Mary Ann Moon

Clinicians should recommend a sleep study using polysomnography for adults who have unexplained daytime sleepiness, according to a clinical practice guideline on diagnosing obstructive sleep apnea.

The guideline was published online Aug. 4 in Annals of Internal Medicine.

There is still "considerable" controversy concerning the type and level of respiratory abnormality that defines obstructive sleep apnea (OSA), as well as the presence and type of signs or symptoms that are diagnostic of the disorder, said Dr. Amir Qaseem, director of clinical policy at the American College of Physicians, Philadelphia.

To formulate a clinical practice guideline, Dr. Qaseem and his associates performed a comprehensive review of the literature through May 2013, which included a comparative effectiveness technology review of portable sleep monitors sponsored by the Agency for Healthcare Research and Quality.

The guideline recommends that internists, family physicians, and other clinicians focus assessment of OSA on their adult patients who have unexplained daytime sleepiness. To do so, they must rule out other potential causes such as thyroid disease or gastroesophageal reflux disease.

Then, clinicians should evaluate patients for risk factors and common presenting symptoms of the disorder. Chief among risk factors is obesity, and frequent symptoms include unintentionally falling asleep during waking hours, unrefreshing sleep, fatigue, insomnia, and snoring (Ann. Intern. Med. 2014;161:210-20).

Once OSA is suspected, the guideline recommends full-night, in-laboratory polysomnography to establish the diagnosis. This requires specialized facilities, is expensive, and demands that patients "spend the night under observation in a foreign environment," but yields the most accurate diagnostic information.

Portable sleep monitors for home use are an alternative if a sleep laboratory is not available, but these can yield substantially different scores on the apnea-hypopnea index, usually because of data loss that limits interpretation of the results.

In addition, the ability of portable sleep monitors to diagnose OSA is questionable in the subset of patients who have comorbid conditions such as chronic lung disease, heart failure, or neurologic disorders.

Development of this clinical practice guideline was supported solely by the American College of Physicians. Dr. Qaseem and his associates reported no relevant financial conflicts of interest.

Clinicians should recommend a sleep study using polysomnography for adults who have unexplained daytime sleepiness, according to a clinical practice guideline on diagnosing obstructive sleep apnea.

The guideline was published online Aug. 4 in Annals of Internal Medicine.

There is still "considerable" controversy concerning the type and level of respiratory abnormality that defines obstructive sleep apnea (OSA), as well as the presence and type of signs or symptoms that are diagnostic of the disorder, said Dr. Amir Qaseem, director of clinical policy at the American College of Physicians, Philadelphia.

To formulate a clinical practice guideline, Dr. Qaseem and his associates performed a comprehensive review of the literature through May 2013, which included a comparative effectiveness technology review of portable sleep monitors sponsored by the Agency for Healthcare Research and Quality.

The guideline recommends that internists, family physicians, and other clinicians focus assessment of OSA on their adult patients who have unexplained daytime sleepiness. To do so, they must rule out other potential causes such as thyroid disease or gastroesophageal reflux disease.

Then, clinicians should evaluate patients for risk factors and common presenting symptoms of the disorder. Chief among risk factors is obesity, and frequent symptoms include unintentionally falling asleep during waking hours, unrefreshing sleep, fatigue, insomnia, and snoring (Ann. Intern. Med. 2014;161:210-20).

Once OSA is suspected, the guideline recommends full-night, in-laboratory polysomnography to establish the diagnosis. This requires specialized facilities, is expensive, and demands that patients "spend the night under observation in a foreign environment," but yields the most accurate diagnostic information.

Portable sleep monitors for home use are an alternative if a sleep laboratory is not available, but these can yield substantially different scores on the apnea-hypopnea index, usually because of data loss that limits interpretation of the results.

In addition, the ability of portable sleep monitors to diagnose OSA is questionable in the subset of patients who have comorbid conditions such as chronic lung disease, heart failure, or neurologic disorders.

Development of this clinical practice guideline was supported solely by the American College of Physicians. Dr. Qaseem and his associates reported no relevant financial conflicts of interest.

Clinicians should recommend a sleep study using polysomnography for adults who have unexplained daytime sleepiness, according to a clinical practice guideline on diagnosing obstructive sleep apnea.

The guideline was published online Aug. 4 in Annals of Internal Medicine.

There is still "considerable" controversy concerning the type and level of respiratory abnormality that defines obstructive sleep apnea (OSA), as well as the presence and type of signs or symptoms that are diagnostic of the disorder, said Dr. Amir Qaseem, director of clinical policy at the American College of Physicians, Philadelphia.

To formulate a clinical practice guideline, Dr. Qaseem and his associates performed a comprehensive review of the literature through May 2013, which included a comparative effectiveness technology review of portable sleep monitors sponsored by the Agency for Healthcare Research and Quality.

The guideline recommends that internists, family physicians, and other clinicians focus assessment of OSA on their adult patients who have unexplained daytime sleepiness. To do so, they must rule out other potential causes such as thyroid disease or gastroesophageal reflux disease.

Then, clinicians should evaluate patients for risk factors and common presenting symptoms of the disorder. Chief among risk factors is obesity, and frequent symptoms include unintentionally falling asleep during waking hours, unrefreshing sleep, fatigue, insomnia, and snoring (Ann. Intern. Med. 2014;161:210-20).

Once OSA is suspected, the guideline recommends full-night, in-laboratory polysomnography to establish the diagnosis. This requires specialized facilities, is expensive, and demands that patients "spend the night under observation in a foreign environment," but yields the most accurate diagnostic information.

Portable sleep monitors for home use are an alternative if a sleep laboratory is not available, but these can yield substantially different scores on the apnea-hypopnea index, usually because of data loss that limits interpretation of the results.

In addition, the ability of portable sleep monitors to diagnose OSA is questionable in the subset of patients who have comorbid conditions such as chronic lung disease, heart failure, or neurologic disorders.

Development of this clinical practice guideline was supported solely by the American College of Physicians. Dr. Qaseem and his associates reported no relevant financial conflicts of interest.

Two interferon-free combination therapies yielded sustained virologic responses of 96%-100% in an international, open-label, phase III, randomized trial involving 186 patients with refractory hepatitis C virus type 1b infection, Dr. Pietro Andreone and his colleagues reported in the August 2014 issue of Gastroenterology (doi:org/10.1053/j.gastro.2014.04.037).

Twelve weeks of treatment using the combination regimen plus ribavirin (91 patients) or the same regimen without ribavirin (95 patients) produced sustained virologic responses (SVRs) that were noninferior to historic SVRs reported in the literature for comparable patients treated with telaprevir plus pegylated-interferon plus ribavirin.

Source: American Gastroenterological Institute

None of the patients taking the new combination regimen experienced virologic failure while taking the drugs or relapse during the year after completing treatment. And adverse effects were characterized as "generally mild and manageable," said Dr. Andreone of the department of medical science and surgery, University of Bologna (Italy), and his associates.

HCV type 1b is the most prevalent genotype worldwide. Patients with this genotype who have failed on standard treatments "have not been extensively studied with currently approved or investigational interferon-free regimens, hence this large patient population represents a group with unmet need," the investigators noted.

They assessed such patients at 43 medical centers in Austria, Belgium, Italy, the Netherlands, Portugal, Puerto Rico, Sweden, Switzerland, Turkey, and the United States. All were aged between 18 and 70 years, and all were free of cirrhosis and coinfections.

The daily oral combination regimen consisted of ABT-450, a protease inhibitor that has shown in-vitro antiviral activity; ritonavir, a CYP3A4 inhibitor that enables once-daily rather than more frequent dosing of the ABT-450; ombitasvir, an HCV NS5A inhibitor; and dasabuvir, an HCV NS5B RNA nonnucleoside polymerase inhibitor.

The primary efficacy endpoint was an SVR rate noninferior to the historical rate for interferon-containing regimens in comparable patients. In the intention-to-treat analysis, the SVRs met and surpassed that standard, at 96.6% for ABT-450/ritonavir/ombitasvir/dasabuvir plus ribavirin and 100% for ABT-450/ritonavir/ombitasvir/dasabuvir without ribavirin.

Moreover, of the three patients who did not achieve a sustained virologic response, two had discontinued the study drug because of adverse events and one was lost to follow-up after only 4 weeks of treatment.

The most common adverse events were fatigue, headache, and nausea, all of which were significantly more frequent among patients taking ribavirin. Insomnia, anemia, rash, and elevated bilirubin also were related to ribavirin and were easily managed.

Only two patients discontinued treatment due to adverse events, neither of which were considered to be related to a study drug. One patient developed pancreatitis and another developed anxiety, tachycardia, and dyspnea.

Three other serious adverse events – cellulitis, nephrolithiasis, and osteoarthritis – also were judged to be unrelated to the study treatments.

Declines in hemoglobin levels occurred in 42% of the patients who received ribavirin but only 5.5% of those who did not. However, clinically significant declines occurred in only two patients, and neither of them required transfusions or erythropoietin.

Their findings show that 12 weeks of combined oral ABT-450/ritonavir/ombitasvir/dasabuvir therapy without ribavirin is at least as effective as interferon-containing regimens, and it produces significantly fewer and less severe adverse effects, the investigators said.

This study was somewhat limited in that it used an open-label design and did not include patients with concomitant cirrhosis, hepatitis B viral infection, or HIV infection, they added.

