after finding out whether they had dementia.
Companions with high levels of anxiety were also less anxious following diagnosis (mean decrease of 6.44 points, P<0.001).
Patients and companions with low levels of anxiety at baseline had no significant changes.
Scores on the anxiety scale decreased significantly in patients and companions who had previously been told the patient might have dementia (mean decrease 7.13 points, P<0.001) and in those who never received that information (mean decrease 3.83 points, P<0.001).
To explain the lower levels of anxiety, Dr. Carpenter and colleagues suggested that "individuals who were given a clean bill of health were reassured, because they learned that nothing was wrong or that there might have been an explanation for their symptoms (e.g., other psychiatric or medical condition) that, although deserving attention, did not have the same gravity as dementia."
"In contrast," they continued, "individuals who were told that they had dementia may have taken some comfort in having an official diagnosis and explanation for symptoms." These patients "have an opportunity to plan and prepare for the future while they are still capable, to learn about community resources and supports, and begin pharmacological interventions that may slow disease progression."
According to the researchers, the study was limited by the assessments of depression and anxiety, which may not have detected subtle changes. Evaluating these factors at only two time points may have restricted the researchers' ability to measure the "ebb and flow" of emotional reactions.
Also, participants who are cognitively impaired may have difficulty describing their mood, they said.
Generalizability of the results may be limited by the fact that the study was conducted in a dedicated Alzheimer's disease research center. "That name alone is likely to influence expectations," the researchers said.
The Alzheimer's Disease Research Center and one of Dr. Carpenter's co-authors are supported by grants from the National Institute on Aging. Support for this study was provided by a grant to another co-author from the University of Missouri Alzheimer's Disease and Related Disorders Program.
The authors reported no conflicts of interest.
Primary source: Journal of the American Geriatrics SocietySource reference:Carpenter B, et al "Reaction to a dementia diagnosis in individuals with Alzheimer's disease and mild cognitive impairment" J Am Geriatrics Soc 2008; DOI: 10.1111/j.1532-5415.2007.01600.x.
By Todd Neale
ST. LOUIS, March 5 -- A medical diagnosis of dementia is not necessarily the emotional roller-coaster it's cracked up to be, researchers here found. Indeed, many patients getting the news of dementia had less anxiety following the diagnosis and did not have major swings in depression, regardless of the level of impairment, Brian Carpenter, Ph.D., of Washington University, and colleagues reported in the March issue of the Journal of the American Geriatrics Society. Likewise, the patients' companions -- spouses, adult children, other family members, and friends -- kept their emotions under control after hearing a diagnosis, the investigators found.
Action Points --->
Explain to interested patients that this study found that learning whether a patient had dementia was not met with increases in depression or anxiety, regardless of diagnosis or dementia severity.
"Disclosure of a dementia diagnosis does not prompt a catastrophic emotional reaction in most people, even those who are only mildly impaired," the researchers said, "and may provide some relief once an explanation for symptoms is known and a treatment plan is developed."
Two recent literature reviews found that physicians are hesitant to disclose a suspected diagnosis of dementia to patients. Possible reasons include being uncomfortable making a diagnosis of dementia in its earliest stages, the thought that patients with cognitive impairment will fail to comprehend the diagnosis, and the lack of effective treatments.
Another reported concern is that the diagnosis will result in excessive emotional reactions, including depression or suicide.
To examine the validity of this last possibility, Dr. Carpenter and colleagues recruited 90 patients who were already involved with the Memory and Aging Project at Washington University's Alzheimer's Disease Research Center. A companion for each patient was enrolled to evaluate the effects of a diagnosis on caregivers.
Each participant completed a questionnaire that was used to rate levels of depression and anxiety prior to the patients receiving a physical and neurological examination.
Anxiety was assessed with the State-Trait Anxiety Inventory and depression was measured using the Geriatric Depression Scale.
Following the examination, patients and companions were brought in for the formal diagnosis.
Anxiety and depression were then reassessed by telephone interviews an average of 2.7 ± 2.0 days after diagnosis.
More than two-thirds (69%) of the patients were told they had dementia, with the rest receiving a diagnosis of no dementia.
More than a quarter (28%) of patients said they previously had been told by a physician that they might have dementia; 48% of companions said the patients had dementia, revealing a significant discrepancy in recollection (P<0.05), according to the researchers.
Compared with baseline, patients had a nonsignificant mean increase of 0.29 points on a depression scale of 15 after learning their dementia status (P=0.18), regardless of diagnosis or dementia severity.
Companions had a significant mean decrease of 0.43 points on the depression scale (P=0.03); however, "despite the statistical significance, this represents a clinically minor shift in depressive symptoms," the researchers said.
Patients with high levels of anxiety before diagnosis had a significant mean decrease of 12.60 points on an anxiety scale of 80 (P<0.001) after finding out whether they had dementia.
Companions with high levels of anxiety were also less anxious following diagnosis (mean decrease of 6.44 points, P<0.001).
Patients and companions with low levels of anxiety at baseline had no significant changes.
Scores on the anxiety scale decreased significantly in patients and companions who had previously been told the patient might have dementia (mean decrease 7.13 points, P<0.001) and in those who never received that information (mean decrease 3.83 points, P<0.001).
To explain the lower levels of anxiety, Dr. Carpenter and colleagues suggested that "individuals who were given a clean bill of health were reassured, because they learned that nothing was wrong or that there might have been an explanation for their symptoms (e.g., other psychiatric or medical condition) that, although deserving attention, did not have the same gravity as dementia."
"In contrast," they continued, "individuals who were told that they had dementia may have taken some comfort in having an official diagnosis and explanation for symptoms." These patients "have an opportunity to plan and prepare for the future while they are still capable, to learn about community resources and supports, and begin pharmacological interventions that may slow disease progression."
According to the researchers, the study was limited by the assessments of depression and anxiety, which may not have detected subtle changes. Evaluating these factors at only two time points may have restricted the researchers' ability to measure the "ebb and flow" of emotional reactions.
Also, participants who are cognitively impaired may have difficulty describing their mood, they said.
Generalizability of the results may be limited by the fact that the study was conducted in a dedicated Alzheimer's disease research center. "That name alone is likely to influence expectations," the researchers said.
The Alzheimer's Disease Research Center and one of Dr. Carpenter's co-authors are supported by grants from the National Institute on Aging. Support for this study was provided by a grant to another co-author from the University of Missouri Alzheimer's Disease and Related Disorders Program.
The authors reported no conflicts of interest.
Primary source: Journal of the American Geriatrics SocietySource reference:Carpenter B, et al "Reaction to a dementia diagnosis in individuals with Alzheimer's disease and mild cognitive impairment" J Am Geriatrics Soc 2008; DOI: 10.1111/j.1532-5415.2007.01600.x.
Elevated Liver Enzymes in Routine Care Hint at Impending Early Mortality
By Judith Groch
ROCHESTER, Minn., March 5 -- High serum aminotransferase levels discovered during routine medical care were associated with an increased risk of death in the next decade, a population-based study found.
Elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) predicted progressive decreases in survival, with an increase in mortality from 21% to 78%, W. Ray Kim, M.D., of the Mayo Clinic here, and colleagues reported in the March issue of Hepatology.
Studies in other countries have shown that elevated liver enzymes are associated with early mortality, but the connection has never been examined in a U.S. population, Dr. Kim and colleagues said.
The findings came from a study of all adult residents (mainly white) in Olmsted County, Minn., in 1995. Most of these patients received medical care at Mayo Clinic facilities. Their AST or ALT results, when available from routine visits, were extracted from a laboratory database.
To determine survival, the patients were followed from January 1995 to April 2006. To eliminate patients with abnormal results because of a terminal illness, deaths within the first two years were excluded. Standardized mortality ratios, serving as the reference, were calculated on the basis of Minnesota White death rates.
During 1995, AST was measured at least once in 18,401 community residents, of whom 2,350 (12.8%) had results greater than the upper limit of normal.
Of 6,823 patients with an ALT measurement, 911 (13%) had results higher than the upper limit of normal.
For AST, a level up to twice the upper limit of normal was associated with a 32% increase in the risk of death, and for more than twice that limit, the risk increased to 78% compared with the reference population.
Similarly, an ALT up to twice the upper limit of normal was associated with a 21% increase in the risk of death, and for more than twice that level, the risk increased to 59% versus the reference population.
In contrast, normal AST or ALT levels were associated with a mortality rate lower than expected (mortality rate 0.95 for AST and 0.61 for ALT).
After a median duration of 10.9 years, 4,639 individuals had died.
Of those who died, 73 (1.6%) died of liver disease including hepatobiliary malignancies (58.9% men), while 1,559 (33.6%) died of cardiovascular causes, 1,015 (21.9%) of other malignancies, and 42% died of other or undetermined causes.
AST was significantly higher among those who died of liver disorders, the researchers said.
Although the precise reasons for the association in this study are unclear, some individuals undoubtedly had elevated enzymes as a result of liver disease, the researchers said.
In addition, they suggested that aminotransferases, particularly ALT, might also be a marker for cardiovascular disease, via the metabolic syndrome, adding to the risk of death. Nearly 34% of the deaths in this study population were due to cardiovascular disease.
Also, they said, AST may become elevated in patients with acute myocardial injury or congestive heart failure.
Other conditions, such as chronic alcohol consumption and associated depression, substance abuse, smoking, and accidents may also have contributed to the mortality risk.
Limitations included the fact that the study individuals came from a routine medical care setting rather than a screening of random individuals in the community.
Only a minority of the community residents had their liver enzymes screened, and this study was based on a single aminotransferase result. Given the long lag-time between testing and death from liver disease, a study with longer follow-up might find a stronger association between the two.
Finally, the large proportion of whites in this study may reduce the generalizability of the data.
Although the findings presented here could not answer questions about routine prevention, measurement of these enzymes from a simple blood test may allow early detection and treatment of conditions that could lead to significant morbidity and mortality in the future, the investigators said.
This study was supported by grants from the National Institutes of Health. No potential conflicts of interest were reported.
Additional source: HepatologySource reference: Lee TH, et al "Serum aminotransferase activity and mortality risk in a United States community" Hepatology 2008; 47: 880-887.
By Judith Groch
ROCHESTER, Minn., March 5 -- High serum aminotransferase levels discovered during routine medical care were associated with an increased risk of death in the next decade, a population-based study found.
Elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) predicted progressive decreases in survival, with an increase in mortality from 21% to 78%, W. Ray Kim, M.D., of the Mayo Clinic here, and colleagues reported in the March issue of Hepatology.
Studies in other countries have shown that elevated liver enzymes are associated with early mortality, but the connection has never been examined in a U.S. population, Dr. Kim and colleagues said.
The findings came from a study of all adult residents (mainly white) in Olmsted County, Minn., in 1995. Most of these patients received medical care at Mayo Clinic facilities. Their AST or ALT results, when available from routine visits, were extracted from a laboratory database.
To determine survival, the patients were followed from January 1995 to April 2006. To eliminate patients with abnormal results because of a terminal illness, deaths within the first two years were excluded. Standardized mortality ratios, serving as the reference, were calculated on the basis of Minnesota White death rates.
During 1995, AST was measured at least once in 18,401 community residents, of whom 2,350 (12.8%) had results greater than the upper limit of normal.
Of 6,823 patients with an ALT measurement, 911 (13%) had results higher than the upper limit of normal.
For AST, a level up to twice the upper limit of normal was associated with a 32% increase in the risk of death, and for more than twice that limit, the risk increased to 78% compared with the reference population.
Similarly, an ALT up to twice the upper limit of normal was associated with a 21% increase in the risk of death, and for more than twice that level, the risk increased to 59% versus the reference population.
In contrast, normal AST or ALT levels were associated with a mortality rate lower than expected (mortality rate 0.95 for AST and 0.61 for ALT).
After a median duration of 10.9 years, 4,639 individuals had died.
Of those who died, 73 (1.6%) died of liver disease including hepatobiliary malignancies (58.9% men), while 1,559 (33.6%) died of cardiovascular causes, 1,015 (21.9%) of other malignancies, and 42% died of other or undetermined causes.
AST was significantly higher among those who died of liver disorders, the researchers said.
Although the precise reasons for the association in this study are unclear, some individuals undoubtedly had elevated enzymes as a result of liver disease, the researchers said.
In addition, they suggested that aminotransferases, particularly ALT, might also be a marker for cardiovascular disease, via the metabolic syndrome, adding to the risk of death. Nearly 34% of the deaths in this study population were due to cardiovascular disease.
Also, they said, AST may become elevated in patients with acute myocardial injury or congestive heart failure.
Other conditions, such as chronic alcohol consumption and associated depression, substance abuse, smoking, and accidents may also have contributed to the mortality risk.
Limitations included the fact that the study individuals came from a routine medical care setting rather than a screening of random individuals in the community.
Only a minority of the community residents had their liver enzymes screened, and this study was based on a single aminotransferase result. Given the long lag-time between testing and death from liver disease, a study with longer follow-up might find a stronger association between the two.
Finally, the large proportion of whites in this study may reduce the generalizability of the data.
Although the findings presented here could not answer questions about routine prevention, measurement of these enzymes from a simple blood test may allow early detection and treatment of conditions that could lead to significant morbidity and mortality in the future, the investigators said.
This study was supported by grants from the National Institutes of Health. No potential conflicts of interest were reported.
Additional source: HepatologySource reference: Lee TH, et al "Serum aminotransferase activity and mortality risk in a United States community" Hepatology 2008; 47: 880-887.
Estrogen Levels in Blood Predict Breast Cancer's Return
By Amanda Gardner
THURSDAY, March 6 (HealthDay News) -- New research shows that women who experienced a recurrence of their breast cancer had almost twice as much estrogen in their blood as women who remained cancer-free after treatment.
This indicates that circulating estrogen levels contribute to a recurrence as much as the initial malignancy does.
That information is not entirely new, said Dr. Jennifer Wu, an obstetrician/gynecologist at Lenox Hill Hospital in New York City. "That's the reason we use drugs that help to lower estrogen levels. Estrogen causes increased cell division; we think it can perhaps start breast cancer," she said. "But this is a good study in that it has a lot of patients and proves that they have a demonstrable increase in estrogen levels over patients who don't have a recurrence."
Where there's a problem, there's also often a solution.
"Anti-estrogen drugs can only have so much impact," said study author Cheryl Rock, a professor of family and preventive medicine at the University of California, San Diego, School of Medicine. "There are two things apart from these drugs that can help to lower estrogen, or we believe it can, because it can in the general population. One is moderate to vigorous exercise, and the other is healthy weight management, achieving an ideal weight."
The hormone estrogen is produced not only by the ovaries, but also by fat tissue.
Previous research has shown that estrogen contributes to the risk of primary breast cancer in postmenopausal women, but there has been less evidence of the role of estrogen in cancer recurrence.
"The relationship between circulating estrogen and risk for primary breast cancer is very well-established, but there were surprisingly few studies in which estrogen levels have been measured in breast cancer survivors," Rock explained.
This study, published in the March issue of Cancer Epidemiology, Biomarkers & Prevention, followed 153 pairs of women who had had breast cancer (one in each pair experienced a recurrence, while one did not) for more than seven years.
Two-thirds of the participants were using tamoxifen, a drug which interferes with estrogen's activity in the body.
In the end, women with more circulating estrogen were more likely to have a recurrence.
There may be other factors at play also, Rock said. For instance, sex hormone-binding globulin basically makes estrogen available to get into tissue. "If estrogen is bound to that protein, it's not going to float right over to the cell," Rock said. "When people are overweight, they have higher blood levels of insulin, which suppresses synthesis of that protein, so exercise not only is related to actually helping weight management but, because it lowers insulin, it might make the hormonal situation look better."
And don't rule out existing anti-estrogen drugs, experts added.
"This study justifies the use of drugs that help decrease estrogen levels like tamoxifen and aromatase inhibitors," Wu said. "[In the future], we may want to titrate different levels of anti-estrogen medications. Right now, we have a standard dosage for everyone, whereas women who are heavier or other women who may have higher estrogen levels for one reason or another may need larger doses."
More information
Visit the National Cancer Institute for more on breast cancer.
By Amanda Gardner
THURSDAY, March 6 (HealthDay News) -- New research shows that women who experienced a recurrence of their breast cancer had almost twice as much estrogen in their blood as women who remained cancer-free after treatment.
This indicates that circulating estrogen levels contribute to a recurrence as much as the initial malignancy does.
That information is not entirely new, said Dr. Jennifer Wu, an obstetrician/gynecologist at Lenox Hill Hospital in New York City. "That's the reason we use drugs that help to lower estrogen levels. Estrogen causes increased cell division; we think it can perhaps start breast cancer," she said. "But this is a good study in that it has a lot of patients and proves that they have a demonstrable increase in estrogen levels over patients who don't have a recurrence."
Where there's a problem, there's also often a solution.
"Anti-estrogen drugs can only have so much impact," said study author Cheryl Rock, a professor of family and preventive medicine at the University of California, San Diego, School of Medicine. "There are two things apart from these drugs that can help to lower estrogen, or we believe it can, because it can in the general population. One is moderate to vigorous exercise, and the other is healthy weight management, achieving an ideal weight."
The hormone estrogen is produced not only by the ovaries, but also by fat tissue.
Previous research has shown that estrogen contributes to the risk of primary breast cancer in postmenopausal women, but there has been less evidence of the role of estrogen in cancer recurrence.
