Sharon Worcester

Associations between serum 25-hydoxyvitamin D concentration and coronary heart disease vary by race, according to findings from the Multi-Ethnic Study of Atherosclerosis (MESA).

Of 6,436 participants in the community-based, prospective cohort study, 361 experienced an incident CHD event during a median of 8.5 years of follow-up. A low baseline serum 25-hydroxyvitamin D (25[OH]D) level was associated with a greater risk of an event in 167 white participants (hazard ratio, 1.26 per 10-ng/mL decrement) and in 27 Chinese participants (HR, 1.67 per 10-ng/mL decrement), but not in 94 black participants or 73 Hispanic participants (HR, 0.93 and 1.01 per 10-ng/mL decrement), Cassianne Robinson-Cohen, Ph.D., of the University of Washington, Seattle, and her colleagues reported online July 9 in JAMA.

©Kaspri/Fotolia.com

"Differences in associations across race/ethnicity groups were consistent for both a broad and restricted definition of CHD and persisted after adjustment for known CHD risk factors," the investigators said.

The findings require confirmation, but suggest that until such confirmation is available, the results of studies evaluating the effects of 25(OH)D in ethnically homogeneous populations should not be extrapolated to other racial or ethnic populations, the investigators said, noting that a low 25(OH)D level has consistently been linked with CHD in study populations composed largely or entirely of white subjects, but that the association has not been studied rigorously in other populations (JAMA 2013;310:179-88).

Study subjects were adults aged 45-84 years (mean, 62 years) who were free of known cardiovascular disease and who were recruited between July 2000 and September 2002. The subjects were followed via telephone every 9-12 months to assess for myocardial infarction, angina, cardiac arrest, or CHD death. Diagnoses were confirmed via death certificates and/or medical record review.

As for possible explanations for the racial and ethnic differences observed in this study, the data suggest that biologic differences account for much of the heterogeneity, the investigators said, explaining that although "results were robust ... we are unable to discern characteristics that could conceivably cause differential confounding by race, and chance findings are unlikely – at least for black vs. white comparison – due to reasonable numbers of events in each race."

Additionally, the lack of any trend toward association in blacks, the statistically significant global and black vs. white P values for interaction, and the fact that findings of studies looking at the associations of 25(OH)D with other health outcomes also support differing associations by race, support a biologic explanation, they said.

The findings in Hispanic and Chinese populations in this study, however, should be interpreted with caution, because the sample sizes for these groups were relatively small, and the number of events was low; additional studies of 25(OH)D and health outcomes are needed in these populations, they said.

Though limited by potential confounding (many unhealthy characteristics are linked with lower 25[OH]D concentrations) and by low power for detecting associations of small magnitude within individual racial and ethnic groups, the findings are bolstered by the large multiethnic population; the evaluation of adjudicated incident CHD events over a relatively long follow-up time; the use of an accurate assay for measuring 25(OH)D; and careful, high-quality approaches to measuring 25(OH)D.

In addition to studies to confirm these findings, well-powered clinical trials are also needed to evaluate the effects of vitamin D supplements on CHD risk, the investigators said, noting that at least five such trials are currently underway, including one (the Vitamin D and Omega-3 Trial, or VITAL) that is targeting enrollment of a large multiracial study population.

The current study was funded by grants from the National Heart, Lung, and Blood Institute. Dr. Robinson-Cohen reported having no relevant financial disclosures, but other study authors reported receiving grant funding, travel accommodations, and/or payment for lectures from the National Institutes of Health, Amgen, and/or Abbott Laboratories.

Associations between serum 25-hydoxyvitamin D concentration and coronary heart disease vary by race, according to findings from the Multi-Ethnic Study of Atherosclerosis (MESA).

Of 6,436 participants in the community-based, prospective cohort study, 361 experienced an incident CHD event during a median of 8.5 years of follow-up. A low baseline serum 25-hydroxyvitamin D (25[OH]D) level was associated with a greater risk of an event in 167 white participants (hazard ratio, 1.26 per 10-ng/mL decrement) and in 27 Chinese participants (HR, 1.67 per 10-ng/mL decrement), but not in 94 black participants or 73 Hispanic participants (HR, 0.93 and 1.01 per 10-ng/mL decrement), Cassianne Robinson-Cohen, Ph.D., of the University of Washington, Seattle, and her colleagues reported online July 9 in JAMA.

©Kaspri/Fotolia.com

"Differences in associations across race/ethnicity groups were consistent for both a broad and restricted definition of CHD and persisted after adjustment for known CHD risk factors," the investigators said.

The findings require confirmation, but suggest that until such confirmation is available, the results of studies evaluating the effects of 25(OH)D in ethnically homogeneous populations should not be extrapolated to other racial or ethnic populations, the investigators said, noting that a low 25(OH)D level has consistently been linked with CHD in study populations composed largely or entirely of white subjects, but that the association has not been studied rigorously in other populations (JAMA 2013;310:179-88).

Study subjects were adults aged 45-84 years (mean, 62 years) who were free of known cardiovascular disease and who were recruited between July 2000 and September 2002. The subjects were followed via telephone every 9-12 months to assess for myocardial infarction, angina, cardiac arrest, or CHD death. Diagnoses were confirmed via death certificates and/or medical record review.