This study was sponsored by AbbVie, which also participated in the study design, data collection and analysis, and manuscript preparation. Dr. Andreone reported receiving research support from, being a consultant for, or serving on advisory committees for Roche, Merck, Gilead Sciences, Janssen Cilag, AbbVie, Boehringer Ingelheim, and BMS; his associates reported ties to numerous industry sources.

Two interferon-free combination therapies yielded sustained virologic responses of 96%-100% in an international, open-label, phase III, randomized trial involving 186 patients with refractory hepatitis C virus type 1b infection, Dr. Pietro Andreone and his colleagues reported in the August 2014 issue of Gastroenterology (doi:org/10.1053/j.gastro.2014.04.037).

Twelve weeks of treatment using the combination regimen plus ribavirin (91 patients) or the same regimen without ribavirin (95 patients) produced sustained virologic responses (SVRs) that were noninferior to historic SVRs reported in the literature for comparable patients treated with telaprevir plus pegylated-interferon plus ribavirin.

Source: American Gastroenterological Institute

None of the patients taking the new combination regimen experienced virologic failure while taking the drugs or relapse during the year after completing treatment. And adverse effects were characterized as "generally mild and manageable," said Dr. Andreone of the department of medical science and surgery, University of Bologna (Italy), and his associates.

HCV type 1b is the most prevalent genotype worldwide. Patients with this genotype who have failed on standard treatments "have not been extensively studied with currently approved or investigational interferon-free regimens, hence this large patient population represents a group with unmet need," the investigators noted.

They assessed such patients at 43 medical centers in Austria, Belgium, Italy, the Netherlands, Portugal, Puerto Rico, Sweden, Switzerland, Turkey, and the United States. All were aged between 18 and 70 years, and all were free of cirrhosis and coinfections.

The daily oral combination regimen consisted of ABT-450, a protease inhibitor that has shown in-vitro antiviral activity; ritonavir, a CYP3A4 inhibitor that enables once-daily rather than more frequent dosing of the ABT-450; ombitasvir, an HCV NS5A inhibitor; and dasabuvir, an HCV NS5B RNA nonnucleoside polymerase inhibitor.

The primary efficacy endpoint was an SVR rate noninferior to the historical rate for interferon-containing regimens in comparable patients. In the intention-to-treat analysis, the SVRs met and surpassed that standard, at 96.6% for ABT-450/ritonavir/ombitasvir/dasabuvir plus ribavirin and 100% for ABT-450/ritonavir/ombitasvir/dasabuvir without ribavirin.

Moreover, of the three patients who did not achieve a sustained virologic response, two had discontinued the study drug because of adverse events and one was lost to follow-up after only 4 weeks of treatment.

The most common adverse events were fatigue, headache, and nausea, all of which were significantly more frequent among patients taking ribavirin. Insomnia, anemia, rash, and elevated bilirubin also were related to ribavirin and were easily managed.

Only two patients discontinued treatment due to adverse events, neither of which were considered to be related to a study drug. One patient developed pancreatitis and another developed anxiety, tachycardia, and dyspnea.

Three other serious adverse events – cellulitis, nephrolithiasis, and osteoarthritis – also were judged to be unrelated to the study treatments.

Declines in hemoglobin levels occurred in 42% of the patients who received ribavirin but only 5.5% of those who did not. However, clinically significant declines occurred in only two patients, and neither of them required transfusions or erythropoietin.

Their findings show that 12 weeks of combined oral ABT-450/ritonavir/ombitasvir/dasabuvir therapy without ribavirin is at least as effective as interferon-containing regimens, and it produces significantly fewer and less severe adverse effects, the investigators said.

This study was somewhat limited in that it used an open-label design and did not include patients with concomitant cirrhosis, hepatitis B viral infection, or HIV infection, they added.

This study was sponsored by AbbVie, which also participated in the study design, data collection and analysis, and manuscript preparation. Dr. Andreone reported receiving research support from, being a consultant for, or serving on advisory committees for Roche, Merck, Gilead Sciences, Janssen Cilag, AbbVie, Boehringer Ingelheim, and BMS; his associates reported ties to numerous industry sources.

Two interferon-free combination therapies yielded sustained virologic responses of 96%-100% in an international, open-label, phase III, randomized trial involving 186 patients with refractory hepatitis C virus type 1b infection, Dr. Pietro Andreone and his colleagues reported in the August 2014 issue of Gastroenterology (doi:org/10.1053/j.gastro.2014.04.037).

Twelve weeks of treatment using the combination regimen plus ribavirin (91 patients) or the same regimen without ribavirin (95 patients) produced sustained virologic responses (SVRs) that were noninferior to historic SVRs reported in the literature for comparable patients treated with telaprevir plus pegylated-interferon plus ribavirin.

Source: American Gastroenterological Institute

None of the patients taking the new combination regimen experienced virologic failure while taking the drugs or relapse during the year after completing treatment. And adverse effects were characterized as "generally mild and manageable," said Dr. Andreone of the department of medical science and surgery, University of Bologna (Italy), and his associates.

HCV type 1b is the most prevalent genotype worldwide. Patients with this genotype who have failed on standard treatments "have not been extensively studied with currently approved or investigational interferon-free regimens, hence this large patient population represents a group with unmet need," the investigators noted.

They assessed such patients at 43 medical centers in Austria, Belgium, Italy, the Netherlands, Portugal, Puerto Rico, Sweden, Switzerland, Turkey, and the United States. All were aged between 18 and 70 years, and all were free of cirrhosis and coinfections.

The daily oral combination regimen consisted of ABT-450, a protease inhibitor that has shown in-vitro antiviral activity; ritonavir, a CYP3A4 inhibitor that enables once-daily rather than more frequent dosing of the ABT-450; ombitasvir, an HCV NS5A inhibitor; and dasabuvir, an HCV NS5B RNA nonnucleoside polymerase inhibitor.

The primary efficacy endpoint was an SVR rate noninferior to the historical rate for interferon-containing regimens in comparable patients. In the intention-to-treat analysis, the SVRs met and surpassed that standard, at 96.6% for ABT-450/ritonavir/ombitasvir/dasabuvir plus ribavirin and 100% for ABT-450/ritonavir/ombitasvir/dasabuvir without ribavirin.

Moreover, of the three patients who did not achieve a sustained virologic response, two had discontinued the study drug because of adverse events and one was lost to follow-up after only 4 weeks of treatment.

The most common adverse events were fatigue, headache, and nausea, all of which were significantly more frequent among patients taking ribavirin. Insomnia, anemia, rash, and elevated bilirubin also were related to ribavirin and were easily managed.

Only two patients discontinued treatment due to adverse events, neither of which were considered to be related to a study drug. One patient developed pancreatitis and another developed anxiety, tachycardia, and dyspnea.

Three other serious adverse events – cellulitis, nephrolithiasis, and osteoarthritis – also were judged to be unrelated to the study treatments.

Declines in hemoglobin levels occurred in 42% of the patients who received ribavirin but only 5.5% of those who did not. However, clinically significant declines occurred in only two patients, and neither of them required transfusions or erythropoietin.

Their findings show that 12 weeks of combined oral ABT-450/ritonavir/ombitasvir/dasabuvir therapy without ribavirin is at least as effective as interferon-containing regimens, and it produces significantly fewer and less severe adverse effects, the investigators said.

This study was somewhat limited in that it used an open-label design and did not include patients with concomitant cirrhosis, hepatitis B viral infection, or HIV infection, they added.

This study was sponsored by AbbVie, which also participated in the study design, data collection and analysis, and manuscript preparation. Dr. Andreone reported receiving research support from, being a consultant for, or serving on advisory committees for Roche, Merck, Gilead Sciences, Janssen Cilag, AbbVie, Boehringer Ingelheim, and BMS; his associates reported ties to numerous industry sources.

Among adults at average risk for colorectal cancer who undergo screening colonoscopy, the yield of large polyps and tumors varies widely by patient age, sex, race, and ethnicity. This means that an across-the-board recommendation to initiate screening for all patients at a particular age "may not appear rational and could negatively impact adherence," Dr. David A. Lieberman and his colleagues said in the August issue of Gastroenterology (doi:org/10.1053/j.gastro.2014.04.037).

In what they described as "the largest and most comprehensive analysis of average-risk screening with colonoscopy in the United States," the investigators found that the rate of detecting large (and therefore likely advanced) neoplastic lesions was much higher or lower at any given age, depending on the patient’s sex, race, and ethnicity. So the fact that most practice guidelines uniformly recommend initiating colonoscopy screens at age 50 years doesn’t make sense.

"We believe these data, combined with [those of] prior studies, are compelling enough to consider customization of the initiation age of screening based on the risk of large polyps," said Dr. Lieberman and his associates at Oregon Health & Science University, Portland.

They analyzed information from the Clinical Outcomes Research Initiative database, which includes endoscopy findings from 84 diverse practice settings across the country that are representative of all U.S. community, academic, and Veterans Administration endoscopy centers. They included 327,785 exams of patients aged 40 years and older who were at average risk for colorectal cancer and were screened in 2000 through 2011.

Women accounted for half of the study subjects, except for those examined at VA centers, who were predominately male. The study population was 83.6% white, 5.7% black, and 7.7% Hispanic. More than 95% of the participants were aged 50-79 years.

The outcome of interest was the detection of a polyp or tumor larger than 9 mm. "These large lesions are a surrogate for advanced neoplasia," the investigators said.

The prevalence of large neoplasias rose steadily with increasing age across all races and ethnicities and in both sexes.

Across all age groups, women had a lower prevalence of large polyps than men did, suggesting that the initiation of screening colonoscopy can be safely delayed until age 60 years, at least in white and Hispanic women.