"The relationship between circulating estrogen and risk for primary breast cancer is very well-established, but there were surprisingly few studies in which estrogen levels have been measured in breast cancer survivors," Rock explained.
This study, published in the March issue of Cancer Epidemiology, Biomarkers & Prevention, followed 153 pairs of women who had had breast cancer (one in each pair experienced a recurrence, while one did not) for more than seven years.
Two-thirds of the participants were using tamoxifen, a drug which interferes with estrogen's activity in the body.
In the end, women with more circulating estrogen were more likely to have a recurrence.
There may be other factors at play also, Rock said. For instance, sex hormone-binding globulin basically makes estrogen available to get into tissue. "If estrogen is bound to that protein, it's not going to float right over to the cell," Rock said. "When people are overweight, they have higher blood levels of insulin, which suppresses synthesis of that protein, so exercise not only is related to actually helping weight management but, because it lowers insulin, it might make the hormonal situation look better."
And don't rule out existing anti-estrogen drugs, experts added.
"This study justifies the use of drugs that help decrease estrogen levels like tamoxifen and aromatase inhibitors," Wu said. "[In the future], we may want to titrate different levels of anti-estrogen medications. Right now, we have a standard dosage for everyone, whereas women who are heavier or other women who may have higher estrogen levels for one reason or another may need larger doses."
More information
Visit the National Cancer Institute for more on breast cancer.
Blood test indicates spread of prostate cancer
Testing men with prostate cancer for a substance called endoglin in their blood may help doctors know if the cancer has spread outside the gland to the lymph nodes, new research shows.
It is known that removing the pelvic lymph nodes can provide important information about the prognosis of prostate cancer, but "it is still not clear in whom this procedure should be done," researcher Dr. Claus G. Roehrborn, from the University of Texas Southwestern Medical Center in Dallas, explained in a statement.
Previous research has identified elevated levels of endoglin in patients with breast cancer and colon cancer that has spread, according to the report in the journal Clinical Cancer Research. Whether endoglin levels are increased in prostate cancer patients had never been looked at until now.
Roehrborn's team studied 425 men who underwent surgical removal of the prostate as well as removal of the pelvic lymph nodes. The investigators found that men with elevated endoglin levels were more likely to have cancer that had spread to the lymph nodes, as well as other signs of more aggressive cancer.
With standard factors, the researchers could predict with 89 percent accuracy whether the cancer had spread to the lymph nodes. When the endoglin measurement was included, the accuracy rose to 98 percent.
If these results are confirmed in other studies, it might be possible to identify men whose prostate cancer has not spread with more certainty, and so spare them from having their lymph nodes removed.
SOURCE: Clinical Cancer Research, March 1, 2008.
Testing men with prostate cancer for a substance called endoglin in their blood may help doctors know if the cancer has spread outside the gland to the lymph nodes, new research shows.
It is known that removing the pelvic lymph nodes can provide important information about the prognosis of prostate cancer, but "it is still not clear in whom this procedure should be done," researcher Dr. Claus G. Roehrborn, from the University of Texas Southwestern Medical Center in Dallas, explained in a statement.
Previous research has identified elevated levels of endoglin in patients with breast cancer and colon cancer that has spread, according to the report in the journal Clinical Cancer Research. Whether endoglin levels are increased in prostate cancer patients had never been looked at until now.
Roehrborn's team studied 425 men who underwent surgical removal of the prostate as well as removal of the pelvic lymph nodes. The investigators found that men with elevated endoglin levels were more likely to have cancer that had spread to the lymph nodes, as well as other signs of more aggressive cancer.
With standard factors, the researchers could predict with 89 percent accuracy whether the cancer had spread to the lymph nodes. When the endoglin measurement was included, the accuracy rose to 98 percent.
If these results are confirmed in other studies, it might be possible to identify men whose prostate cancer has not spread with more certainty, and so spare them from having their lymph nodes removed.
SOURCE: Clinical Cancer Research, March 1, 2008.
Wednesday, March 05, 2008
Primary Care Panel Finds Dementia Drugs to be Peas in a Pod
By Charles Bankhead
PHILADELPLHIA, March 4 -- Two big groups of primary care physicians sat down to sort out the solid evidence for choosing and using drug therapy for dementia and found little to sort.
"No convincing evidence demonstrates that one therapeutic treatment is more effective than another," said the authors of a joint clinical guideline on treatment of dementia by the American College of Physicians and the American Academy of Family Physicians.
The guideline recommendations were reduced to generalities about individualized patient assessment and consideration of each drug's characteristics.
Even there, the recommendations have only weak supporting evidence, reflecting the "urgent need" for more research on the effectiveness of drug therapy for dementia, Amir Qaseem, M.D., Ph.D., of the American College of Physicians, and co-authors wrote in the March 4 issue of Annals of Internal Medicine.
"Because few trials compare one drug with another, evidence about effectiveness is insufficient to support the choice of specific drugs for treatment of dementia," said members of the Joint ACP/AAFP Panel on Dementia. "Therefore, tolerability, adverse effect profile, ease of use, and cost of medication are reasonable criteria to help select a treatment."
The guideline and recommendations evolved from the panelists' review of evidence for the effectiveness of the five FDA-approved medications for dementia: the cholinesterase inhibitors donepezil (Aricept), galantamine (Reminyl), rivastigmine (Exelon), and tacrine (Cognex), and the neuropeptide modifier memantine (Namenda).
In examining the evidence, the panel evaluated clinically important treatment effects, as well as statistically significant effects. For each drug, they sought to answer two questions.
Does the drug improve cognitive symptoms and outcomes?
What is the evidence for efficacy in the treatment of dementia?
The summary findings for each agent were:
Donepezil. The average change in cognitive score was statistically significant but not clinically important. Some, but not all, studies found improvements in activities of daily living scores for patients with Alzheimer's disease and vascular dementia with no adverse effects. The duration of all but one trial was less than one year.
Galantamine. Pooled evidence showed statistically significant improvement in cognition, but not clinical improvement. Three individual studies suggested a beneficial effect in certain subgroups. The duration of trials was less than one year.
Rivastigmine. Cognitive improvement did not reach statistical significance, but clinically important improvement occurred on a global assessment. Behavior and quality-of-life outcomes did not significantly improve. The duration of trials was less than seven months.
Tacrine. The evidence did not substantiate a beneficial effect on cognition or behavior, except for a global assessment in two studies. The evidence also demonstrated a risk of serious adverse effects, including liver damage.
Memantine. Studies demonstrated statistically significant improvement in cognition scores, but the panel found inadequate evidence of clinically important improvement.
Although the five drugs demonstrated significant improvement on various dementia scales, most of the outcomes are not applicable to routine clinical practice, the ACP/AAFP panel said. Effects on quality of life were mixed. Most studies had a treatment duration of less than one year.
Co-author Vincenza Snow, M.D., disclosed financial relationships with Novo Nordisk, Bristol-Myers Squibb, Boehringer-Ingelheim, and Endo Pharmaceuticals. None of the other co-authors had disclosures involving commercial interests.
Additional source: Annals of Internal MedicineSource reference: Qaseem A, et al. "Current pharmacologic treatment of dementia: A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians." Ann Intern Med 2008; 148: 370-378.
By Charles Bankhead
PHILADELPLHIA, March 4 -- Two big groups of primary care physicians sat down to sort out the solid evidence for choosing and using drug therapy for dementia and found little to sort.
"No convincing evidence demonstrates that one therapeutic treatment is more effective than another," said the authors of a joint clinical guideline on treatment of dementia by the American College of Physicians and the American Academy of Family Physicians.
The guideline recommendations were reduced to generalities about individualized patient assessment and consideration of each drug's characteristics.
Even there, the recommendations have only weak supporting evidence, reflecting the "urgent need" for more research on the effectiveness of drug therapy for dementia, Amir Qaseem, M.D., Ph.D., of the American College of Physicians, and co-authors wrote in the March 4 issue of Annals of Internal Medicine.
"Because few trials compare one drug with another, evidence about effectiveness is insufficient to support the choice of specific drugs for treatment of dementia," said members of the Joint ACP/AAFP Panel on Dementia. "Therefore, tolerability, adverse effect profile, ease of use, and cost of medication are reasonable criteria to help select a treatment."
The guideline and recommendations evolved from the panelists' review of evidence for the effectiveness of the five FDA-approved medications for dementia: the cholinesterase inhibitors donepezil (Aricept), galantamine (Reminyl), rivastigmine (Exelon), and tacrine (Cognex), and the neuropeptide modifier memantine (Namenda).
In examining the evidence, the panel evaluated clinically important treatment effects, as well as statistically significant effects. For each drug, they sought to answer two questions.
Does the drug improve cognitive symptoms and outcomes?
What is the evidence for efficacy in the treatment of dementia?
The summary findings for each agent were:
Donepezil. The average change in cognitive score was statistically significant but not clinically important. Some, but not all, studies found improvements in activities of daily living scores for patients with Alzheimer's disease and vascular dementia with no adverse effects. The duration of all but one trial was less than one year.
Galantamine. Pooled evidence showed statistically significant improvement in cognition, but not clinical improvement. Three individual studies suggested a beneficial effect in certain subgroups. The duration of trials was less than one year.
Rivastigmine. Cognitive improvement did not reach statistical significance, but clinically important improvement occurred on a global assessment. Behavior and quality-of-life outcomes did not significantly improve. The duration of trials was less than seven months.
Tacrine. The evidence did not substantiate a beneficial effect on cognition or behavior, except for a global assessment in two studies. The evidence also demonstrated a risk of serious adverse effects, including liver damage.
Memantine. Studies demonstrated statistically significant improvement in cognition scores, but the panel found inadequate evidence of clinically important improvement.
Although the five drugs demonstrated significant improvement on various dementia scales, most of the outcomes are not applicable to routine clinical practice, the ACP/AAFP panel said. Effects on quality of life were mixed. Most studies had a treatment duration of less than one year.
Co-author Vincenza Snow, M.D., disclosed financial relationships with Novo Nordisk, Bristol-Myers Squibb, Boehringer-Ingelheim, and Endo Pharmaceuticals. None of the other co-authors had disclosures involving commercial interests.
Additional source: Annals of Internal MedicineSource reference: Qaseem A, et al. "Current pharmacologic treatment of dementia: A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians." Ann Intern Med 2008; 148: 370-378.
Nonpolypoid Colon Lesions Common and Often Malignant
By Judith Groch
PALO ALTO, Calif., March 4 -- Flat and depressed nonpolypoid colorectal neoplasms are common, hard to detect, and more likely to be malignant than the more familiar colorectal polyps, researchers here reported.
Nonpolypoid neoplasms, with an overall prevalence of more than 9%, were almost 10 times (OR 9.78) more likely to be malignant than polypoid lesions, irrespective of size, Roy Soetikno, M.D., of the Veterans Affairs Palo Alto Health Care System, and colleagues reported in the March 5 issue of the Journal of the American Medical Association.
After adjusting for polyp size, the likelihood that these neoplasms harbored in situ or submucosal carcinoma was more than five times higher than the rate for standard polyps, the researchers found.
Nonpolypoid neoplasms are more difficult to detect by colonoscopy or CT colonography. They appear to be slightly elevated, completely flat, or depressed, the latter being the most difficult to detect, the researchers said.
For detection during colonoscopy, the researchers used chromoendoscopy with indigo carmine spray, to highlight neoplastic lesions.
The findings came from a cross-sectional study of 1,819 patients undergoing elective colonoscopy from July 2003 to June 2004 at a Veterans Affairs hospital in California.
The overall prevalence of the nonpolypoid lesions was 9.35% (95% CI 8.05% to 10.78%, n=170).
The prevalence of nonpolypoid neoplasms in the subpopulations
for screening, surveillance, and symptoms was 5.84% (95% CI 4.13% to 8%, n=36), 15.44% (95% CI 12.76% to 18.44%, n=101), and 6.01% (95% CI 4.17% to 8.34%, n=33), respectively.
The overall prevalence of nonpolypoid lesions with in situ or submucosal invasive carcinoma was 0.82% (95% CI 0.46% to 1.36%, n=15).
In the screening group, the prevalence was 0.32% (95% CI 0.04% to 1.17%, n=2).
Overall, nonpolypoid neoplasms were almost 10 times likelier to be cancerous (OR 9.78, 95% CI 3.93 to 24.4) than polypoid lesions, irrespective of size.
The positive, size-adjusted association of the nonpolypoid lesions with in situ or submucosal invasive carcinoma was also observed in subpopulations for screening (OR 2.01, 95% CI 0.27 to 15.3) and surveillance (OR 63.7, 95% CI 9.41 to 431).
Characterizing morphology into flat, depressed, and polypoid, the size-adjusted multivariate model of flat lesions maintained a five-fold greater association of flat lesions with carcinoma (OR 5.18, 95% CI 1.84 to 14.6).
Although nonpolypoid lesions accounted for only 15% of neoplasms overall, more than half of the in situ or submucosal invasive carcinomas (n=15) were diagnosed in nonpolypoid lesions, the researchers wrote.
The depressed type, the most difficult to detect during colonoscopy, had the highest risk (33%).
Nonpolypoid colorectal neoplasms containing carcinoma were smaller in diameter than the polypoid ones (mean diameter, 15.9 mm versus 19.2 mm, respectively).
Follow-up of colonoscopy data within three years found 13 of 393 patients to have advanced neoplasia, all of which were flat or sessile adenomas 10 mm or larger, except for one T1 carcinoma.
In this study the researchers also diagnosed flat or sessile adenomas that were likely to have been missed by the initial colonoscopy because of incomplete bowel preparation, nonpolypoid shape, or their location between folds in the rectum.
Study limitations included the lack of generalizability of the study in which most of the individuals were men and the lack of long follow-up.
Recent studies have pointed out differences in the genetic mechanisms underlying the two types of colorectal neoplasms, the investigators said.
Future studies, they added, should further evaluate whether the diagnosis and removal of these neoplasms has any effect on the prevention and mortality of colorectal cancer and particularly focus on their genetic and protein abnormalities.
"The elephant in the endoscopy suite is missed lesions," wrote David Lieberman, M.D., of the Oregon Health & Science University in Portland, in an accompanying editorial.
There is increasing recognition that even experienced endoscopists may fail to detect important pathology, he said. In fact, CT colonography studies have shown that optical colonoscopy misses 2% to 12% of polypoid lesions larger than 10 mm.
It is possible, if not likely, Dr. Lieberman wrote, that additional nonpolypoid colorectal neoplasms may be missed by both studies so that these studies underestimate the actual colonoscopic miss rate. These missed lesions may represent the most common explanation for interval cancers.
Nonpolypoid lesions may be biologically distinct from polypoid lesions and appear to be more likely to harbor malignant features. Detection and complete removal at colonoscopy may be challenging, Dr. Lieberman said.
The optimal methods for enhancing colonoscopic imaging of nonpolypoid neoplasms are uncertain and studies are needed. Chromoendoscopy with indigo carmine seems to work, but other methods might be technically easier, he said.
Moreover, additional studies are needed to determine whether imaging modalities such as CT colonography will be able to detect flat or depressed neoplasms.
Finally, longitudinal studies are needed to determine whether
patients with nonpolypoid neoplasms require more intensive colonoscopic surveillance compared with patients with polypoid lesions of similar size and histology, Dr. Lieberman concluded.
Palo Alto Institute provided funding for the study for Research and Education, a nonprofit organization.
The study authors and Dr. Lieberman, the editorialist, reported no financial conflicts.
Primary source: Journal of the American Medical AssociationSource reference:Soetikno RM, et al "Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults" JAMA 2008; 299: 1027-1035. Additional source: Journal of the American Medical AssociationSource reference: Lieberman D "Nonpolypoid colorectal neoplasia in the United States: The parachute is open" JAMA 2008; 299: 1068-1069.
By Judith Groch
PALO ALTO, Calif., March 4 -- Flat and depressed nonpolypoid colorectal neoplasms are common, hard to detect, and more likely to be malignant than the more familiar colorectal polyps, researchers here reported.
Nonpolypoid neoplasms, with an overall prevalence of more than 9%, were almost 10 times (OR 9.78) more likely to be malignant than polypoid lesions, irrespective of size, Roy Soetikno, M.D., of the Veterans Affairs Palo Alto Health Care System, and colleagues reported in the March 5 issue of the Journal of the American Medical Association.
After adjusting for polyp size, the likelihood that these neoplasms harbored in situ or submucosal carcinoma was more than five times higher than the rate for standard polyps, the researchers found.
Nonpolypoid neoplasms are more difficult to detect by colonoscopy or CT colonography. They appear to be slightly elevated, completely flat, or depressed, the latter being the most difficult to detect, the researchers said.
For detection during colonoscopy, the researchers used chromoendoscopy with indigo carmine spray, to highlight neoplastic lesions.
The findings came from a cross-sectional study of 1,819 patients undergoing elective colonoscopy from July 2003 to June 2004 at a Veterans Affairs hospital in California.
The overall prevalence of the nonpolypoid lesions was 9.35% (95% CI 8.05% to 10.78%, n=170).
The prevalence of nonpolypoid neoplasms in the subpopulations
for screening, surveillance, and symptoms was 5.84% (95% CI 4.13% to 8%, n=36), 15.44% (95% CI 12.76% to 18.44%, n=101), and 6.01% (95% CI 4.17% to 8.34%, n=33), respectively.