As for possible explanations for the racial and ethnic differences observed in this study, the data suggest that biologic differences account for much of the heterogeneity, the investigators said, explaining that although "results were robust ... we are unable to discern characteristics that could conceivably cause differential confounding by race, and chance findings are unlikely – at least for black vs. white comparison – due to reasonable numbers of events in each race."

Additionally, the lack of any trend toward association in blacks, the statistically significant global and black vs. white P values for interaction, and the fact that findings of studies looking at the associations of 25(OH)D with other health outcomes also support differing associations by race, support a biologic explanation, they said.

The findings in Hispanic and Chinese populations in this study, however, should be interpreted with caution, because the sample sizes for these groups were relatively small, and the number of events was low; additional studies of 25(OH)D and health outcomes are needed in these populations, they said.

Though limited by potential confounding (many unhealthy characteristics are linked with lower 25[OH]D concentrations) and by low power for detecting associations of small magnitude within individual racial and ethnic groups, the findings are bolstered by the large multiethnic population; the evaluation of adjudicated incident CHD events over a relatively long follow-up time; the use of an accurate assay for measuring 25(OH)D; and careful, high-quality approaches to measuring 25(OH)D.

In addition to studies to confirm these findings, well-powered clinical trials are also needed to evaluate the effects of vitamin D supplements on CHD risk, the investigators said, noting that at least five such trials are currently underway, including one (the Vitamin D and Omega-3 Trial, or VITAL) that is targeting enrollment of a large multiracial study population.

The current study was funded by grants from the National Heart, Lung, and Blood Institute. Dr. Robinson-Cohen reported having no relevant financial disclosures, but other study authors reported receiving grant funding, travel accommodations, and/or payment for lectures from the National Institutes of Health, Amgen, and/or Abbott Laboratories.

Associations between serum 25-hydoxyvitamin D concentration and coronary heart disease vary by race, according to findings from the Multi-Ethnic Study of Atherosclerosis (MESA).

Of 6,436 participants in the community-based, prospective cohort study, 361 experienced an incident CHD event during a median of 8.5 years of follow-up. A low baseline serum 25-hydroxyvitamin D (25[OH]D) level was associated with a greater risk of an event in 167 white participants (hazard ratio, 1.26 per 10-ng/mL decrement) and in 27 Chinese participants (HR, 1.67 per 10-ng/mL decrement), but not in 94 black participants or 73 Hispanic participants (HR, 0.93 and 1.01 per 10-ng/mL decrement), Cassianne Robinson-Cohen, Ph.D., of the University of Washington, Seattle, and her colleagues reported online July 9 in JAMA.

©Kaspri/Fotolia.com

"Differences in associations across race/ethnicity groups were consistent for both a broad and restricted definition of CHD and persisted after adjustment for known CHD risk factors," the investigators said.

The findings require confirmation, but suggest that until such confirmation is available, the results of studies evaluating the effects of 25(OH)D in ethnically homogeneous populations should not be extrapolated to other racial or ethnic populations, the investigators said, noting that a low 25(OH)D level has consistently been linked with CHD in study populations composed largely or entirely of white subjects, but that the association has not been studied rigorously in other populations (JAMA 2013;310:179-88).

Study subjects were adults aged 45-84 years (mean, 62 years) who were free of known cardiovascular disease and who were recruited between July 2000 and September 2002. The subjects were followed via telephone every 9-12 months to assess for myocardial infarction, angina, cardiac arrest, or CHD death. Diagnoses were confirmed via death certificates and/or medical record review.

As for possible explanations for the racial and ethnic differences observed in this study, the data suggest that biologic differences account for much of the heterogeneity, the investigators said, explaining that although "results were robust ... we are unable to discern characteristics that could conceivably cause differential confounding by race, and chance findings are unlikely – at least for black vs. white comparison – due to reasonable numbers of events in each race."

Additionally, the lack of any trend toward association in blacks, the statistically significant global and black vs. white P values for interaction, and the fact that findings of studies looking at the associations of 25(OH)D with other health outcomes also support differing associations by race, support a biologic explanation, they said.

The findings in Hispanic and Chinese populations in this study, however, should be interpreted with caution, because the sample sizes for these groups were relatively small, and the number of events was low; additional studies of 25(OH)D and health outcomes are needed in these populations, they said.

Though limited by potential confounding (many unhealthy characteristics are linked with lower 25[OH]D concentrations) and by low power for detecting associations of small magnitude within individual racial and ethnic groups, the findings are bolstered by the large multiethnic population; the evaluation of adjudicated incident CHD events over a relatively long follow-up time; the use of an accurate assay for measuring 25(OH)D; and careful, high-quality approaches to measuring 25(OH)D.

In addition to studies to confirm these findings, well-powered clinical trials are also needed to evaluate the effects of vitamin D supplements on CHD risk, the investigators said, noting that at least five such trials are currently underway, including one (the Vitamin D and Omega-3 Trial, or VITAL) that is targeting enrollment of a large multiracial study population.