Among men younger than 50 years, the prevalence of large polyps was similar between whites (5.3%) and blacks (5.0%). However, the sample of black men in this age group was small (380 patients), so it is possible that this study was simply underpowered to detect the well-known excess of colorectal neoplasias in younger black men.

The prevalence of large polyps was higher in black men than did white men at all other ages until the age of 70 years, at which point the rates even out. Prevalences were 7.1% vs. 6.2% at 50-54 years, 8.5% vs. 7.4% at 55-59 years, 11.5% vs. 8.6% at 60-64 years, and 12.0% vs. 9.7% at 65-69 years.

Black women had a higher prevalence of large polyps than did white women until age 65 years, when the rates evened out. Prevalences were 5.2% vs. 4.2% at 50-54 years, 6.6% vs. 4.5% at 55-59 years, and 6.9% vs. 5.2% at 60-64 years.

These findings "support intensification of screening in black men and women at age 50 years," Dr. Lieberman and his associates said.

Hispanic men and women had a 25% lower rate of polyps than did whites from age 50 through age 79. This finding suggests that initiation of screening colonoscopy can be delayed in Hispanic men and especially in Hispanic women.

The researchers used white men aged 50-54 years as a reference group to compare rates of detection across the study groups. Screening colonoscopy detected large polyps in 6.2% of white men aged 50-54 years. To achieve a similar yield in Hispanic men or black women, they wouldn’t need to be screened until age 55-59 years. To achieve it in Hispanic women, they wouldn’t need to be screened until age 70-74 years.

This study was supported by the National Institute of Digestive and Kidney Diseases. Dr. Lieberman and his associates reported no relevant financial conflicts of interest.

Among adults at average risk for colorectal cancer who undergo screening colonoscopy, the yield of large polyps and tumors varies widely by patient age, sex, race, and ethnicity. This means that an across-the-board recommendation to initiate screening for all patients at a particular age "may not appear rational and could negatively impact adherence," Dr. David A. Lieberman and his colleagues said in the August issue of Gastroenterology (doi:org/10.1053/j.gastro.2014.04.037).

In what they described as "the largest and most comprehensive analysis of average-risk screening with colonoscopy in the United States," the investigators found that the rate of detecting large (and therefore likely advanced) neoplastic lesions was much higher or lower at any given age, depending on the patient’s sex, race, and ethnicity. So the fact that most practice guidelines uniformly recommend initiating colonoscopy screens at age 50 years doesn’t make sense.

"We believe these data, combined with [those of] prior studies, are compelling enough to consider customization of the initiation age of screening based on the risk of large polyps," said Dr. Lieberman and his associates at Oregon Health & Science University, Portland.

They analyzed information from the Clinical Outcomes Research Initiative database, which includes endoscopy findings from 84 diverse practice settings across the country that are representative of all U.S. community, academic, and Veterans Administration endoscopy centers. They included 327,785 exams of patients aged 40 years and older who were at average risk for colorectal cancer and were screened in 2000 through 2011.

Women accounted for half of the study subjects, except for those examined at VA centers, who were predominately male. The study population was 83.6% white, 5.7% black, and 7.7% Hispanic. More than 95% of the participants were aged 50-79 years.

The outcome of interest was the detection of a polyp or tumor larger than 9 mm. "These large lesions are a surrogate for advanced neoplasia," the investigators said.

The prevalence of large neoplasias rose steadily with increasing age across all races and ethnicities and in both sexes.

Across all age groups, women had a lower prevalence of large polyps than men did, suggesting that the initiation of screening colonoscopy can be safely delayed until age 60 years, at least in white and Hispanic women.

Among men younger than 50 years, the prevalence of large polyps was similar between whites (5.3%) and blacks (5.0%). However, the sample of black men in this age group was small (380 patients), so it is possible that this study was simply underpowered to detect the well-known excess of colorectal neoplasias in younger black men.

The prevalence of large polyps was higher in black men than did white men at all other ages until the age of 70 years, at which point the rates even out. Prevalences were 7.1% vs. 6.2% at 50-54 years, 8.5% vs. 7.4% at 55-59 years, 11.5% vs. 8.6% at 60-64 years, and 12.0% vs. 9.7% at 65-69 years.

Black women had a higher prevalence of large polyps than did white women until age 65 years, when the rates evened out. Prevalences were 5.2% vs. 4.2% at 50-54 years, 6.6% vs. 4.5% at 55-59 years, and 6.9% vs. 5.2% at 60-64 years.

These findings "support intensification of screening in black men and women at age 50 years," Dr. Lieberman and his associates said.

Hispanic men and women had a 25% lower rate of polyps than did whites from age 50 through age 79. This finding suggests that initiation of screening colonoscopy can be delayed in Hispanic men and especially in Hispanic women.

The researchers used white men aged 50-54 years as a reference group to compare rates of detection across the study groups. Screening colonoscopy detected large polyps in 6.2% of white men aged 50-54 years. To achieve a similar yield in Hispanic men or black women, they wouldn’t need to be screened until age 55-59 years. To achieve it in Hispanic women, they wouldn’t need to be screened until age 70-74 years.

This study was supported by the National Institute of Digestive and Kidney Diseases. Dr. Lieberman and his associates reported no relevant financial conflicts of interest.

Among adults at average risk for colorectal cancer who undergo screening colonoscopy, the yield of large polyps and tumors varies widely by patient age, sex, race, and ethnicity. This means that an across-the-board recommendation to initiate screening for all patients at a particular age "may not appear rational and could negatively impact adherence," Dr. David A. Lieberman and his colleagues said in the August issue of Gastroenterology (doi:org/10.1053/j.gastro.2014.04.037).

In what they described as "the largest and most comprehensive analysis of average-risk screening with colonoscopy in the United States," the investigators found that the rate of detecting large (and therefore likely advanced) neoplastic lesions was much higher or lower at any given age, depending on the patient’s sex, race, and ethnicity. So the fact that most practice guidelines uniformly recommend initiating colonoscopy screens at age 50 years doesn’t make sense.

"We believe these data, combined with [those of] prior studies, are compelling enough to consider customization of the initiation age of screening based on the risk of large polyps," said Dr. Lieberman and his associates at Oregon Health & Science University, Portland.

They analyzed information from the Clinical Outcomes Research Initiative database, which includes endoscopy findings from 84 diverse practice settings across the country that are representative of all U.S. community, academic, and Veterans Administration endoscopy centers. They included 327,785 exams of patients aged 40 years and older who were at average risk for colorectal cancer and were screened in 2000 through 2011.

Women accounted for half of the study subjects, except for those examined at VA centers, who were predominately male. The study population was 83.6% white, 5.7% black, and 7.7% Hispanic. More than 95% of the participants were aged 50-79 years.

The outcome of interest was the detection of a polyp or tumor larger than 9 mm. "These large lesions are a surrogate for advanced neoplasia," the investigators said.

The prevalence of large neoplasias rose steadily with increasing age across all races and ethnicities and in both sexes.

Across all age groups, women had a lower prevalence of large polyps than men did, suggesting that the initiation of screening colonoscopy can be safely delayed until age 60 years, at least in white and Hispanic women.

Among men younger than 50 years, the prevalence of large polyps was similar between whites (5.3%) and blacks (5.0%). However, the sample of black men in this age group was small (380 patients), so it is possible that this study was simply underpowered to detect the well-known excess of colorectal neoplasias in younger black men.

The prevalence of large polyps was higher in black men than did white men at all other ages until the age of 70 years, at which point the rates even out. Prevalences were 7.1% vs. 6.2% at 50-54 years, 8.5% vs. 7.4% at 55-59 years, 11.5% vs. 8.6% at 60-64 years, and 12.0% vs. 9.7% at 65-69 years.

Black women had a higher prevalence of large polyps than did white women until age 65 years, when the rates evened out. Prevalences were 5.2% vs. 4.2% at 50-54 years, 6.6% vs. 4.5% at 55-59 years, and 6.9% vs. 5.2% at 60-64 years.

These findings "support intensification of screening in black men and women at age 50 years," Dr. Lieberman and his associates said.

Hispanic men and women had a 25% lower rate of polyps than did whites from age 50 through age 79. This finding suggests that initiation of screening colonoscopy can be delayed in Hispanic men and especially in Hispanic women.

The researchers used white men aged 50-54 years as a reference group to compare rates of detection across the study groups. Screening colonoscopy detected large polyps in 6.2% of white men aged 50-54 years. To achieve a similar yield in Hispanic men or black women, they wouldn’t need to be screened until age 55-59 years. To achieve it in Hispanic women, they wouldn’t need to be screened until age 70-74 years.

This study was supported by the National Institute of Digestive and Kidney Diseases. Dr. Lieberman and his associates reported no relevant financial conflicts of interest.

Only a minority of patients with longstanding inflammatory bowel disease – 19% of those with Crohn’s disease and 11% of those with ulcerative colitis – report having moderate to severe disability, Dr. Eran Israeli and his colleagues reported in the August issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2013.12.009).

These rates compare favorably with those for patients with other chronic inflammatory diseases of long duration such as multiple sclerosis and ankylosing spondylitis, they noted.

Until now, most studies of IBD-related disability "have focused narrowly on work and employment," while data have been limited regarding home, social, and psychological domains. Dr. Israeli and his associates assessed IBD-related disability across all of these domains by analyzing information from the ongoing Manitoba IBD Cohort Study. This longitudinal cohort included patients aged 16 years and older who had had their disease for at least a decade when they enrolled in 2002.The MICS-enrolled patients from a population-based research registry who were representative of the general population of IBD patients in Canada, and tracked disease-related factors through semiannual questionnaires and annual in-person interviews.