The overall prevalence of nonpolypoid lesions with in situ or submucosal invasive carcinoma was 0.82% (95% CI 0.46% to 1.36%, n=15).
In the screening group, the prevalence was 0.32% (95% CI 0.04% to 1.17%, n=2).
Overall, nonpolypoid neoplasms were almost 10 times likelier to be cancerous (OR 9.78, 95% CI 3.93 to 24.4) than polypoid lesions, irrespective of size.
The positive, size-adjusted association of the nonpolypoid lesions with in situ or submucosal invasive carcinoma was also observed in subpopulations for screening (OR 2.01, 95% CI 0.27 to 15.3) and surveillance (OR 63.7, 95% CI 9.41 to 431).
Characterizing morphology into flat, depressed, and polypoid, the size-adjusted multivariate model of flat lesions maintained a five-fold greater association of flat lesions with carcinoma (OR 5.18, 95% CI 1.84 to 14.6).
Although nonpolypoid lesions accounted for only 15% of neoplasms overall, more than half of the in situ or submucosal invasive carcinomas (n=15) were diagnosed in nonpolypoid lesions, the researchers wrote.
The depressed type, the most difficult to detect during colonoscopy, had the highest risk (33%).
Nonpolypoid colorectal neoplasms containing carcinoma were smaller in diameter than the polypoid ones (mean diameter, 15.9 mm versus 19.2 mm, respectively).
Follow-up of colonoscopy data within three years found 13 of 393 patients to have advanced neoplasia, all of which were flat or sessile adenomas 10 mm or larger, except for one T1 carcinoma.
In this study the researchers also diagnosed flat or sessile adenomas that were likely to have been missed by the initial colonoscopy because of incomplete bowel preparation, nonpolypoid shape, or their location between folds in the rectum.
Study limitations included the lack of generalizability of the study in which most of the individuals were men and the lack of long follow-up.
Recent studies have pointed out differences in the genetic mechanisms underlying the two types of colorectal neoplasms, the investigators said.
Future studies, they added, should further evaluate whether the diagnosis and removal of these neoplasms has any effect on the prevention and mortality of colorectal cancer and particularly focus on their genetic and protein abnormalities.
"The elephant in the endoscopy suite is missed lesions," wrote David Lieberman, M.D., of the Oregon Health & Science University in Portland, in an accompanying editorial.
There is increasing recognition that even experienced endoscopists may fail to detect important pathology, he said. In fact, CT colonography studies have shown that optical colonoscopy misses 2% to 12% of polypoid lesions larger than 10 mm.
It is possible, if not likely, Dr. Lieberman wrote, that additional nonpolypoid colorectal neoplasms may be missed by both studies so that these studies underestimate the actual colonoscopic miss rate. These missed lesions may represent the most common explanation for interval cancers.
Nonpolypoid lesions may be biologically distinct from polypoid lesions and appear to be more likely to harbor malignant features. Detection and complete removal at colonoscopy may be challenging, Dr. Lieberman said.
The optimal methods for enhancing colonoscopic imaging of nonpolypoid neoplasms are uncertain and studies are needed. Chromoendoscopy with indigo carmine seems to work, but other methods might be technically easier, he said.
Moreover, additional studies are needed to determine whether imaging modalities such as CT colonography will be able to detect flat or depressed neoplasms.
Finally, longitudinal studies are needed to determine whether
patients with nonpolypoid neoplasms require more intensive colonoscopic surveillance compared with patients with polypoid lesions of similar size and histology, Dr. Lieberman concluded.
Palo Alto Institute provided funding for the study for Research and Education, a nonprofit organization.
The study authors and Dr. Lieberman, the editorialist, reported no financial conflicts.
Primary source: Journal of the American Medical AssociationSource reference:Soetikno RM, et al "Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults" JAMA 2008; 299: 1027-1035. Additional source: Journal of the American Medical AssociationSource reference: Lieberman D "Nonpolypoid colorectal neoplasia in the United States: The parachute is open" JAMA 2008; 299: 1068-1069.
Biomarker Panel May Improve Disease Staging in Chronic HCV
By Michael Smith
ANN ARBOR, Mich., March 5 -- A panel of three biomarkers may be useful in identifying patients with chronic hepatitis C who have progressed to cirrhosis, researchers here found.
The three-marker panel was highly correlated to Ishak score in a prospective sub-study of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, according to Robert Fontana, M.D., of the University of Michigan, and colleagues.
The biomarkers were also more accurate than other non-invasive tests that have been proposed, the researchers reported in the March issue of Hepatology.
The three markers evaluated by the researchers were serum tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), hyaluronic acid (HA), and platelet count.
All were significantly associated with cirrhosis in a univariate analysis (as were several other markers) but in multivariate analysis, the three biomarkers had an area under the receiver operating curve of 0.81.
(A receiver operating curve measures the trade-off between sensitivity and specificity for a given test; if the area under the curve were 1.0, the test would correctly identify both positives and negatives.)
By comparison, Dr. Fontana and colleagues said, three other published models -- the Lok model, the AST-to-platelet ratio index, and the cirrhosis discriminant score -- had lower areas under the curve of 0.79. 0.73, and 0.70 respectively.
For this study, the researchers compared the model's predictions with the biopsy results of 513 patients with chronic hepatitis C and Ishak scores of between two and six. Those with Ishak scores of five and six (38%) were considered to have cirrhosis, while the remaining 62% had fibrosis.
Among those patients, the researchers found, the model would have correctly categorized 153 patients as having a low likelihood of cirrhosis with 86% accuracy.
An additional 146 subjects would have been categorized as having a high likelihood of cirrhosis with 73% accuracy.
The study was limited by the nature of the HALT-C patient population, the researchers said, which meant that there was no independent cohort of patients who also had stored serum available for testing for comparison.
Also, they noted, the model was not tested in an external validation cohort.
Nevertheless, the model "distinguished patients with non-cirrhotic (chronic hepatitis C) from those with cirrhosis" and "performed significantly better than other models based on routine laboratory tests," the researchers concluded.
The implication is that serum fibrosis markers "provide useful, incremental information in estimating disease stage" in chronic hepatitis C that can be obtained without biopsy, they said.
The study was supported by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources of the NIH, and Hoffmann-La Roche Inc.
Dr. Fontana reported being on the speakers bureau for Hoffmann-La Roche.
Additional source: HepatologySource reference: Fontana RJ et al. "Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C." Hepatology 2008; 47: 789-798.
By Michael Smith
ANN ARBOR, Mich., March 5 -- A panel of three biomarkers may be useful in identifying patients with chronic hepatitis C who have progressed to cirrhosis, researchers here found.
The three-marker panel was highly correlated to Ishak score in a prospective sub-study of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, according to Robert Fontana, M.D., of the University of Michigan, and colleagues.
The biomarkers were also more accurate than other non-invasive tests that have been proposed, the researchers reported in the March issue of Hepatology.
The three markers evaluated by the researchers were serum tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), hyaluronic acid (HA), and platelet count.
All were significantly associated with cirrhosis in a univariate analysis (as were several other markers) but in multivariate analysis, the three biomarkers had an area under the receiver operating curve of 0.81.
(A receiver operating curve measures the trade-off between sensitivity and specificity for a given test; if the area under the curve were 1.0, the test would correctly identify both positives and negatives.)
By comparison, Dr. Fontana and colleagues said, three other published models -- the Lok model, the AST-to-platelet ratio index, and the cirrhosis discriminant score -- had lower areas under the curve of 0.79. 0.73, and 0.70 respectively.
For this study, the researchers compared the model's predictions with the biopsy results of 513 patients with chronic hepatitis C and Ishak scores of between two and six. Those with Ishak scores of five and six (38%) were considered to have cirrhosis, while the remaining 62% had fibrosis.
Among those patients, the researchers found, the model would have correctly categorized 153 patients as having a low likelihood of cirrhosis with 86% accuracy.
An additional 146 subjects would have been categorized as having a high likelihood of cirrhosis with 73% accuracy.
The study was limited by the nature of the HALT-C patient population, the researchers said, which meant that there was no independent cohort of patients who also had stored serum available for testing for comparison.
Also, they noted, the model was not tested in an external validation cohort.
Nevertheless, the model "distinguished patients with non-cirrhotic (chronic hepatitis C) from those with cirrhosis" and "performed significantly better than other models based on routine laboratory tests," the researchers concluded.
The implication is that serum fibrosis markers "provide useful, incremental information in estimating disease stage" in chronic hepatitis C that can be obtained without biopsy, they said.
The study was supported by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources of the NIH, and Hoffmann-La Roche Inc.
Dr. Fontana reported being on the speakers bureau for Hoffmann-La Roche.
Additional source: HepatologySource reference: Fontana RJ et al. "Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C." Hepatology 2008; 47: 789-798.
Weight-Loss Drug Fights Alcoholic Fatty Liver Disease
WEDNESDAY, March 5 (HealthDay News) -- Mice given the weight-loss drug rimonabant became resistant to alcohol's fat-building effects in the liver, which suggests the medication may help fight alcoholic fatty liver in humans, says a U.S. study.
Alcoholism is the leading cause of liver disease in Western societies, according to background information in the study.
Rimonabant, which blocks cannabinoid receptors, is approved for weight loss in several European countries but has not been approved in the United States. Last June, a U.S. Food and Drug Administration panel recommended that rimonabant should not be given the FDA's blessing because of continuing concerns about increased risks for suicidal thoughts among some users.
In this latest study, the researchers found that mice fed a low-fat diet and ethanol showed an increase in the gene encoding the CB1 cannabinoid receptor and in liver levels of an endocannabinoid called 2-arachidonoylglycerol (2-AG). These mice developed fatty livers.
Another group of mice that received the same diet plus rimonabant did not differ from mice fed a control diet. And mice lacking CB1 receptors, either throughout the body or only in the liver, were protected from alcoholic fatty liver.
"What makes these findings particularly interesting from our perspective is that they may have practical implications," said study author George Kunos, of the U.S. National Institute on Alcohol Abuse and Alcoholism. "Treatment of animals with a [cannabinoid receptor] antagonist largely prevented alcohol's effect. It suggests that the development of fatty liver in those who use alcohol could be interfered with, or perhaps reversed, with such treatment."
The findings were published in the March issue of Cell Metabolism.
"Although alcoholic fatty liver is reversible in the early stages by cessation of drinking, this is often not feasible," the study authors wrote. "The present findings suggest that treatment with a CB1 antagonist may slow the development of fatty liver and thus prevent its progression to more severe and irreversible forms of liver disease."
Drugs that selectively act on CB1 receptors found outside of the brain might help fight fatty liver with less risk of side effects such as anxiety and depression, they said.
"Rimonabant has recently been introduced in Europe for the treatment of visceral obesity and the metabolic syndrome, which themselves are known risk factors for [liver disease]. Clinical trials testing the effectiveness of CB1 receptor blockers in the treatment of both alcoholic and nonalcoholic fatty liver and their more severe sequelae may be warranted," the researchers concluded.
More information
The American Liver Foundation has more about fatty liver.
WEDNESDAY, March 5 (HealthDay News) -- Mice given the weight-loss drug rimonabant became resistant to alcohol's fat-building effects in the liver, which suggests the medication may help fight alcoholic fatty liver in humans, says a U.S. study.
Alcoholism is the leading cause of liver disease in Western societies, according to background information in the study.
Rimonabant, which blocks cannabinoid receptors, is approved for weight loss in several European countries but has not been approved in the United States. Last June, a U.S. Food and Drug Administration panel recommended that rimonabant should not be given the FDA's blessing because of continuing concerns about increased risks for suicidal thoughts among some users.
In this latest study, the researchers found that mice fed a low-fat diet and ethanol showed an increase in the gene encoding the CB1 cannabinoid receptor and in liver levels of an endocannabinoid called 2-arachidonoylglycerol (2-AG). These mice developed fatty livers.
Another group of mice that received the same diet plus rimonabant did not differ from mice fed a control diet. And mice lacking CB1 receptors, either throughout the body or only in the liver, were protected from alcoholic fatty liver.
"What makes these findings particularly interesting from our perspective is that they may have practical implications," said study author George Kunos, of the U.S. National Institute on Alcohol Abuse and Alcoholism. "Treatment of animals with a [cannabinoid receptor] antagonist largely prevented alcohol's effect. It suggests that the development of fatty liver in those who use alcohol could be interfered with, or perhaps reversed, with such treatment."
The findings were published in the March issue of Cell Metabolism.
"Although alcoholic fatty liver is reversible in the early stages by cessation of drinking, this is often not feasible," the study authors wrote. "The present findings suggest that treatment with a CB1 antagonist may slow the development of fatty liver and thus prevent its progression to more severe and irreversible forms of liver disease."
Drugs that selectively act on CB1 receptors found outside of the brain might help fight fatty liver with less risk of side effects such as anxiety and depression, they said.
"Rimonabant has recently been introduced in Europe for the treatment of visceral obesity and the metabolic syndrome, which themselves are known risk factors for [liver disease]. Clinical trials testing the effectiveness of CB1 receptor blockers in the treatment of both alcoholic and nonalcoholic fatty liver and their more severe sequelae may be warranted," the researchers concluded.
More information
The American Liver Foundation has more about fatty liver.
Tuesday, March 04, 2008
Survey Shows 37% Prevalence of Pelvic Floor Disorders
By Charles Bankhead
SAN DIEGO, March 3 -- More than a third of community-dwelling women have a pelvic floor disorder, and most have more than one disorder, according to a survey here. Overall 37% of women reported one or more pelvic floor disorders, Emily S. Lukacz, M.D., of the University of California San Diego, and colleagues, reported in the March issue of Obstetrics & Gynecology. Anal incontinence, defined as involuntary discharge of gas or fecal matter, led the way with a 25% prevalence, followed by stress urinary incontinence, overactive bladder, and pelvic organ prolapse. To the investigators' surprise, age did not predict an increased risk of the disorders in an adjusted analysis.
As many as 80% of women with one disorder had one or more coexisting pelvic floor disorders.
"The high co-occurrence of pelvic floor disorders suggests that physicians seeing women seeking care for one condition should inquire about symptoms of other disorders," the authors concluded. Recent studies have shown that pelvic floor disorders remain underreported and undertreated, complicating efforts to determine the prevalence of the conditions, the authors noted. Prevalence estimates have ranged from 10% to 58% for urinary incontinence and less than 1% to 39% for anal incontinence.
Moreover, they continued, despite nearly non-existent prevalence data, organ prolapse remains one of the most common indications for hysterectomy.
So with the approval and cooperation of Kaiser Permanente Southern California, the investigators randomly selected 3,050 female members of the health plan from each of four age groups: 25 to 39, 40 to 54, 55 to 69, and 70 to 84.
A validated survey of pelvic floor disorders was mailed to each of the 12,200 women originally selected for the study. Participants returned 4,458 surveys, and after exclusions for insufficient data, the investigators had 4,103 complete surveys for analysis.
The study population was 764 women ages 25 to 39, 981 ages 40 to 54, 1,187 ages 55 to 69, and 1,171 ages 70 to 84. About two thirds of respondents were married or living with a partner; fewer than 30% had no vaginal deliveries with birth weights of more than 2,000g; three-fourths had some college education, one-fourth were obese, and two-thirds were postmenopausal.
The survey showed that 15% of respondents had stress urinary incontinence, 13% had overactive bladder, and 6% had pelvic organ prolapse. Co-occurrence of two or more pelvic floor disorders was reported by:
About 80% of women with stress urinary incontinence or overactive bladder.
About 70% of women with pelvic organ prolapse.
Almost 50% of women with anal incontinence.
Although age did not increase the likelihood of a pelvic floor disorder, menopause had a positive correlation with all of the disorders except pelvic organ prolapse. The covariates most consistently associated with pelvic floor disorders were obesity, increasing vaginal parity, hormone use, and hysterectomy.
A limitation of the study noted by the authors was that the response rate, particularly among younger health plan members, was lower than anticipated. Younger members were hardest to reach; the likelihood of having the survey returned as undeliverable by the post office decreased with increasing age, from 11% of 25- to 39-year-olds to 3% of 70- to 84-year-olds.
The study was supported by the National Institutes of Health and Kaiser Permanente.
Primary source: Obstetrics & GynecologySource reference:Lawrence JM, et al. "Prevalence and co-occurrence of pelvic floor disorders in community-dwelling women" Obstetr Gynecol 2008; 111: DOI: 10.1097/AOG.Ob013e3181660c1b.
By Charles Bankhead
SAN DIEGO, March 3 -- More than a third of community-dwelling women have a pelvic floor disorder, and most have more than one disorder, according to a survey here. Overall 37% of women reported one or more pelvic floor disorders, Emily S. Lukacz, M.D., of the University of California San Diego, and colleagues, reported in the March issue of Obstetrics & Gynecology. Anal incontinence, defined as involuntary discharge of gas or fecal matter, led the way with a 25% prevalence, followed by stress urinary incontinence, overactive bladder, and pelvic organ prolapse. To the investigators' surprise, age did not predict an increased risk of the disorders in an adjusted analysis.
As many as 80% of women with one disorder had one or more coexisting pelvic floor disorders.
"The high co-occurrence of pelvic floor disorders suggests that physicians seeing women seeking care for one condition should inquire about symptoms of other disorders," the authors concluded. Recent studies have shown that pelvic floor disorders remain underreported and undertreated, complicating efforts to determine the prevalence of the conditions, the authors noted. Prevalence estimates have ranged from 10% to 58% for urinary incontinence and less than 1% to 39% for anal incontinence.