The current study was funded by grants from the National Heart, Lung, and Blood Institute. Dr. Robinson-Cohen reported having no relevant financial disclosures, but other study authors reported receiving grant funding, travel accommodations, and/or payment for lectures from the National Institutes of Health, Amgen, and/or Abbott Laboratories.

Tamoxifen for the prevention of breast cancer should be discussed with women aged 35 years or older who are at increased risk for the disease, according to an updated clinical practice guideline from the American Society of Clinical Oncology.

The use of raloxifene and exemestane should be discussed with postmenopausal women who are at increased risk for the disease, according to the update – the third since the guideline, entitled "Use of Pharmacologic Interventions for Breast Cancer Risk Reduction," was first published in 1999, and the first since 2009 (J. Clin. Onco. 2009;27:3235-58).

The new update includes stronger wording regarding discussion about the selective estrogen-receptor modulators tamoxifen and raloxifene, compared with the 2009 version, which stated that tamoxifen and raloxifene "may be offered" to women at increased risk.

"The committee felt that a stronger statement recommending the use of tamoxifen and raloxifene was needed given the weight of evidence from phase III randomized trials demonstrating a reduction in breast cancer risk for both tamoxifen and raloxifene," Update Committee cochair, Dr. Kala Visvanathan of Johns Hopkins Medical Institutions, Baltimore, and the other committee members reported (J. Clin. Oncol. 2013 July 8 [doi 10.1200/JCO.2013.49.3122]).

The guideline recommendations, which were published online on July 8 in the Journal of Clinical Oncology, and which are limited to pharmacologic interventions, specifically call for discussing with patients the options of:

• Oral tamoxifen treatment at a dose of 20 mg daily for 5 years to reduce the risk of estrogen receptor- (ER) positive invasive breast cancer in both pre- and postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have lobular carcinoma in situ (LCIS). Increased risk is defined as a 5-year projected absolute risk of 1.66% or greater according to the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure. This "strong, evidence-based recommendation" is based on data from multiple randomized, controlled trials showing that the risk reduction benefit of this treatment continues for at least 10 years in these patients.

• Oral raloxifene treatment at a dose of 60 mg daily for 5 years to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk or who have LCIS. This "strong, evidence-based recommendation" also is based on data from multiple randomized, controlled trials.

• Oral exemestane at a dose of 25 mg daily for 5 years as an alternative to tamoxifen or raloxifene to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have LCIS. This "moderate, evidence-based recommendation" is based on encouraging evidence from a single randomized, controlled trial of the aromatase inhibitor, which is approved for the treatment of breast cancer but not for breast cancer prevention.

Tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack, nor are they recommended during prolonged immobilization. Tamoxifen is not recommended in women who are pregnant or who may become pregnant or in women who are nursing, and it should not be used in combination with hormone therapy. Exemestane should not be used in premenopausal women, according to the guideline.

"Discussions with patient and health care providers should include both the risks and benefits of each agent under consideration," the committee said.

The guideline update is based on a systematic review of more than 700 potential randomized controlled trials and meta-analyses published between June 2007 and June 2012. Ultimately, 19 articles on six different chemoprevention agents met the selection criteria of the committee, which was convened by the ASCO Clinical Practice Guidelines Committee. Members were experts – with special expertise in breast cancer – from clinical medicine, public health, clinical research, health services, and related areas such as biostatistics and epidemiology. A patient representative also was appointed to the committee.

In addition to the changes regarding the discussion of tamoxifen and raloxifene, the updated guideline also eliminates a recommendation from the 2009 version calling for a baseline gynecologic examination before initiation of treatment and annually thereafter, and removes mention of treatment with fenretinide, which the committee determined is "no longer relevant for breast cancer chemoprevention."

The committee also addressed ongoing challenges with respect to minimizing health disparities, which the committee said "are an important consideration in reducing breast cancer risk."

"Members of racial and ethnic minorities, in general, tend to be diagnosed with cancer at more advanced stages and have worse outcomes ... Awareness of these disparities in quality of care and access to care should be considered in the context of this clinical practice guideline. Health care providers should strive to deliver the highest level of cancer care to all patients," the guideline states.

As for future directions, the committee stressed a need for addressing "the many unresolved issues related to the poor uptake of breast cancer chemoprevention agents in women who are at increased risk of breast cancer."

An estimated 2 million or more women could benefit from breast cancer chemoprevention, yet the agents recommended in this guideline are used infrequently for breast cancer risk reduction, the committee said, noting a need for the design of effective tools and approaches to educate providers and identify women at increased risk, and for efficacious interventions and greater understanding of the disparities and barriers that exist regarding use of chemoprevention strategies.

"Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large. For some women, these therapies can reduce the risk of breast cancer by up to 50%," Dr. Visvanathan said in a press statement.

A data supplement with tables and figures, and clinical tools and resources to help clinicians implement this guideline is available at ASCO’s website.

Dr. Visvanathan reported having no disclosures. Other Update Committee members reported serving as consultants and/or receiving honoraria or research funding from Novartis, Pfizer, Bayer, Champions Biotechnology, and/or AstraZeneca. One author also reported owning Novartis stock.