For their study, Dr. Israeli and his colleagues assessed disability in 125 of these study patients with Crohn’s disease and 119 with ulcerative colitis 8 years after they had enrolled in the MCIS. Approximately 60% were women, and most of the participants were younger than 50 years, married, and working full- or part-time jobs. The median duration of IBD at the time of the disability assessment was 13 years, said Dr. Israeli of Hadassah-Hebrew University Medical Center, Jerusalem, and his associates.

Overall, 19% of the patients with Crohn’s disease and 11% of those with ulcerative colitis reported having significant disability across all spheres of life, as measured using the World Health Organization Disability Schedule and the Work and Social Adjustment Scale.

These rates were remarkably consistent across all domains studied, including patients’ perception of their stress level, as measured by the Cohen Perceived Stress Scale; current emotional distress, as measured by the Brief Symptom Inventory; and quality of life, as measured by the Inflammatory Bowel Disease Questionnaire.

Not only was the prevalence of disability higher in Crohn’s disease than in ulcerative colitis, but the severity of disability also was significantly greater in the realms of home management and social relationships. Patients with Crohn’s disease also reported greater emotional distress (depression and anxiety), higher stress levels, and poorer quality of life than those with ulcerative colitis.

Overall, 27% of the participants had a history of major depression, which often predated the development of IBD. This rate was much higher than that in the general population, and it was higher still in the subgroup of patients with the most significant disability: Depression was reported in 57% of the significantly disabled patients with Crohn’s disease and 37% among the significantly disabled patients with ulcerative colitis.

Both a history of depression and a higher degree of disease activity over time were significant predictors of disability. "The strong predictive effect of lifetime history of depression on disability in IBD suggests that when depression is identified, clinicians should be as aggressive in its treatment as they are in treating the luminal manifestations of the disease," the investigators said.

Somewhat surprisingly, a history of multiple IBD-related surgeries did not predict disability. This may be because surgical resection leads to long-term remission of symptoms, at least among patients with ulcerative colitis, they added.

ginews@gastro.org

Only a minority of patients with longstanding inflammatory bowel disease – 19% of those with Crohn’s disease and 11% of those with ulcerative colitis – report having moderate to severe disability, Dr. Eran Israeli and his colleagues reported in the August issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2013.12.009).

These rates compare favorably with those for patients with other chronic inflammatory diseases of long duration such as multiple sclerosis and ankylosing spondylitis, they noted.

Until now, most studies of IBD-related disability "have focused narrowly on work and employment," while data have been limited regarding home, social, and psychological domains. Dr. Israeli and his associates assessed IBD-related disability across all of these domains by analyzing information from the ongoing Manitoba IBD Cohort Study. This longitudinal cohort included patients aged 16 years and older who had had their disease for at least a decade when they enrolled in 2002.The MICS-enrolled patients from a population-based research registry who were representative of the general population of IBD patients in Canada, and tracked disease-related factors through semiannual questionnaires and annual in-person interviews.

For their study, Dr. Israeli and his colleagues assessed disability in 125 of these study patients with Crohn’s disease and 119 with ulcerative colitis 8 years after they had enrolled in the MCIS. Approximately 60% were women, and most of the participants were younger than 50 years, married, and working full- or part-time jobs. The median duration of IBD at the time of the disability assessment was 13 years, said Dr. Israeli of Hadassah-Hebrew University Medical Center, Jerusalem, and his associates.

Overall, 19% of the patients with Crohn’s disease and 11% of those with ulcerative colitis reported having significant disability across all spheres of life, as measured using the World Health Organization Disability Schedule and the Work and Social Adjustment Scale.

These rates were remarkably consistent across all domains studied, including patients’ perception of their stress level, as measured by the Cohen Perceived Stress Scale; current emotional distress, as measured by the Brief Symptom Inventory; and quality of life, as measured by the Inflammatory Bowel Disease Questionnaire.

Not only was the prevalence of disability higher in Crohn’s disease than in ulcerative colitis, but the severity of disability also was significantly greater in the realms of home management and social relationships. Patients with Crohn’s disease also reported greater emotional distress (depression and anxiety), higher stress levels, and poorer quality of life than those with ulcerative colitis.

Overall, 27% of the participants had a history of major depression, which often predated the development of IBD. This rate was much higher than that in the general population, and it was higher still in the subgroup of patients with the most significant disability: Depression was reported in 57% of the significantly disabled patients with Crohn’s disease and 37% among the significantly disabled patients with ulcerative colitis.

Both a history of depression and a higher degree of disease activity over time were significant predictors of disability. "The strong predictive effect of lifetime history of depression on disability in IBD suggests that when depression is identified, clinicians should be as aggressive in its treatment as they are in treating the luminal manifestations of the disease," the investigators said.

Somewhat surprisingly, a history of multiple IBD-related surgeries did not predict disability. This may be because surgical resection leads to long-term remission of symptoms, at least among patients with ulcerative colitis, they added.

ginews@gastro.org

Only a minority of patients with longstanding inflammatory bowel disease – 19% of those with Crohn’s disease and 11% of those with ulcerative colitis – report having moderate to severe disability, Dr. Eran Israeli and his colleagues reported in the August issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2013.12.009).

These rates compare favorably with those for patients with other chronic inflammatory diseases of long duration such as multiple sclerosis and ankylosing spondylitis, they noted.

Until now, most studies of IBD-related disability "have focused narrowly on work and employment," while data have been limited regarding home, social, and psychological domains. Dr. Israeli and his associates assessed IBD-related disability across all of these domains by analyzing information from the ongoing Manitoba IBD Cohort Study. This longitudinal cohort included patients aged 16 years and older who had had their disease for at least a decade when they enrolled in 2002.The MICS-enrolled patients from a population-based research registry who were representative of the general population of IBD patients in Canada, and tracked disease-related factors through semiannual questionnaires and annual in-person interviews.

For their study, Dr. Israeli and his colleagues assessed disability in 125 of these study patients with Crohn’s disease and 119 with ulcerative colitis 8 years after they had enrolled in the MCIS. Approximately 60% were women, and most of the participants were younger than 50 years, married, and working full- or part-time jobs. The median duration of IBD at the time of the disability assessment was 13 years, said Dr. Israeli of Hadassah-Hebrew University Medical Center, Jerusalem, and his associates.

Overall, 19% of the patients with Crohn’s disease and 11% of those with ulcerative colitis reported having significant disability across all spheres of life, as measured using the World Health Organization Disability Schedule and the Work and Social Adjustment Scale.

These rates were remarkably consistent across all domains studied, including patients’ perception of their stress level, as measured by the Cohen Perceived Stress Scale; current emotional distress, as measured by the Brief Symptom Inventory; and quality of life, as measured by the Inflammatory Bowel Disease Questionnaire.

Not only was the prevalence of disability higher in Crohn’s disease than in ulcerative colitis, but the severity of disability also was significantly greater in the realms of home management and social relationships. Patients with Crohn’s disease also reported greater emotional distress (depression and anxiety), higher stress levels, and poorer quality of life than those with ulcerative colitis.

Overall, 27% of the participants had a history of major depression, which often predated the development of IBD. This rate was much higher than that in the general population, and it was higher still in the subgroup of patients with the most significant disability: Depression was reported in 57% of the significantly disabled patients with Crohn’s disease and 37% among the significantly disabled patients with ulcerative colitis.

Both a history of depression and a higher degree of disease activity over time were significant predictors of disability. "The strong predictive effect of lifetime history of depression on disability in IBD suggests that when depression is identified, clinicians should be as aggressive in its treatment as they are in treating the luminal manifestations of the disease," the investigators said.

Somewhat surprisingly, a history of multiple IBD-related surgeries did not predict disability. This may be because surgical resection leads to long-term remission of symptoms, at least among patients with ulcerative colitis, they added.

ginews@gastro.org

Conventional MRI brain images of patients with multiple sclerosis are "indistinguishable to the expert eye" from those of patients who have an MS-like disease associated with Leber’s hereditary optic neuropathy, according to a retrospective, case-control study.

Leber’s hereditary optic neuropathy (LHON), a mitochondrial abnormality inherited through the maternal line, is characterized by painless, subacute bilateral loss of vision that usually occurs in early adulthood. Very rarely, it is associated with a coexisting MS-like disease, which is often referred to as Harding’s disease. If the brain-imaging traits of these two disorders were found to be similar, it would suggest that they share a common pathophysiologic mechanism, said Dr. Lucy Matthews of the Nuffield Department of Clinical Neurosciences at Oxford (England) University, and her associates.

In what they described as "the first blinded observational study of the MRI features of LHON and LHON-associated MS," Dr. Matthews and her colleagues reviewed brain MRIs from patients treated at six clinical sites in Oxford; Milan and Siena, Italy; London; Bochum, Germany; and Copenhagen. A total of 31 patients had LHON, including 11 with LHON-associated MS. Their MRIs were compared with those from 30 age-matched control subjects who had MS alone (J. Neurol. Neurosurg. Psychiatry 2014 July 22 [doi:10.1136/jnnp-2014-308186]).

Three experts in the field of MRI and MS who were blinded to patients’ clinical and demographic data independently reviewed these MRIs. They found that the morphology and location of cerebral lesions were identical in LHON-associated MS and MS. Brain atrophy and hypointense T1 lesions were observed in both disorders.