Moreover, they continued, despite nearly non-existent prevalence data, organ prolapse remains one of the most common indications for hysterectomy.
So with the approval and cooperation of Kaiser Permanente Southern California, the investigators randomly selected 3,050 female members of the health plan from each of four age groups: 25 to 39, 40 to 54, 55 to 69, and 70 to 84.
A validated survey of pelvic floor disorders was mailed to each of the 12,200 women originally selected for the study. Participants returned 4,458 surveys, and after exclusions for insufficient data, the investigators had 4,103 complete surveys for analysis.
The study population was 764 women ages 25 to 39, 981 ages 40 to 54, 1,187 ages 55 to 69, and 1,171 ages 70 to 84. About two thirds of respondents were married or living with a partner; fewer than 30% had no vaginal deliveries with birth weights of more than 2,000g; three-fourths had some college education, one-fourth were obese, and two-thirds were postmenopausal.
The survey showed that 15% of respondents had stress urinary incontinence, 13% had overactive bladder, and 6% had pelvic organ prolapse. Co-occurrence of two or more pelvic floor disorders was reported by:
About 80% of women with stress urinary incontinence or overactive bladder.
About 70% of women with pelvic organ prolapse.
Almost 50% of women with anal incontinence.
Although age did not increase the likelihood of a pelvic floor disorder, menopause had a positive correlation with all of the disorders except pelvic organ prolapse. The covariates most consistently associated with pelvic floor disorders were obesity, increasing vaginal parity, hormone use, and hysterectomy.
A limitation of the study noted by the authors was that the response rate, particularly among younger health plan members, was lower than anticipated. Younger members were hardest to reach; the likelihood of having the survey returned as undeliverable by the post office decreased with increasing age, from 11% of 25- to 39-year-olds to 3% of 70- to 84-year-olds.
The study was supported by the National Institutes of Health and Kaiser Permanente.
Primary source: Obstetrics & GynecologySource reference:Lawrence JM, et al. "Prevalence and co-occurrence of pelvic floor disorders in community-dwelling women" Obstetr Gynecol 2008; 111: DOI: 10.1097/AOG.Ob013e3181660c1b.
Tamoxifen Efficacy in Bipolar Mania Gets Additional Backing
By John Gever
IZMIR, Turkey, March 3 -- More evidence has suggested that protein kinase C inhibitors may be effective in the manic phase of bipolar disorder, researchers here said.
Point out that tamoxifen is not approved for bipolar disorder and carries safety risks in long-term use.
Explain that a smaller study last year had a similar finding.
Manic patients treated with the breast cancer drug tamoxifen for three weeks showed a mean decrease of 5.84 points on the Young Mania Rating Scale, compared with an increase of 1.50 points among patients receiving placebo (P<0.001), reported Aysegul Yildiz, M.D., of Dokuz Eylul University, and colleagues in the March issue of Archives of General Psychiatry.
In addition to its role as an estrogen-receptor antagonist used against breast caner, tamoxifen is an inhibitor of protein kinase C.
The 66-patient randomized, double-blind trial is the second to show that tamoxifen can reduce mania symptoms. Similar results were reported last September in a placebo-controlled trial of 16 patients. (See: Breast Cancer Drug Tames Acute Mania in Bipolar Disorder).
Dr. Yildiz and colleagues did not recommend tamoxifen as an appropriate drug for long-term management of bipolar disorder because the agent heightens the risk of endometrial cancer.
Rather, they suggested the findings validate "the protein kinase C system as a plausible target for novel mood-stabilizing treatments."
In the current trial, the patients had bipolar I disorder according to DSM-IV criteria, in a manic or mixed state with Young Mania Rating Scale scores of more than 20 at enrollment.
Patients received either tamoxifen or placebo for three weeks, along with up to 5 mg/day lorazepam if clinically indicated.
The starting dose of tamoxifen was 40 mg/day, which was then increased in 10-mg increments to 80 mg/day.
About four-fifths of patients had received some other type of psychiatric medication in the month before entering the study. Mean scores on the Young Mania Rating Scale at baseline were 38.6 (SD 5.0) among patients assigned to tamoxifen and 37.2 (SD 6.6) in the placebo group.
Patients were also assessed with the Clinical Global Impressions-Mania scale, with baseline scores of 6.0 (SD 0.9) and 5.9 (SD 1.0) in the tamoxifen and placebo groups, respectively.
About 17% of patients in the tamoxifen group and 32% of those receiving placebo discontinued treatment prematurely because of clinical worsening. The difference was not statistically significant.
On an intent-to-treat basis, scores on both the Young and Clinical Global Impressions mania evaluations decreased significantly with tamoxifen relative to placebo.
Clinical Global Impressions-Mania scores declined by a mean of 0.73 points with tamoxifen versus an increase of 0.10 points in the placebo group (P<0.001).
Fourteen of 29 patients completing three weeks of tamoxifen treatment showed at least 50% reduction in symptoms according to the Young scale, compared with 5% of patients in the placebo group (P=0.003).
Clinical remission (Young score of 12 or less) was seen in 28% of the tamoxifen group versus none of the placebo group.
Dr. Yildiz and colleagues also found that lorazepam use was significantly lower in the tamoxifen group. The three-week average total dose of lorazepam was 25.2 mg (SD 16.1) in the tamoxifen group and 41.8 mg (SD 36.0) in placebo-treated patients (P=0.04).
Use of lorazepam was similar in the two groups during the first treatment week, but usage diverged markedly after that.
One patient in each group attempted suicide during the trial. Both cases were associated with delusions and neither patient showed signs of depression or a mixed state.
Other adverse events were minor or moderate. They were reported in 20% of tamoxifen patients and 10% of those receiving placebo, with no clear pattern or significant difference between groups.
Dr. Yildiz and colleagues noted that the placebo response was "remarkably poor" relative to what has been reported in other short-term studies of manic patients.
The researchers had no definitive explanation for this finding. They said the placebo group mean may have been skewed by five patients who showed major worsening in Young scores during the trial. These patients had received antipsychotic medication a few weeks before entering the study and were still very ill.
On the other hand, the tamoxifen group included at least six patients with similar histories and illness severity at enrollment, and they all improved substantially with treatment, Dr. Yildiz and colleagues said.
Another possible influence was a significant baseline difference between the placebo and tamoxifen group in pre-trial drug treatment, the researchers said. Some 68% of placebo-group patients versus 49% of those assigned to tamoxifen had received anti-manic or antipsychotic medication prior to entry.
The researchers said a major limitation of their study was its short duration. Such trials, they wrote, "may demonstrate technical 'efficacy' (greater symptomatic improvement than with placebo) but usually are too brief to quantify clinically important rates of syndromal, symptomatic, or functional recovery, which typically evolve over several months."
In an accompanying commentary, Mauricio Tohen, M.D., Dr.P.H., a researcher at Lilly in Indianapolis, pointed to another unusual aspect of the study, which was that Dr. Yildiz conducted all the clinical ratings herself using "all available clinical information." He said that could have introduced subtle biases.
That the study was conducted at a single site is a limitation as well, he said.
"Reproducibility of the results needs to be considered before large multi-site studies are initiated," Dr. Tohen wrote.
But in combination with the earlier clinical trial and other studies, the Turkish study "support[s] further study of agents with central anti-protein kinase C activity," he said.
He observed that no drug has yet been developed for bipolar disorder based on understanding of its pathophysiology or on mechanisms of effective treatments.
"Undoubtedly, this will be an important step to conquer this devastating disorder that affects millions of patients around the globe," Dr. Tohen wrote.
The study was supported by the Stanley Medical Research Institute.
The authors reported no potential conflicts of interest.
Dr. Tohen is an employee and stockholder of Eli Lilly & Co.
Primary source: Archives of General PsychiatrySource reference:Yildiz A, et al "Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen" Archives of General Psychiatry 2008; 65: 255-63.
Additional source: Archives of General PsychiatrySource reference: Tohen M, "Clinical trials in bipolar mania: implications in study design and drug development" Archives of General Psychiatry 2008; 65: 252-53.
By John Gever
IZMIR, Turkey, March 3 -- More evidence has suggested that protein kinase C inhibitors may be effective in the manic phase of bipolar disorder, researchers here said.
Point out that tamoxifen is not approved for bipolar disorder and carries safety risks in long-term use.
Explain that a smaller study last year had a similar finding.
Manic patients treated with the breast cancer drug tamoxifen for three weeks showed a mean decrease of 5.84 points on the Young Mania Rating Scale, compared with an increase of 1.50 points among patients receiving placebo (P<0.001), reported Aysegul Yildiz, M.D., of Dokuz Eylul University, and colleagues in the March issue of Archives of General Psychiatry.
In addition to its role as an estrogen-receptor antagonist used against breast caner, tamoxifen is an inhibitor of protein kinase C.
The 66-patient randomized, double-blind trial is the second to show that tamoxifen can reduce mania symptoms. Similar results were reported last September in a placebo-controlled trial of 16 patients. (See: Breast Cancer Drug Tames Acute Mania in Bipolar Disorder).
Dr. Yildiz and colleagues did not recommend tamoxifen as an appropriate drug for long-term management of bipolar disorder because the agent heightens the risk of endometrial cancer.
Rather, they suggested the findings validate "the protein kinase C system as a plausible target for novel mood-stabilizing treatments."
In the current trial, the patients had bipolar I disorder according to DSM-IV criteria, in a manic or mixed state with Young Mania Rating Scale scores of more than 20 at enrollment.
Patients received either tamoxifen or placebo for three weeks, along with up to 5 mg/day lorazepam if clinically indicated.
The starting dose of tamoxifen was 40 mg/day, which was then increased in 10-mg increments to 80 mg/day.
About four-fifths of patients had received some other type of psychiatric medication in the month before entering the study. Mean scores on the Young Mania Rating Scale at baseline were 38.6 (SD 5.0) among patients assigned to tamoxifen and 37.2 (SD 6.6) in the placebo group.
Patients were also assessed with the Clinical Global Impressions-Mania scale, with baseline scores of 6.0 (SD 0.9) and 5.9 (SD 1.0) in the tamoxifen and placebo groups, respectively.
About 17% of patients in the tamoxifen group and 32% of those receiving placebo discontinued treatment prematurely because of clinical worsening. The difference was not statistically significant.
On an intent-to-treat basis, scores on both the Young and Clinical Global Impressions mania evaluations decreased significantly with tamoxifen relative to placebo.
Clinical Global Impressions-Mania scores declined by a mean of 0.73 points with tamoxifen versus an increase of 0.10 points in the placebo group (P<0.001).
Fourteen of 29 patients completing three weeks of tamoxifen treatment showed at least 50% reduction in symptoms according to the Young scale, compared with 5% of patients in the placebo group (P=0.003).
Clinical remission (Young score of 12 or less) was seen in 28% of the tamoxifen group versus none of the placebo group.
Dr. Yildiz and colleagues also found that lorazepam use was significantly lower in the tamoxifen group. The three-week average total dose of lorazepam was 25.2 mg (SD 16.1) in the tamoxifen group and 41.8 mg (SD 36.0) in placebo-treated patients (P=0.04).
Use of lorazepam was similar in the two groups during the first treatment week, but usage diverged markedly after that.
One patient in each group attempted suicide during the trial. Both cases were associated with delusions and neither patient showed signs of depression or a mixed state.
Other adverse events were minor or moderate. They were reported in 20% of tamoxifen patients and 10% of those receiving placebo, with no clear pattern or significant difference between groups.
Dr. Yildiz and colleagues noted that the placebo response was "remarkably poor" relative to what has been reported in other short-term studies of manic patients.
The researchers had no definitive explanation for this finding. They said the placebo group mean may have been skewed by five patients who showed major worsening in Young scores during the trial. These patients had received antipsychotic medication a few weeks before entering the study and were still very ill.
On the other hand, the tamoxifen group included at least six patients with similar histories and illness severity at enrollment, and they all improved substantially with treatment, Dr. Yildiz and colleagues said.
Another possible influence was a significant baseline difference between the placebo and tamoxifen group in pre-trial drug treatment, the researchers said. Some 68% of placebo-group patients versus 49% of those assigned to tamoxifen had received anti-manic or antipsychotic medication prior to entry.
The researchers said a major limitation of their study was its short duration. Such trials, they wrote, "may demonstrate technical 'efficacy' (greater symptomatic improvement than with placebo) but usually are too brief to quantify clinically important rates of syndromal, symptomatic, or functional recovery, which typically evolve over several months."
In an accompanying commentary, Mauricio Tohen, M.D., Dr.P.H., a researcher at Lilly in Indianapolis, pointed to another unusual aspect of the study, which was that Dr. Yildiz conducted all the clinical ratings herself using "all available clinical information." He said that could have introduced subtle biases.
That the study was conducted at a single site is a limitation as well, he said.
"Reproducibility of the results needs to be considered before large multi-site studies are initiated," Dr. Tohen wrote.
But in combination with the earlier clinical trial and other studies, the Turkish study "support[s] further study of agents with central anti-protein kinase C activity," he said.
He observed that no drug has yet been developed for bipolar disorder based on understanding of its pathophysiology or on mechanisms of effective treatments.
"Undoubtedly, this will be an important step to conquer this devastating disorder that affects millions of patients around the globe," Dr. Tohen wrote.
The study was supported by the Stanley Medical Research Institute.
The authors reported no potential conflicts of interest.
Dr. Tohen is an employee and stockholder of Eli Lilly & Co.
Primary source: Archives of General PsychiatrySource reference:Yildiz A, et al "Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen" Archives of General Psychiatry 2008; 65: 255-63.
Additional source: Archives of General PsychiatrySource reference: Tohen M, "Clinical trials in bipolar mania: implications in study design and drug development" Archives of General Psychiatry 2008; 65: 252-53.
Breast Density Measurement May Help Predict Breast Cancer Risk
By Crystal Phend
SAN FRANCISCO, March 4 -- Incorporating breast density into assessment tools may add to the ability to predict breast cancer risk, but it's no slam-dunk, researchers here said.
Caution patients that the breast density risk prediction model is likely not ready for clinical use.
A simple risk algorithm incorporating breast density discriminated which women would develop breast cancer significantly better -- and "possibly clinically" better -- than the standard Gail model, reported Jeffrey A. Tice, M.D., of the University of California San Francisco, and colleagues in the March 4 issue of the Annals of Internal Medicine.
Like previous models, though, the breast density model had only modest ability to discriminate which women would develop breast cancer (concordance index 0.66 on a scale of 0.5 to 1.0).
Furthermore, the breast density model reclassified risk incorrectly more often than correctly compared with the Gail model although it still had a higher positive predictive value.
Since no single model can address all needs in breast cancer risk assessment, the researchers said, the best, most cost-effective approach might be to start with a simple model and family history then move to more detailed assessment for women at higher risk.
The breast density model "is convenient enough that it could be incorporated into routine breast cancer screening, and primary care physicians could use it to calculate an individual woman's breast cancer risk," they wrote.
"However, its accuracy must be further evaluated in independent populations before it can be recommended for clinical use," they added.
Radiographically dense breasts have consistently been implicated as a major risk factor for breast cancer partly because mammography is less sensitive in dense breasts.
To refine their breast density risk prediction model, the researchers analyzed data from mammography registries of the Breast Cancer Surveillance Consortium, which is a community-based sample broadly representative of the United States.
It included 1,095,484 women 35 or older who had had at least one mammogram with breast density measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system.
The sample was ethnically diverse with 29% of the cohort of black, Asian, Hispanic, or other minority race or ethnicity.
Invasive breast cancer developed among 14,766 women over the median follow-up of 5.3 years.
Factors in the model for five-year risk of invasive breast cancer included age, race or ethnicity, and breast density. Family history and biopsy history were added to adjust incidence estimates when available.
The predicted incidence in the randomly-selected validation sample (60% of the cohort) was well matched to the observed incidence (1.41% versus 1.38%, expected-to-observed ratio 1.03, 95% confidence interval 0.99% to 1.06%).
The model's ability to accurately discriminate which women would develop breast cancer was only modest, though.
Concordance was 0.660 on a scale where 0.5 is no discrimination and 1.0 is perfect discrimination (95% CI 0.651 to 0.669).
However, this was statistically higher than that of the standard Gail model (0.613, 95% CI 0.604 to 0.622).
The breast density model slightly underestimated breast cancer rates in younger women, Asian women, and Hispanic women (expected-to-observed ratios 0.94, 0.95, and 0.94, respectively).
Adding breast density to risk predicted by age, race or ethnicity, family history, and history of breast biopsy reclassified 22% of women correctly either to a higher-risk category for those with cancer or to a lower-risk category for those without cancer.
However, the addition of breast density also incorrectly reclassified 16% of women.
Compared with the Gail model, the breast density model correctly reclassified 14% of women and incorrectly reclassified 35% of women.
And while the breast density model increased the true-positive rate from 28% to 53% and the positive predictive value from 2.3% to 2.4%, it also almost doubled the false-positive rate from 17% to 30%.
"Further comparisons of the two models in additional populations will help to clarify their relative value," the researchers said.
The study was supported by cooperative agreements with the National Cancer Institute-funded Breast Cancer Surveillance Consortium and by a Building Interdisciplinary Research Careers in Women's Health faculty development grant.
Dr. Tice reported receiving grant support from Building Interdisciplinary Careers in Women's Health. A co-author reported consultancies, honoraria, and grant support from Eli Lilly as well as grants from the Lilly Foundation.