Tamoxifen for the prevention of breast cancer should be discussed with women aged 35 years or older who are at increased risk for the disease, according to an updated clinical practice guideline from the American Society of Clinical Oncology.

The use of raloxifene and exemestane should be discussed with postmenopausal women who are at increased risk for the disease, according to the update – the third since the guideline, entitled "Use of Pharmacologic Interventions for Breast Cancer Risk Reduction," was first published in 1999, and the first since 2009 (J. Clin. Onco. 2009;27:3235-58).

The new update includes stronger wording regarding discussion about the selective estrogen-receptor modulators tamoxifen and raloxifene, compared with the 2009 version, which stated that tamoxifen and raloxifene "may be offered" to women at increased risk.

"The committee felt that a stronger statement recommending the use of tamoxifen and raloxifene was needed given the weight of evidence from phase III randomized trials demonstrating a reduction in breast cancer risk for both tamoxifen and raloxifene," Update Committee cochair, Dr. Kala Visvanathan of Johns Hopkins Medical Institutions, Baltimore, and the other committee members reported (J. Clin. Oncol. 2013 July 8 [doi 10.1200/JCO.2013.49.3122]).

The guideline recommendations, which were published online on July 8 in the Journal of Clinical Oncology, and which are limited to pharmacologic interventions, specifically call for discussing with patients the options of:

• Oral tamoxifen treatment at a dose of 20 mg daily for 5 years to reduce the risk of estrogen receptor- (ER) positive invasive breast cancer in both pre- and postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have lobular carcinoma in situ (LCIS). Increased risk is defined as a 5-year projected absolute risk of 1.66% or greater according to the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure. This "strong, evidence-based recommendation" is based on data from multiple randomized, controlled trials showing that the risk reduction benefit of this treatment continues for at least 10 years in these patients.

• Oral raloxifene treatment at a dose of 60 mg daily for 5 years to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk or who have LCIS. This "strong, evidence-based recommendation" also is based on data from multiple randomized, controlled trials.

• Oral exemestane at a dose of 25 mg daily for 5 years as an alternative to tamoxifen or raloxifene to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have LCIS. This "moderate, evidence-based recommendation" is based on encouraging evidence from a single randomized, controlled trial of the aromatase inhibitor, which is approved for the treatment of breast cancer but not for breast cancer prevention.

Tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack, nor are they recommended during prolonged immobilization. Tamoxifen is not recommended in women who are pregnant or who may become pregnant or in women who are nursing, and it should not be used in combination with hormone therapy. Exemestane should not be used in premenopausal women, according to the guideline.

"Discussions with patient and health care providers should include both the risks and benefits of each agent under consideration," the committee said.

The guideline update is based on a systematic review of more than 700 potential randomized controlled trials and meta-analyses published between June 2007 and June 2012. Ultimately, 19 articles on six different chemoprevention agents met the selection criteria of the committee, which was convened by the ASCO Clinical Practice Guidelines Committee. Members were experts – with special expertise in breast cancer – from clinical medicine, public health, clinical research, health services, and related areas such as biostatistics and epidemiology. A patient representative also was appointed to the committee.

In addition to the changes regarding the discussion of tamoxifen and raloxifene, the updated guideline also eliminates a recommendation from the 2009 version calling for a baseline gynecologic examination before initiation of treatment and annually thereafter, and removes mention of treatment with fenretinide, which the committee determined is "no longer relevant for breast cancer chemoprevention."

The committee also addressed ongoing challenges with respect to minimizing health disparities, which the committee said "are an important consideration in reducing breast cancer risk."

"Members of racial and ethnic minorities, in general, tend to be diagnosed with cancer at more advanced stages and have worse outcomes ... Awareness of these disparities in quality of care and access to care should be considered in the context of this clinical practice guideline. Health care providers should strive to deliver the highest level of cancer care to all patients," the guideline states.

As for future directions, the committee stressed a need for addressing "the many unresolved issues related to the poor uptake of breast cancer chemoprevention agents in women who are at increased risk of breast cancer."

An estimated 2 million or more women could benefit from breast cancer chemoprevention, yet the agents recommended in this guideline are used infrequently for breast cancer risk reduction, the committee said, noting a need for the design of effective tools and approaches to educate providers and identify women at increased risk, and for efficacious interventions and greater understanding of the disparities and barriers that exist regarding use of chemoprevention strategies.

"Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large. For some women, these therapies can reduce the risk of breast cancer by up to 50%," Dr. Visvanathan said in a press statement.

A data supplement with tables and figures, and clinical tools and resources to help clinicians implement this guideline is available at ASCO’s website.

Dr. Visvanathan reported having no disclosures. Other Update Committee members reported serving as consultants and/or receiving honoraria or research funding from Novartis, Pfizer, Bayer, Champions Biotechnology, and/or AstraZeneca. One author also reported owning Novartis stock.

Tamoxifen for the prevention of breast cancer should be discussed with women aged 35 years or older who are at increased risk for the disease, according to an updated clinical practice guideline from the American Society of Clinical Oncology.