In contrast, patients who had LHON alone showed T2 hyperintense white matter lesions, notably fewer oval lesions, and no Dawson’s fingers or diffuse-type lesions. Most of their lesions were 2-5 mm in size, while most of the lesions in the MS and LHON-associated MS patients were larger, some as big as 25 mm.

In addition, T2 lesions showed a similar distribution between patients with MS and patients with LHON-associated MS, while T2 lesions in the LHON-only group were uncommon in the corpus callosum and nonexistent in the cerebellum.

A total of 90% of the patients with MS and 73% of those with LHON-associated MS fulfilled McDonald’s criterion for the spatial dissemination of brain lesions, compared with only 6.7% of the patients who had LHON alone.

These findings support the idea that "MRI changes in LHON-associated MS are due to MS pathology and not a separate Leber’s mitochondrial-related process." They also suggest that mitochondrial pathways may be important in the development of MS, the investigators said.

The researchers also observed an "intriguing" influence of gender in these disorders. "The penetrance of LHON in women is much lower than in men. However, it appears that once a woman develops LHON clinically, she has a very high risk of developing either radiological or clinical MS. It is [neither] clear whether those with asymptomatic lesions at the time of MRI will develop clinical features in the future, nor what the risk is in asymptomatic female carriers of Leber’s mutation," they added.

This study was supported in part by the U.K. Medical Research Council. Dr. Matthews’s associates reported numerous ties to industry sources.

Conventional MRI brain images of patients with multiple sclerosis are "indistinguishable to the expert eye" from those of patients who have an MS-like disease associated with Leber’s hereditary optic neuropathy, according to a retrospective, case-control study.

Leber’s hereditary optic neuropathy (LHON), a mitochondrial abnormality inherited through the maternal line, is characterized by painless, subacute bilateral loss of vision that usually occurs in early adulthood. Very rarely, it is associated with a coexisting MS-like disease, which is often referred to as Harding’s disease. If the brain-imaging traits of these two disorders were found to be similar, it would suggest that they share a common pathophysiologic mechanism, said Dr. Lucy Matthews of the Nuffield Department of Clinical Neurosciences at Oxford (England) University, and her associates.

In what they described as "the first blinded observational study of the MRI features of LHON and LHON-associated MS," Dr. Matthews and her colleagues reviewed brain MRIs from patients treated at six clinical sites in Oxford; Milan and Siena, Italy; London; Bochum, Germany; and Copenhagen. A total of 31 patients had LHON, including 11 with LHON-associated MS. Their MRIs were compared with those from 30 age-matched control subjects who had MS alone (J. Neurol. Neurosurg. Psychiatry 2014 July 22 [doi:10.1136/jnnp-2014-308186]).

Three experts in the field of MRI and MS who were blinded to patients’ clinical and demographic data independently reviewed these MRIs. They found that the morphology and location of cerebral lesions were identical in LHON-associated MS and MS. Brain atrophy and hypointense T1 lesions were observed in both disorders.

In contrast, patients who had LHON alone showed T2 hyperintense white matter lesions, notably fewer oval lesions, and no Dawson’s fingers or diffuse-type lesions. Most of their lesions were 2-5 mm in size, while most of the lesions in the MS and LHON-associated MS patients were larger, some as big as 25 mm.

In addition, T2 lesions showed a similar distribution between patients with MS and patients with LHON-associated MS, while T2 lesions in the LHON-only group were uncommon in the corpus callosum and nonexistent in the cerebellum.

A total of 90% of the patients with MS and 73% of those with LHON-associated MS fulfilled McDonald’s criterion for the spatial dissemination of brain lesions, compared with only 6.7% of the patients who had LHON alone.

These findings support the idea that "MRI changes in LHON-associated MS are due to MS pathology and not a separate Leber’s mitochondrial-related process." They also suggest that mitochondrial pathways may be important in the development of MS, the investigators said.

The researchers also observed an "intriguing" influence of gender in these disorders. "The penetrance of LHON in women is much lower than in men. However, it appears that once a woman develops LHON clinically, she has a very high risk of developing either radiological or clinical MS. It is [neither] clear whether those with asymptomatic lesions at the time of MRI will develop clinical features in the future, nor what the risk is in asymptomatic female carriers of Leber’s mutation," they added.

This study was supported in part by the U.K. Medical Research Council. Dr. Matthews’s associates reported numerous ties to industry sources.

Conventional MRI brain images of patients with multiple sclerosis are "indistinguishable to the expert eye" from those of patients who have an MS-like disease associated with Leber’s hereditary optic neuropathy, according to a retrospective, case-control study.

Leber’s hereditary optic neuropathy (LHON), a mitochondrial abnormality inherited through the maternal line, is characterized by painless, subacute bilateral loss of vision that usually occurs in early adulthood. Very rarely, it is associated with a coexisting MS-like disease, which is often referred to as Harding’s disease. If the brain-imaging traits of these two disorders were found to be similar, it would suggest that they share a common pathophysiologic mechanism, said Dr. Lucy Matthews of the Nuffield Department of Clinical Neurosciences at Oxford (England) University, and her associates.

In what they described as "the first blinded observational study of the MRI features of LHON and LHON-associated MS," Dr. Matthews and her colleagues reviewed brain MRIs from patients treated at six clinical sites in Oxford; Milan and Siena, Italy; London; Bochum, Germany; and Copenhagen. A total of 31 patients had LHON, including 11 with LHON-associated MS. Their MRIs were compared with those from 30 age-matched control subjects who had MS alone (J. Neurol. Neurosurg. Psychiatry 2014 July 22 [doi:10.1136/jnnp-2014-308186]).

Three experts in the field of MRI and MS who were blinded to patients’ clinical and demographic data independently reviewed these MRIs. They found that the morphology and location of cerebral lesions were identical in LHON-associated MS and MS. Brain atrophy and hypointense T1 lesions were observed in both disorders.

In contrast, patients who had LHON alone showed T2 hyperintense white matter lesions, notably fewer oval lesions, and no Dawson’s fingers or diffuse-type lesions. Most of their lesions were 2-5 mm in size, while most of the lesions in the MS and LHON-associated MS patients were larger, some as big as 25 mm.

In addition, T2 lesions showed a similar distribution between patients with MS and patients with LHON-associated MS, while T2 lesions in the LHON-only group were uncommon in the corpus callosum and nonexistent in the cerebellum.

A total of 90% of the patients with MS and 73% of those with LHON-associated MS fulfilled McDonald’s criterion for the spatial dissemination of brain lesions, compared with only 6.7% of the patients who had LHON alone.

These findings support the idea that "MRI changes in LHON-associated MS are due to MS pathology and not a separate Leber’s mitochondrial-related process." They also suggest that mitochondrial pathways may be important in the development of MS, the investigators said.

The researchers also observed an "intriguing" influence of gender in these disorders. "The penetrance of LHON in women is much lower than in men. However, it appears that once a woman develops LHON clinically, she has a very high risk of developing either radiological or clinical MS. It is [neither] clear whether those with asymptomatic lesions at the time of MRI will develop clinical features in the future, nor what the risk is in asymptomatic female carriers of Leber’s mutation," they added.

This study was supported in part by the U.K. Medical Research Council. Dr. Matthews’s associates reported numerous ties to industry sources.

The new spiroindolone antimalarial agent, KAE609, rapidly cleared both Plasmodium falciparum and P. vivax from the blood in a small, industry-funded phase II trial reported online July 31 in the New England Journal of Medicine.

The rapidity of clearance is key because slower clearance is associated with drug resistance. "To date, the most rapidly acting antimalarial agents have been the artemisinins; however, these preliminary data suggest that KAE609 may effect an even faster parasitic clearance, including in patients with artemisinin-resistant" malaria, said Dr. Nicholas J. White of Mahidol University, Bangkok, Thailand, and the Centre for Tropical Medicine, University of Oxford (England) and his associates.

Courtesy Jim Gathany/CDC

This open-label exploratory trial involved 21 adults with uncomplicated P. falciparum (11 patients) or P. vivax (10 patients) malaria who were closely monitored at three inpatient facilities in Thailand during treatment. They received three oral 10-mg capsules of KAE609 per day for 3 days. Blood smears were analyzed every 4-6 hours.

The median time to parasite clearance was 12 hours in both groups of patients. The median parasite clearance half-life was 0.95 hours for P. vivax and 0.90 hours for P. falciparum. "By comparison, only 19 of 5,076 patients (less than 1%) with falciparum malaria in [a study in] Southeast Asia who had been treated with oral artesunate and evaluated similarly had a parasite clearance half-life of less than 1 hour," the investigators said (N. Engl. J. Med. 2014 July 31 [doi: 10.1056/NEJMoa1315860]).

Four of five patients who carried kelch protein mutations thought to be associated with resistance to artemisinins showed the same rapid parasite clearance as noncarriers, and the fifth dropped out of the study. Thus, KAE609 (formerly known as NITD6049, Novartis Institute for Tropical Diseases) appears to be effective even against artemisinin-resistant malaria. The drug also showed gametocytocidal activity in in vitro studies, so it may have transmission-blocking properties as well, Dr. White and his associates said.

Nausea, vomiting, and elevated liver enzymes were the most common adverse effects that occurred during treatment, but all of these are characteristic of the underlying infection and may not have been drug related. "Much larger studies will be necessary to assess fully the safety and adverse-event profile of this new antimalarial agent," they added.