Primary source: Annals of Internal MedicineSource reference:Tice JA, et al "Using clinical factors and mammographic breast density to estimate breast cancer risk: Development and validation of a new predictive model" Ann Intern Med 2008; 148: 337-347.
By Crystal Phend
SAN FRANCISCO, March 4 -- Incorporating breast density into assessment tools may add to the ability to predict breast cancer risk, but it's no slam-dunk, researchers here said.
Caution patients that the breast density risk prediction model is likely not ready for clinical use.
A simple risk algorithm incorporating breast density discriminated which women would develop breast cancer significantly better -- and "possibly clinically" better -- than the standard Gail model, reported Jeffrey A. Tice, M.D., of the University of California San Francisco, and colleagues in the March 4 issue of the Annals of Internal Medicine.
Like previous models, though, the breast density model had only modest ability to discriminate which women would develop breast cancer (concordance index 0.66 on a scale of 0.5 to 1.0).
Furthermore, the breast density model reclassified risk incorrectly more often than correctly compared with the Gail model although it still had a higher positive predictive value.
Since no single model can address all needs in breast cancer risk assessment, the researchers said, the best, most cost-effective approach might be to start with a simple model and family history then move to more detailed assessment for women at higher risk.
The breast density model "is convenient enough that it could be incorporated into routine breast cancer screening, and primary care physicians could use it to calculate an individual woman's breast cancer risk," they wrote.
"However, its accuracy must be further evaluated in independent populations before it can be recommended for clinical use," they added.
Radiographically dense breasts have consistently been implicated as a major risk factor for breast cancer partly because mammography is less sensitive in dense breasts.
To refine their breast density risk prediction model, the researchers analyzed data from mammography registries of the Breast Cancer Surveillance Consortium, which is a community-based sample broadly representative of the United States.
It included 1,095,484 women 35 or older who had had at least one mammogram with breast density measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system.
The sample was ethnically diverse with 29% of the cohort of black, Asian, Hispanic, or other minority race or ethnicity.
Invasive breast cancer developed among 14,766 women over the median follow-up of 5.3 years.
Factors in the model for five-year risk of invasive breast cancer included age, race or ethnicity, and breast density. Family history and biopsy history were added to adjust incidence estimates when available.
The predicted incidence in the randomly-selected validation sample (60% of the cohort) was well matched to the observed incidence (1.41% versus 1.38%, expected-to-observed ratio 1.03, 95% confidence interval 0.99% to 1.06%).
The model's ability to accurately discriminate which women would develop breast cancer was only modest, though.
Concordance was 0.660 on a scale where 0.5 is no discrimination and 1.0 is perfect discrimination (95% CI 0.651 to 0.669).
However, this was statistically higher than that of the standard Gail model (0.613, 95% CI 0.604 to 0.622).
The breast density model slightly underestimated breast cancer rates in younger women, Asian women, and Hispanic women (expected-to-observed ratios 0.94, 0.95, and 0.94, respectively).
Adding breast density to risk predicted by age, race or ethnicity, family history, and history of breast biopsy reclassified 22% of women correctly either to a higher-risk category for those with cancer or to a lower-risk category for those without cancer.
However, the addition of breast density also incorrectly reclassified 16% of women.
Compared with the Gail model, the breast density model correctly reclassified 14% of women and incorrectly reclassified 35% of women.
And while the breast density model increased the true-positive rate from 28% to 53% and the positive predictive value from 2.3% to 2.4%, it also almost doubled the false-positive rate from 17% to 30%.
"Further comparisons of the two models in additional populations will help to clarify their relative value," the researchers said.
The study was supported by cooperative agreements with the National Cancer Institute-funded Breast Cancer Surveillance Consortium and by a Building Interdisciplinary Research Careers in Women's Health faculty development grant.
Dr. Tice reported receiving grant support from Building Interdisciplinary Careers in Women's Health. A co-author reported consultancies, honoraria, and grant support from Eli Lilly as well as grants from the Lilly Foundation.
Primary source: Annals of Internal MedicineSource reference:Tice JA, et al "Using clinical factors and mammographic breast density to estimate breast cancer risk: Development and validation of a new predictive model" Ann Intern Med 2008; 148: 337-347.
Traumatic Brain Injury Can Lead to Widespread Tissue Loss
By Judith Groch
TORONTO, March 4 -- A loss of brain tissue after a traumatic head injury may help explain the cognitive and emotional fallout that often follows the event, researchers here found.
In a study of mild to severe traumatic brain injury, the more severe the injury, the greater the tissue loss after a year, particularly white matter, Brian Levine, Ph.D., of the University of Toronto, and colleagues reported in the March 4 issue of Neurology.
The analysis, using high-resolution MRI, found a stepwise, dose-response relationship between loss of volume and brain injury, encompassing both frontal and posterior brain regions, the researchers said.
Notably, even patients with a mild injury had changes that could be reliably distinguished from the noninjured controls. The most reliable effects were in the frontal, temporal, and cingulated regions, although there were effects to varying degrees in nearly every brain region.
The patterns of diffuse tissue loss even in the absence of focal injury helped explain the well-known substantial handicap that patients have in the wake with a traumatic brain injury, particularly with concentration, working memory, organizing, planning, and mood changes, the researchers said.
To assess the relationship between regional brain volume changes and the severity of traumatic brain injury in patients with and without the focal lesions, the researchers recruited 69 chronic-phase traumatic brain-injury patients from consecutive hospital admissions to a large trauma center. Fifty-five of the patients (80%) were injured in a motor vehicle accident.
The patients, spanning the full range of severity, received high-resolution structural MRI a minimum of one year after the injury.
Analyzed with a technique that permitted template matching, the imaging technique detected tissue loss after a significant blow to the head that might otherwise evade detection by traditional qualitative radiological examination, the investigators said.
Multivariate statistical analyses assessed covariance patterns between volumes of gray matter, white matter, and sulcal/subdural and ventricular cerebrospinal fluid across 38 brain regions.
Severity of the brain injury was assessed by depth of coma or consciousness alteration at the time of injury. Some patients had minor injuries (13) while twenty-six had severe injuries including extended loss of consciousness.
Patients with diffuse and diffuse plus focal injury were analyzed both separately and together and compared with 12 age- and sex-matched non-injured controls. The controls had significantly more education than the injured groups.
All group differences in correlations for mild, moderate, and severe injury were reliably different from that of the non-injured group, and correlations for the moderate and severe injury groups were reliably different from that of the mild injury patients.
A spatially extensive pattern of volume loss varied along with injury severity, with particularly widespread effects in white matter volume and sulcal/subdural cerebrospinal fluid.
Focal lesions were associated with greater loss of volume in the left medial ventral frontal and posterior temporal regions, but volume loss included other regions and remained marked even when analyses were restricted to patients with diffuse injury.
Loss of white matter, also widespread, was greatest in the lateral superior frontal, superior parietal, posterior temporal, and posterior cingulated regions bilaterally, with a tendency toward greater volume loss in the right hemisphere.
However, the researchers noted that although white matter loss was greater, gray matter loss was nonetheless marked. In fact, Dr. Levine said, localized gray matter loss may have greater implications for specific behavioral changes than localized white matter loss.
Patterns of volumetric changes can differentiate the severity of levels of traumatic brain injury, even in mild injury. This form of brain injury causes a spatially extensive pattern of volume loss that reflects independent but overlapping contributions of focal and diffuse injury, the researchers said.
Although the sample size was large compared with previous studies, the size of the brain injury groups, particularly the mild group, was small. Also, the current study did not investigate the significance of tissue loss on behavior, a topic now being studied in this group of patients, the researchers said.
In addition, the researchers said, the MRI technique used, although well suited to patients with distorted brain anatomy, lacked the anatomic precision of manual tracing and the resolution of voxel-based methods. A fuller appreciation will require additional imaging technologies, such as functional neuroimaging and MR spectroscopy, the researchers concluded.
This study was supported by grants from the Canadian Institutes of Health Research and the NIH-National Institute of Child Health and Human Development.
The authors reported no conflicts of interest.
Primary source: NeurologySource reference:Levine B, et al "The Toronto traumatic brain injury study: Injury severity and quantified MRI" Neurology 2008; 70: 771-778.
By Judith Groch
TORONTO, March 4 -- A loss of brain tissue after a traumatic head injury may help explain the cognitive and emotional fallout that often follows the event, researchers here found.
In a study of mild to severe traumatic brain injury, the more severe the injury, the greater the tissue loss after a year, particularly white matter, Brian Levine, Ph.D., of the University of Toronto, and colleagues reported in the March 4 issue of Neurology.
The analysis, using high-resolution MRI, found a stepwise, dose-response relationship between loss of volume and brain injury, encompassing both frontal and posterior brain regions, the researchers said.
Notably, even patients with a mild injury had changes that could be reliably distinguished from the noninjured controls. The most reliable effects were in the frontal, temporal, and cingulated regions, although there were effects to varying degrees in nearly every brain region.
The patterns of diffuse tissue loss even in the absence of focal injury helped explain the well-known substantial handicap that patients have in the wake with a traumatic brain injury, particularly with concentration, working memory, organizing, planning, and mood changes, the researchers said.
To assess the relationship between regional brain volume changes and the severity of traumatic brain injury in patients with and without the focal lesions, the researchers recruited 69 chronic-phase traumatic brain-injury patients from consecutive hospital admissions to a large trauma center. Fifty-five of the patients (80%) were injured in a motor vehicle accident.
The patients, spanning the full range of severity, received high-resolution structural MRI a minimum of one year after the injury.
Analyzed with a technique that permitted template matching, the imaging technique detected tissue loss after a significant blow to the head that might otherwise evade detection by traditional qualitative radiological examination, the investigators said.
Multivariate statistical analyses assessed covariance patterns between volumes of gray matter, white matter, and sulcal/subdural and ventricular cerebrospinal fluid across 38 brain regions.
Severity of the brain injury was assessed by depth of coma or consciousness alteration at the time of injury. Some patients had minor injuries (13) while twenty-six had severe injuries including extended loss of consciousness.
Patients with diffuse and diffuse plus focal injury were analyzed both separately and together and compared with 12 age- and sex-matched non-injured controls. The controls had significantly more education than the injured groups.
All group differences in correlations for mild, moderate, and severe injury were reliably different from that of the non-injured group, and correlations for the moderate and severe injury groups were reliably different from that of the mild injury patients.
A spatially extensive pattern of volume loss varied along with injury severity, with particularly widespread effects in white matter volume and sulcal/subdural cerebrospinal fluid.
Focal lesions were associated with greater loss of volume in the left medial ventral frontal and posterior temporal regions, but volume loss included other regions and remained marked even when analyses were restricted to patients with diffuse injury.
Loss of white matter, also widespread, was greatest in the lateral superior frontal, superior parietal, posterior temporal, and posterior cingulated regions bilaterally, with a tendency toward greater volume loss in the right hemisphere.
However, the researchers noted that although white matter loss was greater, gray matter loss was nonetheless marked. In fact, Dr. Levine said, localized gray matter loss may have greater implications for specific behavioral changes than localized white matter loss.
Patterns of volumetric changes can differentiate the severity of levels of traumatic brain injury, even in mild injury. This form of brain injury causes a spatially extensive pattern of volume loss that reflects independent but overlapping contributions of focal and diffuse injury, the researchers said.
Although the sample size was large compared with previous studies, the size of the brain injury groups, particularly the mild group, was small. Also, the current study did not investigate the significance of tissue loss on behavior, a topic now being studied in this group of patients, the researchers said.
In addition, the researchers said, the MRI technique used, although well suited to patients with distorted brain anatomy, lacked the anatomic precision of manual tracing and the resolution of voxel-based methods. A fuller appreciation will require additional imaging technologies, such as functional neuroimaging and MR spectroscopy, the researchers concluded.
This study was supported by grants from the Canadian Institutes of Health Research and the NIH-National Institute of Child Health and Human Development.
The authors reported no conflicts of interest.
Primary source: NeurologySource reference:Levine B, et al "The Toronto traumatic brain injury study: Injury severity and quantified MRI" Neurology 2008; 70: 771-778.
TB Test Combination Rules Out Active Infection
By John Gever
LONDON, March 4 -- Combining new and old tests for latent tuberculosis infection can effectively rule out active TB, researchers here said. When results on the traditional tuberculin skin test and an experimental immunologic blood test are both negative, patients almost certainly do not have active disease, reported Ajit Lalvani, M.D., of Imperial College London, and colleagues in the March 4 issue of Annals of Internal Medicine. In a prospective study involving 389 adults with moderate to high clinical suspicion of tuberculosis, the investigators found a likelihood ratio for active disease of 0.02 (95% CI 0 to 0.09) when results on both tests were negative.
Point out that the original ELISpot assay is not yet approved in the U.S. and that the enhanced version is not available in any market.
Dr. Lalvani predicted in an interview that the findings would be "practice-changing."
The experimental test is an enhanced version of a diagnostic called ELISpot first developed about seven years ago in Dr. Lalvani's lab.
ELISpot is now commercially available in Europe under the name T-Spot.TB as a test for latent TB infection. FDA-approval is pending.
Both the original and the enhanced versions of ELISpot detect gamma-interferon released from T cells in a patient blood sample exposed in vitro to Mycobacterium tuberculosis antigens.
The antigens used in the original assay are derived from early secretory antigenic target-6 and culture filtrate protein-10. The enhanced version, dubbed ELISpot-Plus, adds additional peptides from another M. tuberculosis region, known as Rv3879c, to the antigen mix.
In the clinical study, patients with suspected TB underwent testing with the tuberculin skin test, the original ELISpot, and ELISpot-Plus.
Most patients were of South Asian or black ethnicity and were evaluated at two hospitals in England. Of the 389 patients, active TB was confirmed or considered highly probable in 194 on the basis of clinical examination and/or microbiological culture. In 154, active TB was ruled out. The rest were clinically indeterminate.
About one-quarter of all patients in the study had double-negative results on tuberculin skin testing and ELISpot-Plus, of whom only one actually did have active TB.
In 27% of the sample, ELISpot-Plus and tuberculin skin testing gave discordant results, which were of no diagnostic value, the researchers said.
Double-negative results with the original ELISpot and tuberculin skin testing were associated with a likelihood ratio of 0.04 (95% CI 0.02 to 0.12) for active infection.
Dr. Lalvani and colleagues found that both ELISpot assays in combination with tuberculin skin testing were highly sensitive for active infection.
In patients with culture-confirmed or highly probable clinical diagnoses of TB, positive results with both the original ELISpot and tuberculin skin testing had a sensitivity of 97% (95% CI 93% to 99%). Positive results on both ELISpot-Plus and tuberculin skin testing had a sensitivity of 99% (95% CI 95% to 100%).
However, ELISpot-Plus by itself had a specificity of only 69% among patients in whom active TB had been excluded by other tests. This was poorer than the specificity of tuberculin skin testing (81%; P=0.03), Dr. Lalvani and colleagues found.
In 121 patients with positive results on both tests, 15 were determined not to have active TB, for a specificity of 88%.
Similar specificity results were found with the original ELISpot combined with tuberculin skin testing.
Because of the imperfect specificity, Dr. Lalvani stressed that double-positive results on tuberculin skin testing and the ELISpot assays could not be used to diagnose active infection.
On the other hand, he and his colleagues said they could still be helpful in clinical evaluation.
"Double-positive results may help guide decisions about early initiation of presumptive treatment in severe disease while awaiting culture results and in extrapulmonary disease, in which culture is frequently negative," they wrote.
Dr. Lalvani added that double-negative results should not be the last word in making a diagnosis. "The results have to be taken in the overall clinical context," he said.
"If it's a very high pre-test probability [of active TB], then I think you have to go with the overall clinical picture, rather than a given blood test result."
Nevertheless, he compared the clinical potential of tuberculin skin testing plus ELISpot-Plus to that of D-dimer testing to rule out deep vein thrombosis.
In an accompanying commentary, Dick Menzies, M.D., of McGill University in Montreal, said the study has important strengths. They included its prospective design and careful clinical evaluation of all patients.
On the other hand, he said, it was limited by the fact that tuberculin skin testing was missing in 17% of patients and that the now-discontinued Heaf method for tuberculin testing was used in another 27% of patients.
He also pointed out that 21% of cases had no microbiological confirmation.
More importantly, he questioned the clinical utility of a 0.02 likelihood ratio for active infection with the combination of tests.
"The post-test probability after a negative result on both of these tests may still exceed some physicians' threshold probability for starting treatment of patients with a high pre-test probability of active tuberculosis infection," he wrote.
He noted that 95% of TB infections occur in populations where the disease is endemic. "In these populations, the search for a rapid accurate test must go on," Dr. Menzies concluded.
Both he and Dr. Lalvani said it would be important to confirm the study's findings in additional trials.
Dr. Lalvani said the ELISpot-Plus assay does not have a commercial sponsor. The study was supported by the Wellcome Trust, the Sir Halley Stewart Trust, and the U.K. Department of Health. Dr. Lalvani and two co-authors of the study reported past or current relationships with Oxford Immunotec Ltd., which markets the T-Spot.TB test. Dr. Menzies reported no potential conflicts of interest.
Additional source: Annals of Internal MedicineSource reference: Dosanjh D, et al "Improved diagnostic evaluation of suspected tuberculosis" Ann Intern Med 2008; 148: 325-36.