The use of raloxifene and exemestane should be discussed with postmenopausal women who are at increased risk for the disease, according to the update – the third since the guideline, entitled "Use of Pharmacologic Interventions for Breast Cancer Risk Reduction," was first published in 1999, and the first since 2009 (J. Clin. Onco. 2009;27:3235-58).

The new update includes stronger wording regarding discussion about the selective estrogen-receptor modulators tamoxifen and raloxifene, compared with the 2009 version, which stated that tamoxifen and raloxifene "may be offered" to women at increased risk.

"The committee felt that a stronger statement recommending the use of tamoxifen and raloxifene was needed given the weight of evidence from phase III randomized trials demonstrating a reduction in breast cancer risk for both tamoxifen and raloxifene," Update Committee cochair, Dr. Kala Visvanathan of Johns Hopkins Medical Institutions, Baltimore, and the other committee members reported (J. Clin. Oncol. 2013 July 8 [doi 10.1200/JCO.2013.49.3122]).

The guideline recommendations, which were published online on July 8 in the Journal of Clinical Oncology, and which are limited to pharmacologic interventions, specifically call for discussing with patients the options of:

• Oral tamoxifen treatment at a dose of 20 mg daily for 5 years to reduce the risk of estrogen receptor- (ER) positive invasive breast cancer in both pre- and postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have lobular carcinoma in situ (LCIS). Increased risk is defined as a 5-year projected absolute risk of 1.66% or greater according to the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure. This "strong, evidence-based recommendation" is based on data from multiple randomized, controlled trials showing that the risk reduction benefit of this treatment continues for at least 10 years in these patients.

• Oral raloxifene treatment at a dose of 60 mg daily for 5 years to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk or who have LCIS. This "strong, evidence-based recommendation" also is based on data from multiple randomized, controlled trials.

• Oral exemestane at a dose of 25 mg daily for 5 years as an alternative to tamoxifen or raloxifene to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have LCIS. This "moderate, evidence-based recommendation" is based on encouraging evidence from a single randomized, controlled trial of the aromatase inhibitor, which is approved for the treatment of breast cancer but not for breast cancer prevention.

Tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack, nor are they recommended during prolonged immobilization. Tamoxifen is not recommended in women who are pregnant or who may become pregnant or in women who are nursing, and it should not be used in combination with hormone therapy. Exemestane should not be used in premenopausal women, according to the guideline.

"Discussions with patient and health care providers should include both the risks and benefits of each agent under consideration," the committee said.

The guideline update is based on a systematic review of more than 700 potential randomized controlled trials and meta-analyses published between June 2007 and June 2012. Ultimately, 19 articles on six different chemoprevention agents met the selection criteria of the committee, which was convened by the ASCO Clinical Practice Guidelines Committee. Members were experts – with special expertise in breast cancer – from clinical medicine, public health, clinical research, health services, and related areas such as biostatistics and epidemiology. A patient representative also was appointed to the committee.

In addition to the changes regarding the discussion of tamoxifen and raloxifene, the updated guideline also eliminates a recommendation from the 2009 version calling for a baseline gynecologic examination before initiation of treatment and annually thereafter, and removes mention of treatment with fenretinide, which the committee determined is "no longer relevant for breast cancer chemoprevention."

The committee also addressed ongoing challenges with respect to minimizing health disparities, which the committee said "are an important consideration in reducing breast cancer risk."

"Members of racial and ethnic minorities, in general, tend to be diagnosed with cancer at more advanced stages and have worse outcomes ... Awareness of these disparities in quality of care and access to care should be considered in the context of this clinical practice guideline. Health care providers should strive to deliver the highest level of cancer care to all patients," the guideline states.

As for future directions, the committee stressed a need for addressing "the many unresolved issues related to the poor uptake of breast cancer chemoprevention agents in women who are at increased risk of breast cancer."

An estimated 2 million or more women could benefit from breast cancer chemoprevention, yet the agents recommended in this guideline are used infrequently for breast cancer risk reduction, the committee said, noting a need for the design of effective tools and approaches to educate providers and identify women at increased risk, and for efficacious interventions and greater understanding of the disparities and barriers that exist regarding use of chemoprevention strategies.

"Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large. For some women, these therapies can reduce the risk of breast cancer by up to 50%," Dr. Visvanathan said in a press statement.

A data supplement with tables and figures, and clinical tools and resources to help clinicians implement this guideline is available at ASCO’s website.

Dr. Visvanathan reported having no disclosures. Other Update Committee members reported serving as consultants and/or receiving honoraria or research funding from Novartis, Pfizer, Bayer, Champions Biotechnology, and/or AstraZeneca. One author also reported owning Novartis stock.

Babies who are first exposed to solid food before the age of 4 months or at age 6 months or older are significantly more likely to develop type 1 diabetes mellitus than those with a first exposure at 4-5 months of age, findings from a longitudinal observational study have shown.

Of 1,835 children at increased genetic risk for type 1 diabetes mellitus (T1DM) who were included in the Diabetes Autoimmunity Study in the Young (DAISY), 53 developed the disease during follow-up. After adjustment for the human leukocyte antigen (HLA)-DR genotype, a first-degree relative with T1DM, maternal education, and delivery type, both the early and late first solid food exposures significantly predicted T1DM development (adjusted hazard ratios, 1.91 and 3.02, respectively), Brittni Frederiksen of the University of Colorado, Aurora, and her colleagues reported online on July 8 in JAMA Pediatrics.