This study was funded by Novartis; the Mahidol-Oxford Tropical Medicine Research Unit is supported by the Wellcome Trust of Great Britain. Dr. White and his associates reported no other ties to industry sources.

The new spiroindolone antimalarial agent, KAE609, rapidly cleared both Plasmodium falciparum and P. vivax from the blood in a small, industry-funded phase II trial reported online July 31 in the New England Journal of Medicine.

The rapidity of clearance is key because slower clearance is associated with drug resistance. "To date, the most rapidly acting antimalarial agents have been the artemisinins; however, these preliminary data suggest that KAE609 may effect an even faster parasitic clearance, including in patients with artemisinin-resistant" malaria, said Dr. Nicholas J. White of Mahidol University, Bangkok, Thailand, and the Centre for Tropical Medicine, University of Oxford (England) and his associates.

Courtesy Jim Gathany/CDC

This open-label exploratory trial involved 21 adults with uncomplicated P. falciparum (11 patients) or P. vivax (10 patients) malaria who were closely monitored at three inpatient facilities in Thailand during treatment. They received three oral 10-mg capsules of KAE609 per day for 3 days. Blood smears were analyzed every 4-6 hours.

The median time to parasite clearance was 12 hours in both groups of patients. The median parasite clearance half-life was 0.95 hours for P. vivax and 0.90 hours for P. falciparum. "By comparison, only 19 of 5,076 patients (less than 1%) with falciparum malaria in [a study in] Southeast Asia who had been treated with oral artesunate and evaluated similarly had a parasite clearance half-life of less than 1 hour," the investigators said (N. Engl. J. Med. 2014 July 31 [doi: 10.1056/NEJMoa1315860]).

Four of five patients who carried kelch protein mutations thought to be associated with resistance to artemisinins showed the same rapid parasite clearance as noncarriers, and the fifth dropped out of the study. Thus, KAE609 (formerly known as NITD6049, Novartis Institute for Tropical Diseases) appears to be effective even against artemisinin-resistant malaria. The drug also showed gametocytocidal activity in in vitro studies, so it may have transmission-blocking properties as well, Dr. White and his associates said.

Nausea, vomiting, and elevated liver enzymes were the most common adverse effects that occurred during treatment, but all of these are characteristic of the underlying infection and may not have been drug related. "Much larger studies will be necessary to assess fully the safety and adverse-event profile of this new antimalarial agent," they added.

This study was funded by Novartis; the Mahidol-Oxford Tropical Medicine Research Unit is supported by the Wellcome Trust of Great Britain. Dr. White and his associates reported no other ties to industry sources.

The new spiroindolone antimalarial agent, KAE609, rapidly cleared both Plasmodium falciparum and P. vivax from the blood in a small, industry-funded phase II trial reported online July 31 in the New England Journal of Medicine.

The rapidity of clearance is key because slower clearance is associated with drug resistance. "To date, the most rapidly acting antimalarial agents have been the artemisinins; however, these preliminary data suggest that KAE609 may effect an even faster parasitic clearance, including in patients with artemisinin-resistant" malaria, said Dr. Nicholas J. White of Mahidol University, Bangkok, Thailand, and the Centre for Tropical Medicine, University of Oxford (England) and his associates.

Courtesy Jim Gathany/CDC

This open-label exploratory trial involved 21 adults with uncomplicated P. falciparum (11 patients) or P. vivax (10 patients) malaria who were closely monitored at three inpatient facilities in Thailand during treatment. They received three oral 10-mg capsules of KAE609 per day for 3 days. Blood smears were analyzed every 4-6 hours.

The median time to parasite clearance was 12 hours in both groups of patients. The median parasite clearance half-life was 0.95 hours for P. vivax and 0.90 hours for P. falciparum. "By comparison, only 19 of 5,076 patients (less than 1%) with falciparum malaria in [a study in] Southeast Asia who had been treated with oral artesunate and evaluated similarly had a parasite clearance half-life of less than 1 hour," the investigators said (N. Engl. J. Med. 2014 July 31 [doi: 10.1056/NEJMoa1315860]).

Four of five patients who carried kelch protein mutations thought to be associated with resistance to artemisinins showed the same rapid parasite clearance as noncarriers, and the fifth dropped out of the study. Thus, KAE609 (formerly known as NITD6049, Novartis Institute for Tropical Diseases) appears to be effective even against artemisinin-resistant malaria. The drug also showed gametocytocidal activity in in vitro studies, so it may have transmission-blocking properties as well, Dr. White and his associates said.

Nausea, vomiting, and elevated liver enzymes were the most common adverse effects that occurred during treatment, but all of these are characteristic of the underlying infection and may not have been drug related. "Much larger studies will be necessary to assess fully the safety and adverse-event profile of this new antimalarial agent," they added.

This study was funded by Novartis; the Mahidol-Oxford Tropical Medicine Research Unit is supported by the Wellcome Trust of Great Britain. Dr. White and his associates reported no other ties to industry sources.

Artemisinin-resistant Plasmodium falciparum malaria remains uncontained. It is now "firmly established" in western Cambodia and Thailand, southern Vietnam, and eastern Myanmar and is emerging in southern Laos and northeastern Cambodia, according to a report published online July 31 in the New England Journal of Medicine.

"Radical measures will be necessary in Southeast Asia to prevent resistance to artemisinins and their partner drugs from spreading to the Indian subcontinent and then to Africa," said Dr. Elizabeth A. Ashley of the Mahidol-Oxford Tropical Medicine Research Unit, affiliated with both Mahidol University in Bangkok, Thailand, and the University of Oxford (England), and her associates.

CDC/Neva Gleason

Artemisinin resistance was first reported in western Cambodia in 2008, and that is where resistance to previous first-line antimalarials also first emerged. "Defining the extent and severity of artemisinin resistance is essential for planning containment and elimination strategies," the investigators noted.

To map the current extent of artemisinin resistance, they performed an open-label, randomized trial at 15 sites in Cambodia, Thailand, Laos, Vietnam, Myanmar, Bangladesh, India, Nigeria, Kenya, and the Congo. Over a 2-year period, 1,241 patients aged 6 months to 65 years with acute, uncomplicated falciparum malaria were randomly assigned to receive either 2 mg or 4 mg of oral artesunate for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite clearance half-life was then determined using serial blood smears. Longer parasite clearance half-life is associated with the organism’s increasing resistance to the drug.

Parasite clearance half-life varied widely across the sites in Southeast Asia, from a low of 2 hours in Laos to a high of 7 hours in Thailand. Slowly clearing infections, which were defined as a parasite clearance half-life of 5 hours or longer and indicated established resistance, were detected throughout mainland Southeast Asia, but they were not yet common in India or Africa. Another measure of artemisinin resistance – the proportion of patients with parasitemia detectable on day 3 – ranged from 0% in Kenya to 68% in eastern Thailand (N. Engl. J. Med. 2014 July 31 [doi: 10.1056/NEJMoa1314981]).

However, "despite the recent spread of resistance, we found that artemisinin-based combination therapies ... were still highly efficacious, presumably because of increased reliance on the efficacy of the partner drug as the potency of the artemisinin component waned," Dr. Ashley and her associates said.

Nevertheless, they cautioned that treatment failure rates for artesunate plus mefloquine (in Thailand) and for dihydroartemisinin plus piperaquine (in Cambodia) have risen by a factor of 5.

This study was supported by the U.K. Department for International Development, the Worldwide Antimalarial Resistance Network, the U.S. National Institute of Allergy and Infectious Diseases, and the Bill & Melinda Gates Foundation. Dr. Ashley and her associates reported no relevant conflicts of interest.

Artemisinin-resistant Plasmodium falciparum malaria remains uncontained. It is now "firmly established" in western Cambodia and Thailand, southern Vietnam, and eastern Myanmar and is emerging in southern Laos and northeastern Cambodia, according to a report published online July 31 in the New England Journal of Medicine.

"Radical measures will be necessary in Southeast Asia to prevent resistance to artemisinins and their partner drugs from spreading to the Indian subcontinent and then to Africa," said Dr. Elizabeth A. Ashley of the Mahidol-Oxford Tropical Medicine Research Unit, affiliated with both Mahidol University in Bangkok, Thailand, and the University of Oxford (England), and her associates.

CDC/Neva Gleason

Artemisinin resistance was first reported in western Cambodia in 2008, and that is where resistance to previous first-line antimalarials also first emerged. "Defining the extent and severity of artemisinin resistance is essential for planning containment and elimination strategies," the investigators noted.

To map the current extent of artemisinin resistance, they performed an open-label, randomized trial at 15 sites in Cambodia, Thailand, Laos, Vietnam, Myanmar, Bangladesh, India, Nigeria, Kenya, and the Congo. Over a 2-year period, 1,241 patients aged 6 months to 65 years with acute, uncomplicated falciparum malaria were randomly assigned to receive either 2 mg or 4 mg of oral artesunate for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite clearance half-life was then determined using serial blood smears. Longer parasite clearance half-life is associated with the organism’s increasing resistance to the drug.

Parasite clearance half-life varied widely across the sites in Southeast Asia, from a low of 2 hours in Laos to a high of 7 hours in Thailand. Slowly clearing infections, which were defined as a parasite clearance half-life of 5 hours or longer and indicated established resistance, were detected throughout mainland Southeast Asia, but they were not yet common in India or Africa. Another measure of artemisinin resistance – the proportion of patients with parasitemia detectable on day 3 – ranged from 0% in Kenya to 68% in eastern Thailand (N. Engl. J. Med. 2014 July 31 [doi: 10.1056/NEJMoa1314981]).