Additional source: Annals of Internal MedicineSource reference: Menzies D, "Using tests for latent tuberculous infection to diagnose active tuberculosis: can we eat our cake and have it too?" Ann Intern Med 2008; 148: 398-99.
By John Gever
LONDON, March 4 -- Combining new and old tests for latent tuberculosis infection can effectively rule out active TB, researchers here said. When results on the traditional tuberculin skin test and an experimental immunologic blood test are both negative, patients almost certainly do not have active disease, reported Ajit Lalvani, M.D., of Imperial College London, and colleagues in the March 4 issue of Annals of Internal Medicine. In a prospective study involving 389 adults with moderate to high clinical suspicion of tuberculosis, the investigators found a likelihood ratio for active disease of 0.02 (95% CI 0 to 0.09) when results on both tests were negative.
Point out that the original ELISpot assay is not yet approved in the U.S. and that the enhanced version is not available in any market.
Dr. Lalvani predicted in an interview that the findings would be "practice-changing."
The experimental test is an enhanced version of a diagnostic called ELISpot first developed about seven years ago in Dr. Lalvani's lab.
ELISpot is now commercially available in Europe under the name T-Spot.TB as a test for latent TB infection. FDA-approval is pending.
Both the original and the enhanced versions of ELISpot detect gamma-interferon released from T cells in a patient blood sample exposed in vitro to Mycobacterium tuberculosis antigens.
The antigens used in the original assay are derived from early secretory antigenic target-6 and culture filtrate protein-10. The enhanced version, dubbed ELISpot-Plus, adds additional peptides from another M. tuberculosis region, known as Rv3879c, to the antigen mix.
In the clinical study, patients with suspected TB underwent testing with the tuberculin skin test, the original ELISpot, and ELISpot-Plus.
Most patients were of South Asian or black ethnicity and were evaluated at two hospitals in England. Of the 389 patients, active TB was confirmed or considered highly probable in 194 on the basis of clinical examination and/or microbiological culture. In 154, active TB was ruled out. The rest were clinically indeterminate.
About one-quarter of all patients in the study had double-negative results on tuberculin skin testing and ELISpot-Plus, of whom only one actually did have active TB.
In 27% of the sample, ELISpot-Plus and tuberculin skin testing gave discordant results, which were of no diagnostic value, the researchers said.
Double-negative results with the original ELISpot and tuberculin skin testing were associated with a likelihood ratio of 0.04 (95% CI 0.02 to 0.12) for active infection.
Dr. Lalvani and colleagues found that both ELISpot assays in combination with tuberculin skin testing were highly sensitive for active infection.
In patients with culture-confirmed or highly probable clinical diagnoses of TB, positive results with both the original ELISpot and tuberculin skin testing had a sensitivity of 97% (95% CI 93% to 99%). Positive results on both ELISpot-Plus and tuberculin skin testing had a sensitivity of 99% (95% CI 95% to 100%).
However, ELISpot-Plus by itself had a specificity of only 69% among patients in whom active TB had been excluded by other tests. This was poorer than the specificity of tuberculin skin testing (81%; P=0.03), Dr. Lalvani and colleagues found.
In 121 patients with positive results on both tests, 15 were determined not to have active TB, for a specificity of 88%.
Similar specificity results were found with the original ELISpot combined with tuberculin skin testing.
Because of the imperfect specificity, Dr. Lalvani stressed that double-positive results on tuberculin skin testing and the ELISpot assays could not be used to diagnose active infection.
On the other hand, he and his colleagues said they could still be helpful in clinical evaluation.
"Double-positive results may help guide decisions about early initiation of presumptive treatment in severe disease while awaiting culture results and in extrapulmonary disease, in which culture is frequently negative," they wrote.
Dr. Lalvani added that double-negative results should not be the last word in making a diagnosis. "The results have to be taken in the overall clinical context," he said.
"If it's a very high pre-test probability [of active TB], then I think you have to go with the overall clinical picture, rather than a given blood test result."
Nevertheless, he compared the clinical potential of tuberculin skin testing plus ELISpot-Plus to that of D-dimer testing to rule out deep vein thrombosis.
In an accompanying commentary, Dick Menzies, M.D., of McGill University in Montreal, said the study has important strengths. They included its prospective design and careful clinical evaluation of all patients.
On the other hand, he said, it was limited by the fact that tuberculin skin testing was missing in 17% of patients and that the now-discontinued Heaf method for tuberculin testing was used in another 27% of patients.
He also pointed out that 21% of cases had no microbiological confirmation.
More importantly, he questioned the clinical utility of a 0.02 likelihood ratio for active infection with the combination of tests.
"The post-test probability after a negative result on both of these tests may still exceed some physicians' threshold probability for starting treatment of patients with a high pre-test probability of active tuberculosis infection," he wrote.
He noted that 95% of TB infections occur in populations where the disease is endemic. "In these populations, the search for a rapid accurate test must go on," Dr. Menzies concluded.
Both he and Dr. Lalvani said it would be important to confirm the study's findings in additional trials.
Dr. Lalvani said the ELISpot-Plus assay does not have a commercial sponsor. The study was supported by the Wellcome Trust, the Sir Halley Stewart Trust, and the U.K. Department of Health. Dr. Lalvani and two co-authors of the study reported past or current relationships with Oxford Immunotec Ltd., which markets the T-Spot.TB test. Dr. Menzies reported no potential conflicts of interest.
Additional source: Annals of Internal MedicineSource reference: Dosanjh D, et al "Improved diagnostic evaluation of suspected tuberculosis" Ann Intern Med 2008; 148: 325-36.
Additional source: Annals of Internal MedicineSource reference: Menzies D, "Using tests for latent tuberculous infection to diagnose active tuberculosis: can we eat our cake and have it too?" Ann Intern Med 2008; 148: 398-99.
Monday, March 03, 2008
FDA Approves Desvenlafaxine (Pristiq) for Major Depression
By Peggy Peck
MADISON, N.J., March 3 -- The FDA has approved desvenlafaxine (Pristiq), a serotonin-norepinephrine reuptake inhibitor (SNRI) for use in adults for major depressive disorder, according to an announcement by Wyeth.
Desvenlafaxine is a metabolite and follow-on compound of the company's venlafaxine (Effexor), an antidepressant with patent protection expiring this year. The FDA approval came more than a year after it had issued an approvable letter to Wyeth.
The company said the efficacy of the drug as a treatment for depression was established in four eight-week, randomized, placebo-controlled, fixed-dose studies in adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder. At the recommended dose of 50mg, the discontinuation rate because of adverse experiences for desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%).
A meta-analysis of seven randomized trials of desvenlafaxine reported last May at the American Psychiatric Association meeting found that that the drug reduced anxiety (See: APA: Successor to Effexor Effective Against Anxiety in Depression).
Wyeth said the FDA approval was subject to several post-marketing commitments, including conducting and submitting data from a new long-term maintenance (relapse prevention) study, a sexual dysfunction study, pediatric studies, and a study exploring lower doses. The agency also requested an additional non-clinical toxicity study.
The drug must not be used concomitantly with a monoamine oxidase inhibitor or within 14 days of stopping MAOI therapy and seven days should be allowed after stopping desvenlafaxine and beginning an MAOI.
By Peggy Peck
MADISON, N.J., March 3 -- The FDA has approved desvenlafaxine (Pristiq), a serotonin-norepinephrine reuptake inhibitor (SNRI) for use in adults for major depressive disorder, according to an announcement by Wyeth.
Desvenlafaxine is a metabolite and follow-on compound of the company's venlafaxine (Effexor), an antidepressant with patent protection expiring this year. The FDA approval came more than a year after it had issued an approvable letter to Wyeth.
The company said the efficacy of the drug as a treatment for depression was established in four eight-week, randomized, placebo-controlled, fixed-dose studies in adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder. At the recommended dose of 50mg, the discontinuation rate because of adverse experiences for desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%).
A meta-analysis of seven randomized trials of desvenlafaxine reported last May at the American Psychiatric Association meeting found that that the drug reduced anxiety (See: APA: Successor to Effexor Effective Against Anxiety in Depression).
Wyeth said the FDA approval was subject to several post-marketing commitments, including conducting and submitting data from a new long-term maintenance (relapse prevention) study, a sexual dysfunction study, pediatric studies, and a study exploring lower doses. The agency also requested an additional non-clinical toxicity study.
The drug must not be used concomitantly with a monoamine oxidase inhibitor or within 14 days of stopping MAOI therapy and seven days should be allowed after stopping desvenlafaxine and beginning an MAOI.
Long workweeks keeping Americans up late
Hey you! Dozing at your desk! Wake up, go home and get more sleep! That could be the message from a survey released Monday by the National Sleep Foundation. The survey of 1,000 people found participants average six hours and 40 minutes of sleep a night on weeknights, even though they estimated they'd need roughly another 40 minutes of sleep to be at their best.
Roughly one-third of those surveyed said they had fallen asleep or become very sleepy at work in the past month.
Just how big a deal that is depends, of course, on your job. Last week, the chairman of the Nuclear Regulatory Commission acknowledged it should have done more to investigate a tip that security guards routinely took naps while on the job at a Pennsylvania nuclear plant.
It wasn't until a videotape of guards sleeping in a "ready room" at the Peach Bottom plant in south-central Pennsylvania surfaced several months after it got the tip that the NRC announced in September a special investigation.
While sleepy workers know they're not performing as well as they could during the day, work is what's keeping them up nights, according to the survey, which found workdays are getting longer and time spent working from home averages close to four-and-a-half hours each week.
It seems people are also trying to squeeze in more time for themselves and their families, even if it means less sleep. The average wake up is at 5:35 a.m. and it's followed by about two hours and 15 minutes at home before heading out to work, according to the survey. Average bedtime is 10:53.
Hey you! Dozing at your desk! Wake up, go home and get more sleep! That could be the message from a survey released Monday by the National Sleep Foundation. The survey of 1,000 people found participants average six hours and 40 minutes of sleep a night on weeknights, even though they estimated they'd need roughly another 40 minutes of sleep to be at their best.
Roughly one-third of those surveyed said they had fallen asleep or become very sleepy at work in the past month.
Just how big a deal that is depends, of course, on your job. Last week, the chairman of the Nuclear Regulatory Commission acknowledged it should have done more to investigate a tip that security guards routinely took naps while on the job at a Pennsylvania nuclear plant.
It wasn't until a videotape of guards sleeping in a "ready room" at the Peach Bottom plant in south-central Pennsylvania surfaced several months after it got the tip that the NRC announced in September a special investigation.
While sleepy workers know they're not performing as well as they could during the day, work is what's keeping them up nights, according to the survey, which found workdays are getting longer and time spent working from home averages close to four-and-a-half hours each week.
It seems people are also trying to squeeze in more time for themselves and their families, even if it means less sleep. The average wake up is at 5:35 a.m. and it's followed by about two hours and 15 minutes at home before heading out to work, according to the survey. Average bedtime is 10:53.
GTx prostate-cancer drug reduces hot flashes in men
Biotechnology company GTx Inc said a late-stage trial showed its experimental drug, toremifene citrate, reduced hot flashes in men who were on Androgen deprivation therapy (ADT), a common treatment for advanced prostate cancer.
Reducing hot flashes was a secondary goal for the 80 milligram dose of the drug in the trial, which studied 1,389 patients over a period of two years.
In late February, the company said a late-stage trial showed the drug reduced spinal fractures and other side effects caused by ADT, a hormone therapy which works by reducing testosterone and estrogen.
"Hot flashes are the most common and bothersome symptomatic side effect of ADT. Up to 80 percent of men on ADT report being troubled by hot flashes, which are often cited as a cause of noncompliance with hormone therapy," Matthew Smith, the lead investigator of the trial, said in a statement.
GTx plans to seek U.S. approval for toremifene, licensed from Finland's Orion Corp, by this summer and expects a priority review, putting it on track for approval by the end of this year or early 2009.
Biotechnology company GTx Inc said a late-stage trial showed its experimental drug, toremifene citrate, reduced hot flashes in men who were on Androgen deprivation therapy (ADT), a common treatment for advanced prostate cancer.
Reducing hot flashes was a secondary goal for the 80 milligram dose of the drug in the trial, which studied 1,389 patients over a period of two years.
In late February, the company said a late-stage trial showed the drug reduced spinal fractures and other side effects caused by ADT, a hormone therapy which works by reducing testosterone and estrogen.
"Hot flashes are the most common and bothersome symptomatic side effect of ADT. Up to 80 percent of men on ADT report being troubled by hot flashes, which are often cited as a cause of noncompliance with hormone therapy," Matthew Smith, the lead investigator of the trial, said in a statement.
GTx plans to seek U.S. approval for toremifene, licensed from Finland's Orion Corp, by this summer and expects a priority review, putting it on track for approval by the end of this year or early 2009.
Sunday, March 02, 2008
Fibromyalgia Is Not a Rheumatologic Disease Anymore
George T. Griffing, MD
Think of your last patient with difficult-to-treat fibromyalgia: Aren't they all? Did you refer that person to a rheumatologist?
Since the 1950s, when it was first described by Dr. Graham, "fibrositis" or fibromyalgia was thought to be a rheumatologic disorder because it was characterized by musculoskeletal pain similar to other rheumatologic diseases.[1]
In 1990, The American College of Rheumatology established diagnostic criteria based on the scoring of 18 potential tender points.[2] It turns out, however, that these tender points have nothing to do with fibromyalgia. Biopsy of the tender points shows no pathologic changes, and numerous studies have not shown any abnormalities in the musculoskeletal tissues that are painful.
Current evidence points to a neurologic disorder of central pain processing.[3] Fibromyalgia patients experience pain differently and have lower pain thresholds compared to normals. Research has demonstrated that various pain-related processes in the brain and spinal cord are abnormal in fibromyalgia.[4] But more work remains to be done.
Market surveys show the number one class of drugs used to treat fibromyalgia is nonsteroidal anti-inflammatory drugs.[5] Since fibromyalgia is not an inflammatory disease, it is not surprising we have a lot of treatment failures.
The pharmaceutical industry knows this, and they are viewing fibromyalgia as the prototypical central pain state. The 2 main drug classes of interest are the dual receptor reuptake inhibitors, like duloxetine or Cymbalta, and the antiepileptic drugs, like pregabalin or Lyrica. In fact, pregabalin has shown enough efficacy, that it is the first and only drug approved by the FDA for the treatment of fibromyalgia.[6]
Therefore, in the future, with new insights and therapies on the horizon, we will no longer need to refer our fibromyalgia patients to the rheumatologist.
That's my opinion. I'm Dr. George Griffing, Professor of Medicine at St. Louis University and Editor-in-Chief of Internal Medicine for eMedicine.
References
Graham W. The fibrositis syndrome. Bull Rheum Dis. 1953;3:33-34.
Wolfe F, Symthe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-172.
Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review: the pathophysiology of fibromyalgia. Ann Intern Med. 2007;146:726-734.
Clauw DJ. Fibromyalgia: update on mechanisms and management. J Clin Rheumatol. 2007;13:102-109.
Rooks DS. Fibromyalgia treatment update. Curr Opin Rheumat. 2007;19:111-117.
Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264-1273.
George T. Griffing, MD
Think of your last patient with difficult-to-treat fibromyalgia: Aren't they all? Did you refer that person to a rheumatologist?
Since the 1950s, when it was first described by Dr. Graham, "fibrositis" or fibromyalgia was thought to be a rheumatologic disorder because it was characterized by musculoskeletal pain similar to other rheumatologic diseases.[1]
In 1990, The American College of Rheumatology established diagnostic criteria based on the scoring of 18 potential tender points.[2] It turns out, however, that these tender points have nothing to do with fibromyalgia. Biopsy of the tender points shows no pathologic changes, and numerous studies have not shown any abnormalities in the musculoskeletal tissues that are painful.
Current evidence points to a neurologic disorder of central pain processing.[3] Fibromyalgia patients experience pain differently and have lower pain thresholds compared to normals. Research has demonstrated that various pain-related processes in the brain and spinal cord are abnormal in fibromyalgia.[4] But more work remains to be done.
Market surveys show the number one class of drugs used to treat fibromyalgia is nonsteroidal anti-inflammatory drugs.[5] Since fibromyalgia is not an inflammatory disease, it is not surprising we have a lot of treatment failures.
The pharmaceutical industry knows this, and they are viewing fibromyalgia as the prototypical central pain state. The 2 main drug classes of interest are the dual receptor reuptake inhibitors, like duloxetine or Cymbalta, and the antiepileptic drugs, like pregabalin or Lyrica. In fact, pregabalin has shown enough efficacy, that it is the first and only drug approved by the FDA for the treatment of fibromyalgia.[6]
Therefore, in the future, with new insights and therapies on the horizon, we will no longer need to refer our fibromyalgia patients to the rheumatologist.
That's my opinion. I'm Dr. George Griffing, Professor of Medicine at St. Louis University and Editor-in-Chief of Internal Medicine for eMedicine.
References
Graham W. The fibrositis syndrome. Bull Rheum Dis. 1953;3:33-34.
Wolfe F, Symthe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-172.
Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review: the pathophysiology of fibromyalgia. Ann Intern Med. 2007;146:726-734.
Clauw DJ. Fibromyalgia: update on mechanisms and management. J Clin Rheumatol. 2007;13:102-109.
Rooks DS. Fibromyalgia treatment update. Curr Opin Rheumat. 2007;19:111-117.
Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264-1273.
PC beats doctor in scan tests A computer does better than a doctor at diagnosing certain brain diseases, research has suggested
Experts taught a standard computer how to diagnose Alzheimer's from brain scans, and got a 96% success rate.
The accuracy of diagnosis from standard scans, blood tests and interviews carried out by a clinician is 85%.
The findings, published in the journal Brain, could lead to earlier diagnosis and more successful treatment of dementias, say scientists.
Researchers from the Wellcome Trust Centre for Neuroimaging at University College London say computers have several advantages for diagnosing Alzheimer's - a condition caused by the build-up of plaques and tangles of tissue in the brain.
From the point of view of developing new pharmaceuticals for these disorders there's great potential Prof Richard Frackowiak
Professor Richard Frackowiak said the computers were better able to distinguish signs of Alzheimer's than humans, and proved cheaper, faster and more accurate than current methods.
"It's beginning to look like it will have to come into clinical practice," he said. "Machines are clearly able to do that sort of thing better."
The method involves teaching a standard computer the difference between brain scans from patients with proven Alzheimer's disease and people with no signs of the disease at all.
The two conditions can be distinguished with a high degree of accuracy on a single clinical MRI scan without the need for time consuming follow-up tests, say the scientists.
They think the technique will be particularly useful for reassuring elderly people with mild memory loss that they are not suffering from Alzheimer's disease.
It may also allow researchers to study progression of the disease in a patient, and perhaps eventually lead to a way of screening new drugs.
"In the long-run, we'd like to use these techniques as ways of classifying patients with something like a degenerative disease into various stages," explained Professor Frackowiak.
"From the point-of-view of developing new pharmaceuticals for these disorders there's great potential," he added.
Experts taught a standard computer how to diagnose Alzheimer's from brain scans, and got a 96% success rate.
The accuracy of diagnosis from standard scans, blood tests and interviews carried out by a clinician is 85%.
The findings, published in the journal Brain, could lead to earlier diagnosis and more successful treatment of dementias, say scientists.
Researchers from the Wellcome Trust Centre for Neuroimaging at University College London say computers have several advantages for diagnosing Alzheimer's - a condition caused by the build-up of plaques and tangles of tissue in the brain.
From the point of view of developing new pharmaceuticals for these disorders there's great potential Prof Richard Frackowiak
Professor Richard Frackowiak said the computers were better able to distinguish signs of Alzheimer's than humans, and proved cheaper, faster and more accurate than current methods.
"It's beginning to look like it will have to come into clinical practice," he said. "Machines are clearly able to do that sort of thing better."
The method involves teaching a standard computer the difference between brain scans from patients with proven Alzheimer's disease and people with no signs of the disease at all.
The two conditions can be distinguished with a high degree of accuracy on a single clinical MRI scan without the need for time consuming follow-up tests, say the scientists.
They think the technique will be particularly useful for reassuring elderly people with mild memory loss that they are not suffering from Alzheimer's disease.
It may also allow researchers to study progression of the disease in a patient, and perhaps eventually lead to a way of screening new drugs.
"In the long-run, we'd like to use these techniques as ways of classifying patients with something like a degenerative disease into various stages," explained Professor Frackowiak.
"From the point-of-view of developing new pharmaceuticals for these disorders there's great potential," he added.
Patient Is a Virtue
By LISA SANDERS, M.D.
1. Symptoms
The lights at the Metropolitan Opera House were already beginning to dim as the elderly couple made their way past the pumps and wingtips of the mostly seated audience. As the familiar notes of “La Traviata” began to sound from the orchestra, the man leaned over to his wife of 60-some years. “I feel terrible,” he whispered. He struggled to his feet, and the two edged back down the row.
The man leaned heavily on his wife. His right leg was too weak to support him. In the lobby, he gratefully lowered himself into a wheelchair. He felt awful and wondered if he might be dying. Finally, he heard a siren announcing that an ambulance was on its way.
In the emergency room at Roosevelt Hospital, Dr. Barbara Kilian hurried to see the new arrival. He looked younger than 81, trim and, judging from the way he filled the stretcher, quite tall. His angular face was pale and covered with sweat. The young doctor glanced at the monitors. Heart rate was slow and steady; blood pressure was normal. The patient seemed comfortable. She had a little time.
He was a neurosurgeon, the patient told the doctor. He and his wife went to the opera to celebrate her 77th birthday. He felt fine all day until quite suddenly he did not. He was generally healthy despite a little high blood pressure and mild Parkinson’s disease. The terrible feeling he had in the theater was gone, but his right leg was numb, and he couldn’t move it. Could he be having a stroke? “I’m wondering that myself,” the doctor told him. “Then you should give me tPA,” he told her. TPA, short for tissue plasminogen activator, is a clot-busting medicine used to treat strokes and heart attacks. These diseases are caused by a blood clot blocking an artery, leaving the tissues beyond to die. When used early it can prevent this damage, but the powerful drug can also cause life-threatening bleeding. The twin responsibilities of an E.R. physician are to treat diseases that are true emergencies — the ones that can kill you before morning — while simultaneously making sure not to harm the patient in the process. “Let’s see what you’ve got before we start treating you,” she told him.
2. Investigation
A few minutes later the patient-doctor was whisked out of the E.R. to get a CT scan of his head. If this was a stroke, there was a good chance it would show up. The scan was a completely normal. By the time the patient returned to the E.R., his symptoms had changed: he could move his right leg, but it was unbearably painful, especially at the thigh. Kilian quickly examined the leg: no cuts or bruises, no swelling or redness. If anything, the right leg was a little paler than the left. Was it possible that he had a clot, not in his brain where it would cause a stroke, but in his leg? Kilian ordered some morphine for the pain and called the vascular surgeon.
When the surgical resident arrived, the older man was sitting up in bed. His mind was clear, despite the hefty dose of opiate. The resident introduced himself then reviewed the events of the night. Initially, you thought you were having a stroke, the resident stated. Yes, the patient said, but then added thoughtfully that a stroke didn’t really make sense. His leg had been weak, but he had no weakness anywhere else. Usually a stroke devastating enough to paralyze a leg will also affect the arm on the same side, and his arm was fine.
On exam, the surgeon noticed that the right leg was still weaker than the left leg. Was that from a stroke too small to be seen on the scan or from the pain he still had, despite the morphine he’d been given? It wasn’t clear. Or maybe this was a T.I.A. — a transient ischemic attack — a temporary stroke where blood flow is restored before permanent damage is done. But then what about this pain? Strokes and T.I.A.’s are usually painless. Could he have a clot blocking the blood flow to the right leg? And if so, why? Almost all clots like this occur in patients with a chronically irregular heartbeat — a condition known as atrial fibrillation. This patient had no history of that.
He explained his thinking to the patient, who listened, nodding. As he moved toward the door, the doctor-patient couldn’t resist adding one more possibility to the list: “Could I have dissected my aorta?” he asked. The aorta is the thick, muscular blood vessel that delivers oxygenated blood from the heart to the rest of the body. Sometimes the inner lining of the artery can get torn — often from a spike in blood pressure. When that happens, blood pours into the tear, creating a separate channel between the inner layers of the vessel and the outer muscular wall. This new channel can compress the arteries leading off the aorta, starving the tissues they normally feed.
The resident asked the patient whether he’d had chest pain or back pain. These were by far the most common symptoms of a dissection. No, the patient said, he’d had neither of those. That made the diagnosis fairly unlikely, the resident said. Also, he’d seen several dissections in the course of his training. Those patients, all men in their 50s or 60s, were writhing in pain.
The resident found Kilian, and they discussed the possibilities. The resident thought the most likely was that the patient did have a clot blocking blood to the leg and suggested Kilian start him on the blood thinner Heparin.
The blood clot would account for the pallor in his leg, Kilian thought, but it wasn’t a perfect fit. What else could it be? More important, was there any condition she hadn’t yet ruled out that could worsen if she started a blood thinner? Like the doctor-patient, she thought of an aortic dissection. It was unlikely given the patient’s age and the absence of chest pain, but if he had torn his aorta, anticoagulation could cause the patient to bleed to death. She sent the patient back to get a CT scan of his chest and abdomen.
3. Resolution
A few minutes later, Kilian heard her name paged with instructions to call radiology. The radiologist was breathless with excitement. “You can’t believe the size of this dissection,” she told Kilian. “It starts up in his carotid arteries and continues through the heart. I don’t know where it ends, because he’s still getting scanned. Just wanted to give you a heads up.”
Kilian quickly dialed up the CT scan on her desktop computer. She could see the wide mouth of the aorta as well as a new channel filled with the blood that had flowed through the tear in the inner layers of the vessel. His aorta now looked like some strange double-barreled shotgun. This guy needed surgery immediately. In a case like this, the chance of mortality increases 1 percent to 2 percent with every passing hour.
Within the hour, the patient was on his way to the operating room. The next day, Kilian went by the surgical I.C.U. to see how the patient fared. She had seen only two other patients with this condition; both were younger than her patient and one had died. Not this guy, though. Twenty-four hours after his operation, he was sitting up in a chair. He looked great.
An aortic dissection is one of the classic difficult diagnoses in medicine. Far too often it’s not even considered. Or as in the case of John Ritter, who died of a dissection in 2003, it is considered but too late. (That case is now being litigated in a Glendale, Calif., courtroom, with Ritter’s family charging wrongful death.) In the case of this elderly patient, it was the very hardest kind of diagnosis — an unusual presentation of an unusual disease. A dissection without the usual accompanying chest or back pain. In spite of that, two physicians reached this diagnosis coming at it from two different perspectives — that of an E.R. doctor who conscientiously made sure that she first did no harm and that of a patient who couldn’t stop himself from thinking like a doctor.
By LISA SANDERS, M.D.
1. Symptoms
The lights at the Metropolitan Opera House were already beginning to dim as the elderly couple made their way past the pumps and wingtips of the mostly seated audience. As the familiar notes of “La Traviata” began to sound from the orchestra, the man leaned over to his wife of 60-some years. “I feel terrible,” he whispered. He struggled to his feet, and the two edged back down the row.
The man leaned heavily on his wife. His right leg was too weak to support him. In the lobby, he gratefully lowered himself into a wheelchair. He felt awful and wondered if he might be dying. Finally, he heard a siren announcing that an ambulance was on its way.
In the emergency room at Roosevelt Hospital, Dr. Barbara Kilian hurried to see the new arrival. He looked younger than 81, trim and, judging from the way he filled the stretcher, quite tall. His angular face was pale and covered with sweat. The young doctor glanced at the monitors. Heart rate was slow and steady; blood pressure was normal. The patient seemed comfortable. She had a little time.
He was a neurosurgeon, the patient told the doctor. He and his wife went to the opera to celebrate her 77th birthday. He felt fine all day until quite suddenly he did not. He was generally healthy despite a little high blood pressure and mild Parkinson’s disease. The terrible feeling he had in the theater was gone, but his right leg was numb, and he couldn’t move it. Could he be having a stroke? “I’m wondering that myself,” the doctor told him. “Then you should give me tPA,” he told her. TPA, short for tissue plasminogen activator, is a clot-busting medicine used to treat strokes and heart attacks. These diseases are caused by a blood clot blocking an artery, leaving the tissues beyond to die. When used early it can prevent this damage, but the powerful drug can also cause life-threatening bleeding. The twin responsibilities of an E.R. physician are to treat diseases that are true emergencies — the ones that can kill you before morning — while simultaneously making sure not to harm the patient in the process. “Let’s see what you’ve got before we start treating you,” she told him.
2. Investigation
A few minutes later the patient-doctor was whisked out of the E.R. to get a CT scan of his head. If this was a stroke, there was a good chance it would show up. The scan was a completely normal. By the time the patient returned to the E.R., his symptoms had changed: he could move his right leg, but it was unbearably painful, especially at the thigh. Kilian quickly examined the leg: no cuts or bruises, no swelling or redness. If anything, the right leg was a little paler than the left. Was it possible that he had a clot, not in his brain where it would cause a stroke, but in his leg? Kilian ordered some morphine for the pain and called the vascular surgeon.
When the surgical resident arrived, the older man was sitting up in bed. His mind was clear, despite the hefty dose of opiate. The resident introduced himself then reviewed the events of the night. Initially, you thought you were having a stroke, the resident stated. Yes, the patient said, but then added thoughtfully that a stroke didn’t really make sense. His leg had been weak, but he had no weakness anywhere else. Usually a stroke devastating enough to paralyze a leg will also affect the arm on the same side, and his arm was fine.
On exam, the surgeon noticed that the right leg was still weaker than the left leg. Was that from a stroke too small to be seen on the scan or from the pain he still had, despite the morphine he’d been given? It wasn’t clear. Or maybe this was a T.I.A. — a transient ischemic attack — a temporary stroke where blood flow is restored before permanent damage is done. But then what about this pain? Strokes and T.I.A.’s are usually painless. Could he have a clot blocking the blood flow to the right leg? And if so, why? Almost all clots like this occur in patients with a chronically irregular heartbeat — a condition known as atrial fibrillation. This patient had no history of that.
He explained his thinking to the patient, who listened, nodding. As he moved toward the door, the doctor-patient couldn’t resist adding one more possibility to the list: “Could I have dissected my aorta?” he asked. The aorta is the thick, muscular blood vessel that delivers oxygenated blood from the heart to the rest of the body. Sometimes the inner lining of the artery can get torn — often from a spike in blood pressure. When that happens, blood pours into the tear, creating a separate channel between the inner layers of the vessel and the outer muscular wall. This new channel can compress the arteries leading off the aorta, starving the tissues they normally feed.
The resident asked the patient whether he’d had chest pain or back pain. These were by far the most common symptoms of a dissection. No, the patient said, he’d had neither of those. That made the diagnosis fairly unlikely, the resident said. Also, he’d seen several dissections in the course of his training. Those patients, all men in their 50s or 60s, were writhing in pain.
The resident found Kilian, and they discussed the possibilities. The resident thought the most likely was that the patient did have a clot blocking blood to the leg and suggested Kilian start him on the blood thinner Heparin.
The blood clot would account for the pallor in his leg, Kilian thought, but it wasn’t a perfect fit. What else could it be? More important, was there any condition she hadn’t yet ruled out that could worsen if she started a blood thinner? Like the doctor-patient, she thought of an aortic dissection. It was unlikely given the patient’s age and the absence of chest pain, but if he had torn his aorta, anticoagulation could cause the patient to bleed to death. She sent the patient back to get a CT scan of his chest and abdomen.
3. Resolution
A few minutes later, Kilian heard her name paged with instructions to call radiology. The radiologist was breathless with excitement. “You can’t believe the size of this dissection,” she told Kilian. “It starts up in his carotid arteries and continues through the heart. I don’t know where it ends, because he’s still getting scanned. Just wanted to give you a heads up.”
Kilian quickly dialed up the CT scan on her desktop computer. She could see the wide mouth of the aorta as well as a new channel filled with the blood that had flowed through the tear in the inner layers of the vessel. His aorta now looked like some strange double-barreled shotgun. This guy needed surgery immediately. In a case like this, the chance of mortality increases 1 percent to 2 percent with every passing hour.
Within the hour, the patient was on his way to the operating room. The next day, Kilian went by the surgical I.C.U. to see how the patient fared. She had seen only two other patients with this condition; both were younger than her patient and one had died. Not this guy, though. Twenty-four hours after his operation, he was sitting up in a chair. He looked great.
An aortic dissection is one of the classic difficult diagnoses in medicine. Far too often it’s not even considered. Or as in the case of John Ritter, who died of a dissection in 2003, it is considered but too late. (That case is now being litigated in a Glendale, Calif., courtroom, with Ritter’s family charging wrongful death.) In the case of this elderly patient, it was the very hardest kind of diagnosis — an unusual presentation of an unusual disease. A dissection without the usual accompanying chest or back pain. In spite of that, two physicians reached this diagnosis coming at it from two different perspectives — that of an E.R. doctor who conscientiously made sure that she first did no harm and that of a patient who couldn’t stop himself from thinking like a doctor.
Anticonvulsant Hypersensitivity Syndrome: Implications for Pharmaceutical Care
KarenBeth H. Bohan
Abstract
Anticonvulsant hypersensitivity syndrome (AHS) is a delayed adverse drug reaction associated with the use of aromatic anticonvulsant drugs. It has been most commonly reported with the use of phenytoin, carbamazepine, and phenobarbital. Although its occurrence is rare, 1 in every 1000–10,000 exposures, AHS is a serious adverse event often resulting in hospitalization and even death. The clinical manifestations of AHS include a triad of symptoms consisting of dermatologic rashes, fever, and evidence of systemic organ involvement. Diagnosis is most frequently based on the recognition of this triad of symptoms and clinical judgment. The exact mechanism of AHS remains to be determined but is thought to have at least three components: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants, associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes. Arene oxides, the toxic intermediaries in the metabolism of anticonvulsant drugs, can accumulate and directly bind to macromolecules, causing cell death, as well as act as prohaptens that bind to T cells, initiating an immune response and systemic reactions. Management of AHS primarily includes discontinuation of the associated anticonvulsant drug. Systemic corticosteroids are usually required for full recovery. An important issue regarding AHS is the cross-sensitivity among aromatic anticonvulsant drugs, which has been reported to be 40–80%. This means that patients with a history of AHS should avoid further use of any aromatic anticonvulsant drug. In addition, a familial association with AHS exists, and family members of the patient with AHS should be educated that they may be at increased risk for developing AHS if they use aromatic anticonvulsant drugs. Anticonvulsant drugs that are generally considered safe are valproic acid and benzodiazepines. Other nonaromatic anticonvulsant drugs should also be acceptable. Pharmacists as health care providers can play an important role in the diagnosis, treatment, and prevention of AHS.