Specifically, babies with early exposure to fruit and those with late exposure to rice/oat (non–gluten-containing foods) were at increased risk of T1DM development (HR, 2.23 and 2.88, respectively), the investigators found (JAMA Pediatr. July [doi:10.1001/jamapediatrics.2013.317]).

©thinkstockphotos.com

Of note, babies who were still breastfeeding at the time of introduction to wheat/barley (gluten-containing food) had a significantly reduced risk of T1DM development (HR, 0.47), suggesting that breastfeeding confers some protection against the disease, they said.

The timing of the introduction of vegetables and meat did not predict T1DM in the DAISY cohort.

DAISY participants included two groups of children at increased genetic risk for developing T1DM – a group found to have diabetes-susceptibility alleles in the HLA region on cord blood screening, and a group of unaffected children with a first-degree relative with T1DM. Children included in the current analysis were those followed from birth, who completed clinic visits at 9, 15, and 24 months, and annually thereafter.

The findings, which support those from an earlier DAISY report demonstrating "a window of time for introduction of cereals, 4-6 months, outside of which the risk for development of islet autoimmunity (preclinical T1DM) increased." are important given the increasing worldwide incidence of T1DM. That increase is most rapid among children younger than age 5 years, the investigators noted.

As for the mechanisms of associations between early and late food exposures and T1DM development, the risk predicted by early exposure "might suggest a mechanism involving an abnormal immune response to solid food antigens in an immature gut immune system in susceptible individuals," and the increased risk predicted by late exposures "may be related to the larger amounts given at initial exposure to older children," the investigators said.

Also, the late introduction of solid foods, when breast milk no longer meets energy and nutrient needs, could lead to nutrient deficiencies that could increase T1DM risk. Similarly, late solid food exposures may be related to the cessation of breastfeeding before solid food introduction, resulting in the loss of the protective effects of breast milk in that setting, they suggested.

Although the findings require confirmation in a larger cohort, they provide some guidance for the introduction of solid foods.

"While much of the focus of infant diet and T1DM research has been on the timing of the introduction of a single antigen (i.e., milk or gluten), our data suggest multiple foods/antigens play a role and that there is a complex relationship between the timing and type of infant food exposures and T1DM risk. In summary, there appears to be a safe window in which to introduce solid foods between 4 and 5 months of age; solid foods should be introduced while continuing to breastfeed to minimize T1DM risk in genetically susceptible children," the investigators concluded.

This study was supported by a National Institutes of Health grant and a Diabetes Endocrine Research Center Clinical Investigation and Bioinformatics Core grant. The authors reported having no relevant financial disclosures.

Babies who are first exposed to solid food before the age of 4 months or at age 6 months or older are significantly more likely to develop type 1 diabetes mellitus than those with a first exposure at 4-5 months of age, findings from a longitudinal observational study have shown.

Of 1,835 children at increased genetic risk for type 1 diabetes mellitus (T1DM) who were included in the Diabetes Autoimmunity Study in the Young (DAISY), 53 developed the disease during follow-up. After adjustment for the human leukocyte antigen (HLA)-DR genotype, a first-degree relative with T1DM, maternal education, and delivery type, both the early and late first solid food exposures significantly predicted T1DM development (adjusted hazard ratios, 1.91 and 3.02, respectively), Brittni Frederiksen of the University of Colorado, Aurora, and her colleagues reported online on July 8 in JAMA Pediatrics.

Specifically, babies with early exposure to fruit and those with late exposure to rice/oat (non–gluten-containing foods) were at increased risk of T1DM development (HR, 2.23 and 2.88, respectively), the investigators found (JAMA Pediatr. July [doi:10.1001/jamapediatrics.2013.317]).

©thinkstockphotos.com

Of note, babies who were still breastfeeding at the time of introduction to wheat/barley (gluten-containing food) had a significantly reduced risk of T1DM development (HR, 0.47), suggesting that breastfeeding confers some protection against the disease, they said.

The timing of the introduction of vegetables and meat did not predict T1DM in the DAISY cohort.

DAISY participants included two groups of children at increased genetic risk for developing T1DM – a group found to have diabetes-susceptibility alleles in the HLA region on cord blood screening, and a group of unaffected children with a first-degree relative with T1DM. Children included in the current analysis were those followed from birth, who completed clinic visits at 9, 15, and 24 months, and annually thereafter.

The findings, which support those from an earlier DAISY report demonstrating "a window of time for introduction of cereals, 4-6 months, outside of which the risk for development of islet autoimmunity (preclinical T1DM) increased." are important given the increasing worldwide incidence of T1DM. That increase is most rapid among children younger than age 5 years, the investigators noted.

As for the mechanisms of associations between early and late food exposures and T1DM development, the risk predicted by early exposure "might suggest a mechanism involving an abnormal immune response to solid food antigens in an immature gut immune system in susceptible individuals," and the increased risk predicted by late exposures "may be related to the larger amounts given at initial exposure to older children," the investigators said.