However, "despite the recent spread of resistance, we found that artemisinin-based combination therapies ... were still highly efficacious, presumably because of increased reliance on the efficacy of the partner drug as the potency of the artemisinin component waned," Dr. Ashley and her associates said.

Nevertheless, they cautioned that treatment failure rates for artesunate plus mefloquine (in Thailand) and for dihydroartemisinin plus piperaquine (in Cambodia) have risen by a factor of 5.

This study was supported by the U.K. Department for International Development, the Worldwide Antimalarial Resistance Network, the U.S. National Institute of Allergy and Infectious Diseases, and the Bill & Melinda Gates Foundation. Dr. Ashley and her associates reported no relevant conflicts of interest.

Artemisinin-resistant Plasmodium falciparum malaria remains uncontained. It is now "firmly established" in western Cambodia and Thailand, southern Vietnam, and eastern Myanmar and is emerging in southern Laos and northeastern Cambodia, according to a report published online July 31 in the New England Journal of Medicine.

"Radical measures will be necessary in Southeast Asia to prevent resistance to artemisinins and their partner drugs from spreading to the Indian subcontinent and then to Africa," said Dr. Elizabeth A. Ashley of the Mahidol-Oxford Tropical Medicine Research Unit, affiliated with both Mahidol University in Bangkok, Thailand, and the University of Oxford (England), and her associates.

CDC/Neva Gleason

Artemisinin resistance was first reported in western Cambodia in 2008, and that is where resistance to previous first-line antimalarials also first emerged. "Defining the extent and severity of artemisinin resistance is essential for planning containment and elimination strategies," the investigators noted.

To map the current extent of artemisinin resistance, they performed an open-label, randomized trial at 15 sites in Cambodia, Thailand, Laos, Vietnam, Myanmar, Bangladesh, India, Nigeria, Kenya, and the Congo. Over a 2-year period, 1,241 patients aged 6 months to 65 years with acute, uncomplicated falciparum malaria were randomly assigned to receive either 2 mg or 4 mg of oral artesunate for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite clearance half-life was then determined using serial blood smears. Longer parasite clearance half-life is associated with the organism’s increasing resistance to the drug.

Parasite clearance half-life varied widely across the sites in Southeast Asia, from a low of 2 hours in Laos to a high of 7 hours in Thailand. Slowly clearing infections, which were defined as a parasite clearance half-life of 5 hours or longer and indicated established resistance, were detected throughout mainland Southeast Asia, but they were not yet common in India or Africa. Another measure of artemisinin resistance – the proportion of patients with parasitemia detectable on day 3 – ranged from 0% in Kenya to 68% in eastern Thailand (N. Engl. J. Med. 2014 July 31 [doi: 10.1056/NEJMoa1314981]).

However, "despite the recent spread of resistance, we found that artemisinin-based combination therapies ... were still highly efficacious, presumably because of increased reliance on the efficacy of the partner drug as the potency of the artemisinin component waned," Dr. Ashley and her associates said.

Nevertheless, they cautioned that treatment failure rates for artesunate plus mefloquine (in Thailand) and for dihydroartemisinin plus piperaquine (in Cambodia) have risen by a factor of 5.

This study was supported by the U.K. Department for International Development, the Worldwide Antimalarial Resistance Network, the U.S. National Institute of Allergy and Infectious Diseases, and the Bill & Melinda Gates Foundation. Dr. Ashley and her associates reported no relevant conflicts of interest.

Combination therapy with the epidermal growth factor receptor–-blocker afatinib and cetuximab, a monoclonal antibody with anti-EGFR action, showed "robust and durable" clinical activity against advanced lung cancers that had acquired resistance to erlotinib or gefitinib in an international, uncontrolled industry-sponsored phase Ib clinical trial, according to a report published online July 29 in Cancer Discovery.

Until now, there have been no effective therapies for patients who initially showed dramatic tumor regression and prolonged survival with the EGFR inhibitors erlotinib or gefitinib but then, inevitably, developed resistance to those agents and had recurrences. "This study demonstrates that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent upon EGFR signaling for survival, and confirms the preclinical hypothesis that dual EGFR inhibition is particularly meaningful in this patient population," said Dr. Yelena Y. Janjigian of thoracic oncology and gastrointestinal oncology services at Memorial Sloan-Kettering Cancer Center, New York, and her associates.

They assessed the combination therapy in 126 patients at six centers in the Netherlands and the United States who had progressive lung cancer despite receiving multiple previous therapies, including 1-7 years on the EGFR tyrosine kinase inhibitors erlotinib or gefitinib. A total of 37 patients (29%) showed an objective partial response to afatinib plus cetuximab, including 22 (18%) who had tumor shrinkage of 50% or more. The median duration of response to the combination therapy was 5.7 months (range, 1.8-24.4 months). This "is particularly meaningful considering the majority of patients were heavily pretreated; that is, 52% had failed two or more lines of standard cytotoxic chemotherapy in addition to an EGFR tyrosine kinase inhibitor," Dr. Janjigian and her associates said (Cancer Discovery 2014 July 29 [doi:10.1158/2159-8290.CD-14-0326]).

The combination therapy’s safety profile was deemed "manageable," with most patients developing rash, diarrhea, stomatitis, and fatigue, and half of them developing grade 3 adverse events. A total of 14% of patients developed serious adverse events – usually drug hypersensitivity or dehydration – and 13% discontinued therapy due to treatment-related adverse effects.

This study was sponsored by Boehringer Ingelheim. Dr. Janjigian reported receiving grants from Boehringer Ingelheim, Bayer, Genentech, and Eli Lilly; her associates reported ties to Novartis, Roche, Infinity, Pfizer, Millennium, GlaxoSmithKline, Ariad, Mersana, Foundation Medicine, Abbott, and Celgene.

Combination therapy with the epidermal growth factor receptor–-blocker afatinib and cetuximab, a monoclonal antibody with anti-EGFR action, showed "robust and durable" clinical activity against advanced lung cancers that had acquired resistance to erlotinib or gefitinib in an international, uncontrolled industry-sponsored phase Ib clinical trial, according to a report published online July 29 in Cancer Discovery.

Until now, there have been no effective therapies for patients who initially showed dramatic tumor regression and prolonged survival with the EGFR inhibitors erlotinib or gefitinib but then, inevitably, developed resistance to those agents and had recurrences. "This study demonstrates that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent upon EGFR signaling for survival, and confirms the preclinical hypothesis that dual EGFR inhibition is particularly meaningful in this patient population," said Dr. Yelena Y. Janjigian of thoracic oncology and gastrointestinal oncology services at Memorial Sloan-Kettering Cancer Center, New York, and her associates.

They assessed the combination therapy in 126 patients at six centers in the Netherlands and the United States who had progressive lung cancer despite receiving multiple previous therapies, including 1-7 years on the EGFR tyrosine kinase inhibitors erlotinib or gefitinib. A total of 37 patients (29%) showed an objective partial response to afatinib plus cetuximab, including 22 (18%) who had tumor shrinkage of 50% or more. The median duration of response to the combination therapy was 5.7 months (range, 1.8-24.4 months). This "is particularly meaningful considering the majority of patients were heavily pretreated; that is, 52% had failed two or more lines of standard cytotoxic chemotherapy in addition to an EGFR tyrosine kinase inhibitor," Dr. Janjigian and her associates said (Cancer Discovery 2014 July 29 [doi:10.1158/2159-8290.CD-14-0326]).

The combination therapy’s safety profile was deemed "manageable," with most patients developing rash, diarrhea, stomatitis, and fatigue, and half of them developing grade 3 adverse events. A total of 14% of patients developed serious adverse events – usually drug hypersensitivity or dehydration – and 13% discontinued therapy due to treatment-related adverse effects.

This study was sponsored by Boehringer Ingelheim. Dr. Janjigian reported receiving grants from Boehringer Ingelheim, Bayer, Genentech, and Eli Lilly; her associates reported ties to Novartis, Roche, Infinity, Pfizer, Millennium, GlaxoSmithKline, Ariad, Mersana, Foundation Medicine, Abbott, and Celgene.

Combination therapy with the epidermal growth factor receptor–-blocker afatinib and cetuximab, a monoclonal antibody with anti-EGFR action, showed "robust and durable" clinical activity against advanced lung cancers that had acquired resistance to erlotinib or gefitinib in an international, uncontrolled industry-sponsored phase Ib clinical trial, according to a report published online July 29 in Cancer Discovery.

Until now, there have been no effective therapies for patients who initially showed dramatic tumor regression and prolonged survival with the EGFR inhibitors erlotinib or gefitinib but then, inevitably, developed resistance to those agents and had recurrences. "This study demonstrates that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent upon EGFR signaling for survival, and confirms the preclinical hypothesis that dual EGFR inhibition is particularly meaningful in this patient population," said Dr. Yelena Y. Janjigian of thoracic oncology and gastrointestinal oncology services at Memorial Sloan-Kettering Cancer Center, New York, and her associates.

They assessed the combination therapy in 126 patients at six centers in the Netherlands and the United States who had progressive lung cancer despite receiving multiple previous therapies, including 1-7 years on the EGFR tyrosine kinase inhibitors erlotinib or gefitinib. A total of 37 patients (29%) showed an objective partial response to afatinib plus cetuximab, including 22 (18%) who had tumor shrinkage of 50% or more. The median duration of response to the combination therapy was 5.7 months (range, 1.8-24.4 months). This "is particularly meaningful considering the majority of patients were heavily pretreated; that is, 52% had failed two or more lines of standard cytotoxic chemotherapy in addition to an EGFR tyrosine kinase inhibitor," Dr. Janjigian and her associates said (Cancer Discovery 2014 July 29 [doi:10.1158/2159-8290.CD-14-0326]).