KarenBeth H. Bohan
Abstract
Anticonvulsant hypersensitivity syndrome (AHS) is a delayed adverse drug reaction associated with the use of aromatic anticonvulsant drugs. It has been most commonly reported with the use of phenytoin, carbamazepine, and phenobarbital. Although its occurrence is rare, 1 in every 1000–10,000 exposures, AHS is a serious adverse event often resulting in hospitalization and even death. The clinical manifestations of AHS include a triad of symptoms consisting of dermatologic rashes, fever, and evidence of systemic organ involvement. Diagnosis is most frequently based on the recognition of this triad of symptoms and clinical judgment. The exact mechanism of AHS remains to be determined but is thought to have at least three components: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants, associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes. Arene oxides, the toxic intermediaries in the metabolism of anticonvulsant drugs, can accumulate and directly bind to macromolecules, causing cell death, as well as act as prohaptens that bind to T cells, initiating an immune response and systemic reactions. Management of AHS primarily includes discontinuation of the associated anticonvulsant drug. Systemic corticosteroids are usually required for full recovery. An important issue regarding AHS is the cross-sensitivity among aromatic anticonvulsant drugs, which has been reported to be 40–80%. This means that patients with a history of AHS should avoid further use of any aromatic anticonvulsant drug. In addition, a familial association with AHS exists, and family members of the patient with AHS should be educated that they may be at increased risk for developing AHS if they use aromatic anticonvulsant drugs. Anticonvulsant drugs that are generally considered safe are valproic acid and benzodiazepines. Other nonaromatic anticonvulsant drugs should also be acceptable. Pharmacists as health care providers can play an important role in the diagnosis, treatment, and prevention of AHS.
Web surfing isn't just for cyberchondriacs
Tapping into medical information on the Net can make your visit to the doctor's office more efficient
ANDRE PICARD
A physician who treats himself has a fool for a patient," said the legendary Canadian physician Sir William Osler.
Today, thanks to the Internet, we are all physicians. And potential fools.
All you need to do is Google your symptoms and, presto, you have a diagnosis. A few more key strokes and you have a course of treatment - thanks to products hawked aggressively online.
No need to book an appointment with the doctor, no need to wait in the interminable line at the clinic or the emergency department.
You can simply sit at home in front of the computer and wait to die.
If you enter enough symptoms into a search engine, you will invariably come up with a diagnosis of cancer or something else fatal.
Thankfully, most people - with the exception of a hard core of cyberchondriacs - do not take everything they read online at face value.
Rather, they rely on good old-fashioned medicine and use the Web to get a second (or first) opinion.
Is there a way to get the best of both worlds - to tap into the seemingly unlimited information on the Web to make your interactions with health professionals more efficient and effective?
There are many.
First, there are good diagnostic tools online. Sites such as EasyDiagnosis.com, Mayo Clinic and WebMD have "symptom checkers" that can, if nothing else, help you figure out if junior's fever and cough is something that should be checked out by a doctor.
Diagnosis is not easy because a broad swatch of conditions, big and small, have common symptoms.
A headache, a hangover, a migraine, a concussion and a brain tumour all have similarities, but trained health professionals can make the distinction pretty quickly and they have access to specialized tests that are required if there are real concerns.
Physicians and nurse practitioners tend to use differential diagnosis, a systematic method of eliminating possibilities to pinpoint the cause of a problem.
A computer program can do this, but only to a degree. Even physicians are abandoning the classic Physicians' Desk Reference and using instead computer programs like DiagnosisPro and eMedicine to assist them. But, ultimately, there is no substitute for training and experience.
One of the most effective uses of the Web is for basic health information, or wellness information, if you will.
You can get excellent information online about diet, exercise and other lifestyle issues. But beware of charlatans selling dubious "fat melting" products and stick to reliable sites like the Heart and Stroke Foundation and the Canadian Health Network. (It remains a travesty that funding has been cut to the latter, a wonderful resource that is dying at the hands of short-sighted bureaucrats.)
People living with chronic conditions such as arthritis, heart disease and chronic obstructive pulmonary disease can also benefit greatly from Web resources, in particularly by hooking up with like-minded (or like-suffering) individuals. The Web-based communities that have formed in recent years have been a blessing for many, and the basis for some exciting consumer activism.
The unfortunate thing, however, is that these activities remain the exception rather than the norm.
Canada is a laggard when it comes to health-related technological innovation. Only one in four doctors in this country have an office computer that serves for something other than billing. Electronic health records and electronic medical records, tragically, remain a curiosity in much of the country.
The Canadian public also seems slow on the cyber-uptake. New data published this month by Statistics Canada show that the majority of adults - 16.8 million - use the Internet, but only 8.7 million use the Web to search for health information.
Not surprisingly, women - the custodians of health in Canadian families - are twice as likely as men to use the Web to seek health information and advice, particularly when they have young children.
More than one-third of users report discussing the results of their Internet finds with a physician. As much as some doctors dread patients who come in with a stack of printouts, this is a positive development because dialogue is an essential element of good care.
The challenge for the health system is to encourage and integrate this quest for knowledge into practice and care.
Rather than dismiss the Web as a minefield of quackery and half-truths (which it can be), we need to empower patients with good information and the ability to find credible sources.
Right now, we are failing to do so. Most provinces have telehealth lines and some are starting to implement the 8-1-1 health information line.
But where is the Web version of 8-1-1? Where should Canadians concerned about their health and wellness begin their quest?
Providing that starting point, that portal, should be a priority in the delivery of health care. Failing to address this need for patients is foolish indeed.
HEALTH IN CYBERSPACE
The following websites can
be used for diagnosing your
own ailments:
EasyDiagnosis.com
MayoClinic.com
WebMD.com
Other reliable sites include:
Canadian-health-network.ca emedicine.com
Heartandstroke.ca
PDRhealth.com
Tapping into medical information on the Net can make your visit to the doctor's office more efficient
ANDRE PICARD
A physician who treats himself has a fool for a patient," said the legendary Canadian physician Sir William Osler.
Today, thanks to the Internet, we are all physicians. And potential fools.
All you need to do is Google your symptoms and, presto, you have a diagnosis. A few more key strokes and you have a course of treatment - thanks to products hawked aggressively online.
No need to book an appointment with the doctor, no need to wait in the interminable line at the clinic or the emergency department.
You can simply sit at home in front of the computer and wait to die.
If you enter enough symptoms into a search engine, you will invariably come up with a diagnosis of cancer or something else fatal.
Thankfully, most people - with the exception of a hard core of cyberchondriacs - do not take everything they read online at face value.
Rather, they rely on good old-fashioned medicine and use the Web to get a second (or first) opinion.
Is there a way to get the best of both worlds - to tap into the seemingly unlimited information on the Web to make your interactions with health professionals more efficient and effective?
There are many.
First, there are good diagnostic tools online. Sites such as EasyDiagnosis.com, Mayo Clinic and WebMD have "symptom checkers" that can, if nothing else, help you figure out if junior's fever and cough is something that should be checked out by a doctor.
Diagnosis is not easy because a broad swatch of conditions, big and small, have common symptoms.
A headache, a hangover, a migraine, a concussion and a brain tumour all have similarities, but trained health professionals can make the distinction pretty quickly and they have access to specialized tests that are required if there are real concerns.
Physicians and nurse practitioners tend to use differential diagnosis, a systematic method of eliminating possibilities to pinpoint the cause of a problem.
A computer program can do this, but only to a degree. Even physicians are abandoning the classic Physicians' Desk Reference and using instead computer programs like DiagnosisPro and eMedicine to assist them. But, ultimately, there is no substitute for training and experience.
One of the most effective uses of the Web is for basic health information, or wellness information, if you will.
You can get excellent information online about diet, exercise and other lifestyle issues. But beware of charlatans selling dubious "fat melting" products and stick to reliable sites like the Heart and Stroke Foundation and the Canadian Health Network. (It remains a travesty that funding has been cut to the latter, a wonderful resource that is dying at the hands of short-sighted bureaucrats.)
People living with chronic conditions such as arthritis, heart disease and chronic obstructive pulmonary disease can also benefit greatly from Web resources, in particularly by hooking up with like-minded (or like-suffering) individuals. The Web-based communities that have formed in recent years have been a blessing for many, and the basis for some exciting consumer activism.
The unfortunate thing, however, is that these activities remain the exception rather than the norm.
Canada is a laggard when it comes to health-related technological innovation. Only one in four doctors in this country have an office computer that serves for something other than billing. Electronic health records and electronic medical records, tragically, remain a curiosity in much of the country.
The Canadian public also seems slow on the cyber-uptake. New data published this month by Statistics Canada show that the majority of adults - 16.8 million - use the Internet, but only 8.7 million use the Web to search for health information.
Not surprisingly, women - the custodians of health in Canadian families - are twice as likely as men to use the Web to seek health information and advice, particularly when they have young children.
More than one-third of users report discussing the results of their Internet finds with a physician. As much as some doctors dread patients who come in with a stack of printouts, this is a positive development because dialogue is an essential element of good care.
The challenge for the health system is to encourage and integrate this quest for knowledge into practice and care.
Rather than dismiss the Web as a minefield of quackery and half-truths (which it can be), we need to empower patients with good information and the ability to find credible sources.
Right now, we are failing to do so. Most provinces have telehealth lines and some are starting to implement the 8-1-1 health information line.
But where is the Web version of 8-1-1? Where should Canadians concerned about their health and wellness begin their quest?
Providing that starting point, that portal, should be a priority in the delivery of health care. Failing to address this need for patients is foolish indeed.
HEALTH IN CYBERSPACE
The following websites can
be used for diagnosing your
own ailments:
EasyDiagnosis.com
MayoClinic.com
WebMD.com
Other reliable sites include:
Canadian-health-network.ca emedicine.com
Heartandstroke.ca
PDRhealth.com
Patient fired by her doctor
CARLY WEEKS
Emerald Matthews suffers from such severe depression she sometimes finds it difficult to get out of bed or leave the house for weeks on end.
She cancels appointments, cuts herself off from the world and is trapped with the dark feelings that can overtake her mind.
Although Ms. Matthews, 33, of London, Ont., says she is physically unwell and that her mental illness interferes with her daily life, she never expected the type of shock she received earlier this month in a letter from her doctor's office.
Ms. Matthews was told she was being fired as a patient.
"I'm still in shock," Ms. Matthews said yesterday. "I don't think I've ever been blindsided this hard."
Ms. Matthews, who was a patient of a London-area health group, provided a letter to The Globe and Mail that outlines her physician's termination of treatment.
Dated Feb. 19, the letter states that it has become evident Ms. Matthews is "unable to comply with medical advice," that there have been "too many cancelled appointments" and that her doctor "will no longer be in a position" to provide her with medical treatment after March 4.
The problem started several months ago when a chest X-ray revealed a shadow on Ms. Matthews' lung.
Her doctor recommended a follow-up X-ray to see if the shadow might be cancer, or another medical problem, but Ms. Matthews delayed the X-ray and cancelled several appointments. She finally re-scheduled and had the X-ray earlier this month. But when she returned home after the procedure, the letter from her doctor's office was waiting in the mailbox.
"I was so angry and upset, I just wanted to know, what now?" Ms. Matthews said. "It took me almost three years ... before we even got a doctor and with no [warning] I have no doctor."
Ms. Matthews' case illustrates the difficulty many people with mental illness have functioning in society. But it also highlights the grey area in doctor-patient relationships that can emerge when a patient is seen to refuse treatment, be unco-operative or display other behaviour that causes friction.
The Canadian Medical Association has guidelines governing the relationship between doctors and patients and says that patients should have the chance to find a new family doctor before a physician terminates treatment.
However, doctors in Canada have the right to stop seeing patients at their discretion, particularly if a patient is difficult or won't accept treatment, said Jeff Blackmer, executive director in the CMA's office of ethics.
"The most common scenario I think I hear about is a breakdown or a profound disagreement about the goals of therapy, and that can mean any number of things," Dr. Blackmer said. "It's usually a pattern of that sort of approach to health care on behalf of the patient where the physician ends up saying, 'I really want to help you but I just can't because you're not allowing me to.' "
The health group declined to discuss this patient's specific situation, citing confidentiality reasons, and said the doctor would not agree to an interview. But the medical office manager at the clinic said Ms. Matthews was never denied medical treatment.
"She has just been released from [her former doctor's] care, but she was offered more than once the opportunity to come in and use our walk-in facility, which is open seven days a week," she said.
For Ms. Matthews, however, losing a family doctor is a difficult blow that has not only affected how she receives medical treatment, but how she sees herself.
"It tells me I'm not worth it. It tells me I'm not important," she said.
That sort of reaction is typical of people who suffer from depression and emphasizes how difficult it can be for them to break out of their cycle of behaviour, said Zindel Segal, a psychiatry professor at the University of Toronto.
"The real challenge is to get people with depression to see these are not flaws in their character," he said.
People often get frustrated with those suffering from depression because they may fail to keep commitments and seem unreliable. But that is just a symptom of a disease that can be very difficult to recognize and treat, Dr. Segal said.
"Depression exacts a very high toll on sufferers that is often invisible to the people around them."
Ms. Matthews hasn't started to look for a new doctor yet and says she thinks it will be difficult for her to find one. But she still has to contend with the issues that contributed to the situation she has found herself in - the feelings of depression that make it difficult for her to function on a daily basis.
"I don't do anything. I'm not okay," she said. "I understand that mental illness and society do not go hand in hand."
CARLY WEEKS
Emerald Matthews suffers from such severe depression she sometimes finds it difficult to get out of bed or leave the house for weeks on end.
She cancels appointments, cuts herself off from the world and is trapped with the dark feelings that can overtake her mind.
Although Ms. Matthews, 33, of London, Ont., says she is physically unwell and that her mental illness interferes with her daily life, she never expected the type of shock she received earlier this month in a letter from her doctor's office.
Ms. Matthews was told she was being fired as a patient.
"I'm still in shock," Ms. Matthews said yesterday. "I don't think I've ever been blindsided this hard."
Ms. Matthews, who was a patient of a London-area health group, provided a letter to The Globe and Mail that outlines her physician's termination of treatment.
Dated Feb. 19, the letter states that it has become evident Ms. Matthews is "unable to comply with medical advice," that there have been "too many cancelled appointments" and that her doctor "will no longer be in a position" to provide her with medical treatment after March 4.
The problem started several months ago when a chest X-ray revealed a shadow on Ms. Matthews' lung.
Her doctor recommended a follow-up X-ray to see if the shadow might be cancer, or another medical problem, but Ms. Matthews delayed the X-ray and cancelled several appointments. She finally re-scheduled and had the X-ray earlier this month. But when she returned home after the procedure, the letter from her doctor's office was waiting in the mailbox.
"I was so angry and upset, I just wanted to know, what now?" Ms. Matthews said. "It took me almost three years ... before we even got a doctor and with no [warning] I have no doctor."
Ms. Matthews' case illustrates the difficulty many people with mental illness have functioning in society. But it also highlights the grey area in doctor-patient relationships that can emerge when a patient is seen to refuse treatment, be unco-operative or display other behaviour that causes friction.
The Canadian Medical Association has guidelines governing the relationship between doctors and patients and says that patients should have the chance to find a new family doctor before a physician terminates treatment.
However, doctors in Canada have the right to stop seeing patients at their discretion, particularly if a patient is difficult or won't accept treatment, said Jeff Blackmer, executive director in the CMA's office of ethics.
"The most common scenario I think I hear about is a breakdown or a profound disagreement about the goals of therapy, and that can mean any number of things," Dr. Blackmer said. "It's usually a pattern of that sort of approach to health care on behalf of the patient where the physician ends up saying, 'I really want to help you but I just can't because you're not allowing me to.' "
The health group declined to discuss this patient's specific situation, citing confidentiality reasons, and said the doctor would not agree to an interview. But the medical office manager at the clinic said Ms. Matthews was never denied medical treatment.
"She has just been released from [her former doctor's] care, but she was offered more than once the opportunity to come in and use our walk-in facility, which is open seven days a week," she said.
For Ms. Matthews, however, losing a family doctor is a difficult blow that has not only affected how she receives medical treatment, but how she sees herself.
"It tells me I'm not worth it. It tells me I'm not important," she said.
That sort of reaction is typical of people who suffer from depression and emphasizes how difficult it can be for them to break out of their cycle of behaviour, said Zindel Segal, a psychiatry professor at the University of Toronto.
"The real challenge is to get people with depression to see these are not flaws in their character," he said.
People often get frustrated with those suffering from depression because they may fail to keep commitments and seem unreliable. But that is just a symptom of a disease that can be very difficult to recognize and treat, Dr. Segal said.
"Depression exacts a very high toll on sufferers that is often invisible to the people around them."
Ms. Matthews hasn't started to look for a new doctor yet and says she thinks it will be difficult for her to find one. But she still has to contend with the issues that contributed to the situation she has found herself in - the feelings of depression that make it difficult for her to function on a daily basis.
"I don't do anything. I'm not okay," she said. "I understand that mental illness and society do not go hand in hand."
Subscribe to:
Posts (Atom)