Also, the late introduction of solid foods, when breast milk no longer meets energy and nutrient needs, could lead to nutrient deficiencies that could increase T1DM risk. Similarly, late solid food exposures may be related to the cessation of breastfeeding before solid food introduction, resulting in the loss of the protective effects of breast milk in that setting, they suggested.

Although the findings require confirmation in a larger cohort, they provide some guidance for the introduction of solid foods.

"While much of the focus of infant diet and T1DM research has been on the timing of the introduction of a single antigen (i.e., milk or gluten), our data suggest multiple foods/antigens play a role and that there is a complex relationship between the timing and type of infant food exposures and T1DM risk. In summary, there appears to be a safe window in which to introduce solid foods between 4 and 5 months of age; solid foods should be introduced while continuing to breastfeed to minimize T1DM risk in genetically susceptible children," the investigators concluded.

This study was supported by a National Institutes of Health grant and a Diabetes Endocrine Research Center Clinical Investigation and Bioinformatics Core grant. The authors reported having no relevant financial disclosures.

Babies who are first exposed to solid food before the age of 4 months or at age 6 months or older are significantly more likely to develop type 1 diabetes mellitus than those with a first exposure at 4-5 months of age, findings from a longitudinal observational study have shown.

Of 1,835 children at increased genetic risk for type 1 diabetes mellitus (T1DM) who were included in the Diabetes Autoimmunity Study in the Young (DAISY), 53 developed the disease during follow-up. After adjustment for the human leukocyte antigen (HLA)-DR genotype, a first-degree relative with T1DM, maternal education, and delivery type, both the early and late first solid food exposures significantly predicted T1DM development (adjusted hazard ratios, 1.91 and 3.02, respectively), Brittni Frederiksen of the University of Colorado, Aurora, and her colleagues reported online on July 8 in JAMA Pediatrics.

Specifically, babies with early exposure to fruit and those with late exposure to rice/oat (non–gluten-containing foods) were at increased risk of T1DM development (HR, 2.23 and 2.88, respectively), the investigators found (JAMA Pediatr. July [doi:10.1001/jamapediatrics.2013.317]).

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Of note, babies who were still breastfeeding at the time of introduction to wheat/barley (gluten-containing food) had a significantly reduced risk of T1DM development (HR, 0.47), suggesting that breastfeeding confers some protection against the disease, they said.

The timing of the introduction of vegetables and meat did not predict T1DM in the DAISY cohort.

DAISY participants included two groups of children at increased genetic risk for developing T1DM – a group found to have diabetes-susceptibility alleles in the HLA region on cord blood screening, and a group of unaffected children with a first-degree relative with T1DM. Children included in the current analysis were those followed from birth, who completed clinic visits at 9, 15, and 24 months, and annually thereafter.

The findings, which support those from an earlier DAISY report demonstrating "a window of time for introduction of cereals, 4-6 months, outside of which the risk for development of islet autoimmunity (preclinical T1DM) increased." are important given the increasing worldwide incidence of T1DM. That increase is most rapid among children younger than age 5 years, the investigators noted.

As for the mechanisms of associations between early and late food exposures and T1DM development, the risk predicted by early exposure "might suggest a mechanism involving an abnormal immune response to solid food antigens in an immature gut immune system in susceptible individuals," and the increased risk predicted by late exposures "may be related to the larger amounts given at initial exposure to older children," the investigators said.

Also, the late introduction of solid foods, when breast milk no longer meets energy and nutrient needs, could lead to nutrient deficiencies that could increase T1DM risk. Similarly, late solid food exposures may be related to the cessation of breastfeeding before solid food introduction, resulting in the loss of the protective effects of breast milk in that setting, they suggested.

Although the findings require confirmation in a larger cohort, they provide some guidance for the introduction of solid foods.

"While much of the focus of infant diet and T1DM research has been on the timing of the introduction of a single antigen (i.e., milk or gluten), our data suggest multiple foods/antigens play a role and that there is a complex relationship between the timing and type of infant food exposures and T1DM risk. In summary, there appears to be a safe window in which to introduce solid foods between 4 and 5 months of age; solid foods should be introduced while continuing to breastfeed to minimize T1DM risk in genetically susceptible children," the investigators concluded.

This study was supported by a National Institutes of Health grant and a Diabetes Endocrine Research Center Clinical Investigation and Bioinformatics Core grant. The authors reported having no relevant financial disclosures.

Epstein-Barr virus-positive diffuse large B-cell lymphoma, or EBV+ DLBCL, represents only a small proportion of DLBCLs, and has an activated B-cell type immunophenotype and a unique gene expression profile and genetic signature that distinguish the neoplasm from EBV-negative DLBCL, according to a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

Further, CD30 expression is more common in EBV+ DLBCL than in EBV-negative DLBCL and confers an adverse outcome, Dr. Ken He Young reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

The findings are based on a study of 451 HIV-negative de novo DLBCL patients who had tissue microarrays from primary biopsy specimens available. All were uniformly treated with rituximab plus chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), said Dr. Young of the department of hematopathology at the University of Texas MD Anderson Cancer Center, Houston (Hematol. Oncol. 2013;31[(Suppl 1]:96-150[abstract 9]).