The combination therapy’s safety profile was deemed "manageable," with most patients developing rash, diarrhea, stomatitis, and fatigue, and half of them developing grade 3 adverse events. A total of 14% of patients developed serious adverse events – usually drug hypersensitivity or dehydration – and 13% discontinued therapy due to treatment-related adverse effects.

This study was sponsored by Boehringer Ingelheim. Dr. Janjigian reported receiving grants from Boehringer Ingelheim, Bayer, Genentech, and Eli Lilly; her associates reported ties to Novartis, Roche, Infinity, Pfizer, Millennium, GlaxoSmithKline, Ariad, Mersana, Foundation Medicine, Abbott, and Celgene.

Among patients with resectable esophageal adenocarcinoma, tumor stage after completion of neoadjuvant chemotherapy is a much more important predictor of survival than is initial tumor stage at presentation, according to a report published online July 28 in Journal of Clinical Oncology.

Researchers analyzed data regarding 584 consecutive resections for adenocarcinoma of the esophagus or esophagogastric junction during a 10-year period at two high-volume centers in London. Tumors were initially staged by a multidisciplinary team after patients were evaluated via endoscopy, computed tomography (CT), endoscopic ultrasound, and/or latterly fluorodeoxyglucose positron emission tomography, said Dr. Andrew R. Davies of the department of surgery, St. Thomas’ Hospital, London, and his associates.

A total of 184 patients underwent immediate surgical resection, while 400 had neoadjuvant chemotherapy followed by surgical resection. The predominant chemotherapy regimens were cisplatin and fluorouracil; epirubicin, cisplatin, and fluorouracil; or epirubicin, cisplatin, and capecitabine. For the majority of patients, two, three, or four cycles of neoadjuvant treatment were administered.

Tumors were restaged via CT after chemotherapy was completed; cancers in 175 of these patients (44%) were downstaged. Compared with patients whose esophageal cancers were not downstaged, these treatment responders showed greatly improved rates of 5-year survival (52.5% vs 12.6%; P less than .001)), higher rates of clear surgical margins at resection (74% vs 40%; P less than .001), lower rates of isolated local recurrence (6% vs 13%; P = .03), and lower rates of systemic metastatic recurrence (19% vs 29%; P = .027). The chemotherapy regimen did not significantly affect the likelihood of tumor downstaging.

These findings show that "pathological stage after chemotherapy strongly dictates prognosis, whereas the initial pretreatment staging does this only to a limited extent. This indicates that advanced diagnostic staging procedures (e.g., PET-CT, esophageal ultrasound, or MRI) should be used after neoadjuvant chemotherapy. The major clinical decision making should be based on this staging rather than the initial staging. The main purpose of initial staging would be to identify any distant metastases (thus precluding curatively intended treatment) and to provide a baseline from which to compare the response to treatment. This would be a novel clinical approach that might improve clinical decision making and survival after curatively intended treatment," Dr. Davies and his colleagues said (J. Clin. Oncol. 2014 July 28 [doi:10.1200/JCO.2014.55.9070]).

"No previous study has been able to quantify the local and systemic downstaging effects of systemic therapy in this manner and combine it with robust long-term follow-up data," they noted.

This study was supported by the Swedish Research Council, the Swedish Cancer Society, and the National Institute of Health Research, Royal Marsden /Institute of Cancer Research Biomedical Research Center. Dr. Davies’ associates reported ties to Eli Lilly, Nestle, Astellas, Roche, Sanofi-Aventis, AstraZeneca, Amgen, Merck, Celgene, and Novartis.

Among patients with resectable esophageal adenocarcinoma, tumor stage after completion of neoadjuvant chemotherapy is a much more important predictor of survival than is initial tumor stage at presentation, according to a report published online July 28 in Journal of Clinical Oncology.

Researchers analyzed data regarding 584 consecutive resections for adenocarcinoma of the esophagus or esophagogastric junction during a 10-year period at two high-volume centers in London. Tumors were initially staged by a multidisciplinary team after patients were evaluated via endoscopy, computed tomography (CT), endoscopic ultrasound, and/or latterly fluorodeoxyglucose positron emission tomography, said Dr. Andrew R. Davies of the department of surgery, St. Thomas’ Hospital, London, and his associates.

A total of 184 patients underwent immediate surgical resection, while 400 had neoadjuvant chemotherapy followed by surgical resection. The predominant chemotherapy regimens were cisplatin and fluorouracil; epirubicin, cisplatin, and fluorouracil; or epirubicin, cisplatin, and capecitabine. For the majority of patients, two, three, or four cycles of neoadjuvant treatment were administered.

Tumors were restaged via CT after chemotherapy was completed; cancers in 175 of these patients (44%) were downstaged. Compared with patients whose esophageal cancers were not downstaged, these treatment responders showed greatly improved rates of 5-year survival (52.5% vs 12.6%; P less than .001)), higher rates of clear surgical margins at resection (74% vs 40%; P less than .001), lower rates of isolated local recurrence (6% vs 13%; P = .03), and lower rates of systemic metastatic recurrence (19% vs 29%; P = .027). The chemotherapy regimen did not significantly affect the likelihood of tumor downstaging.

These findings show that "pathological stage after chemotherapy strongly dictates prognosis, whereas the initial pretreatment staging does this only to a limited extent. This indicates that advanced diagnostic staging procedures (e.g., PET-CT, esophageal ultrasound, or MRI) should be used after neoadjuvant chemotherapy. The major clinical decision making should be based on this staging rather than the initial staging. The main purpose of initial staging would be to identify any distant metastases (thus precluding curatively intended treatment) and to provide a baseline from which to compare the response to treatment. This would be a novel clinical approach that might improve clinical decision making and survival after curatively intended treatment," Dr. Davies and his colleagues said (J. Clin. Oncol. 2014 July 28 [doi:10.1200/JCO.2014.55.9070]).

"No previous study has been able to quantify the local and systemic downstaging effects of systemic therapy in this manner and combine it with robust long-term follow-up data," they noted.

This study was supported by the Swedish Research Council, the Swedish Cancer Society, and the National Institute of Health Research, Royal Marsden /Institute of Cancer Research Biomedical Research Center. Dr. Davies’ associates reported ties to Eli Lilly, Nestle, Astellas, Roche, Sanofi-Aventis, AstraZeneca, Amgen, Merck, Celgene, and Novartis.

Among patients with resectable esophageal adenocarcinoma, tumor stage after completion of neoadjuvant chemotherapy is a much more important predictor of survival than is initial tumor stage at presentation, according to a report published online July 28 in Journal of Clinical Oncology.

Researchers analyzed data regarding 584 consecutive resections for adenocarcinoma of the esophagus or esophagogastric junction during a 10-year period at two high-volume centers in London. Tumors were initially staged by a multidisciplinary team after patients were evaluated via endoscopy, computed tomography (CT), endoscopic ultrasound, and/or latterly fluorodeoxyglucose positron emission tomography, said Dr. Andrew R. Davies of the department of surgery, St. Thomas’ Hospital, London, and his associates.

A total of 184 patients underwent immediate surgical resection, while 400 had neoadjuvant chemotherapy followed by surgical resection. The predominant chemotherapy regimens were cisplatin and fluorouracil; epirubicin, cisplatin, and fluorouracil; or epirubicin, cisplatin, and capecitabine. For the majority of patients, two, three, or four cycles of neoadjuvant treatment were administered.

Tumors were restaged via CT after chemotherapy was completed; cancers in 175 of these patients (44%) were downstaged. Compared with patients whose esophageal cancers were not downstaged, these treatment responders showed greatly improved rates of 5-year survival (52.5% vs 12.6%; P less than .001)), higher rates of clear surgical margins at resection (74% vs 40%; P less than .001), lower rates of isolated local recurrence (6% vs 13%; P = .03), and lower rates of systemic metastatic recurrence (19% vs 29%; P = .027). The chemotherapy regimen did not significantly affect the likelihood of tumor downstaging.

These findings show that "pathological stage after chemotherapy strongly dictates prognosis, whereas the initial pretreatment staging does this only to a limited extent. This indicates that advanced diagnostic staging procedures (e.g., PET-CT, esophageal ultrasound, or MRI) should be used after neoadjuvant chemotherapy. The major clinical decision making should be based on this staging rather than the initial staging. The main purpose of initial staging would be to identify any distant metastases (thus precluding curatively intended treatment) and to provide a baseline from which to compare the response to treatment. This would be a novel clinical approach that might improve clinical decision making and survival after curatively intended treatment," Dr. Davies and his colleagues said (J. Clin. Oncol. 2014 July 28 [doi:10.1200/JCO.2014.55.9070]).

"No previous study has been able to quantify the local and systemic downstaging effects of systemic therapy in this manner and combine it with robust long-term follow-up data," they noted.

This study was supported by the Swedish Research Council, the Swedish Cancer Society, and the National Institute of Health Research, Royal Marsden /Institute of Cancer Research Biomedical Research Center. Dr. Davies’ associates reported ties to Eli Lilly, Nestle, Astellas, Roche, Sanofi-Aventis, AstraZeneca, Amgen, Merck, Celgene, and Novartis.