Of the 451 patients, 27 (6%) had positive EBV-encoded RNA (EBER) test results, defined as reactivity in more than 10% of malignant cells. The median age of the EBV+ and EBV- patients was similar at 61 and 64 years, respectively, as were the presenting clinical characteristics, Dr. Young noted.

However, an activated B-cell type signature occurred in 70% of EBV+ patients, compared with 48% or 49% (based on gene expression profiling and immunohistochemistry using the Visco-Young algorithm, respectively) in the EBV- patients, and CD30 expression occurred in 48% of EBV+ patients, compared with 15% of EBV- patients, he said.

No difference was seen in the expression of BCL2, MYC or both proteins between the EBV+ and EBV- groups, but the EBV+ patients had no detrimental TP53 mutation and only 18% presented rearrangements involving BCL2, C-MYC, or BCL6 genes.

Five-year overall survival appeared inferior in the EBV+ DLBCL patients at 50%, compared with 62% for the EBV- DLBCL patients, even after stratification by age, but the difference between the groups did not reach statistical significance. The same was true for progression-free survival, Dr. Young noted.

Among EBV+ DLBCL patients with CD30 expression, however, the prognosis was dismal, with median overall and progression-free survival of 37% and 35%, respectively, compared with 74% and 56%, respectively, in those with CD30 negative EBV+ DLBCL. These differences were statistically significant, Dr. Young said, adding that gene expression profiling revealed a unique expression signature in EBV+ DLBCL with NF-kB pathway activation.

In a separate report from the International DLBCL Rituximab-CHOP Consortium Program Study published online in May in Blood, Dr. Young and his colleagues explained that EBV+ DLBCL of the elderly, which was initially described 10 years ago, is a provisional entity within the World Health Organization classification system, and is defined as "an EBV-positive monoclonal large B-cell proliferation that occurs in patients greater than 50 years of age and in whom there is no known immunodeficiency or history of lymphoma," (2013;121: 2715-24 [doi:10.1182/blood-2012-10-461848]).

"It is hoped that the improved understanding of these tumors will lead to development of novel therapeutic approaches, enhance the effective clinical trials, and improve the prognosis," the investigators said.

Epstein-Barr virus-positive diffuse large B-cell lymphoma, or EBV+ DLBCL, represents only a small proportion of DLBCLs, and has an activated B-cell type immunophenotype and a unique gene expression profile and genetic signature that distinguish the neoplasm from EBV-negative DLBCL, according to a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

Further, CD30 expression is more common in EBV+ DLBCL than in EBV-negative DLBCL and confers an adverse outcome, Dr. Ken He Young reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

The findings are based on a study of 451 HIV-negative de novo DLBCL patients who had tissue microarrays from primary biopsy specimens available. All were uniformly treated with rituximab plus chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), said Dr. Young of the department of hematopathology at the University of Texas MD Anderson Cancer Center, Houston (Hematol. Oncol. 2013;31[(Suppl 1]:96-150[abstract 9]).

Of the 451 patients, 27 (6%) had positive EBV-encoded RNA (EBER) test results, defined as reactivity in more than 10% of malignant cells. The median age of the EBV+ and EBV- patients was similar at 61 and 64 years, respectively, as were the presenting clinical characteristics, Dr. Young noted.

However, an activated B-cell type signature occurred in 70% of EBV+ patients, compared with 48% or 49% (based on gene expression profiling and immunohistochemistry using the Visco-Young algorithm, respectively) in the EBV- patients, and CD30 expression occurred in 48% of EBV+ patients, compared with 15% of EBV- patients, he said.

No difference was seen in the expression of BCL2, MYC or both proteins between the EBV+ and EBV- groups, but the EBV+ patients had no detrimental TP53 mutation and only 18% presented rearrangements involving BCL2, C-MYC, or BCL6 genes.

Five-year overall survival appeared inferior in the EBV+ DLBCL patients at 50%, compared with 62% for the EBV- DLBCL patients, even after stratification by age, but the difference between the groups did not reach statistical significance. The same was true for progression-free survival, Dr. Young noted.

Among EBV+ DLBCL patients with CD30 expression, however, the prognosis was dismal, with median overall and progression-free survival of 37% and 35%, respectively, compared with 74% and 56%, respectively, in those with CD30 negative EBV+ DLBCL. These differences were statistically significant, Dr. Young said, adding that gene expression profiling revealed a unique expression signature in EBV+ DLBCL with NF-kB pathway activation.

In a separate report from the International DLBCL Rituximab-CHOP Consortium Program Study published online in May in Blood, Dr. Young and his colleagues explained that EBV+ DLBCL of the elderly, which was initially described 10 years ago, is a provisional entity within the World Health Organization classification system, and is defined as "an EBV-positive monoclonal large B-cell proliferation that occurs in patients greater than 50 years of age and in whom there is no known immunodeficiency or history of lymphoma," (2013;121: 2715-24 [doi:10.1182/blood-2012-10-461848]).

"It is hoped that the improved understanding of these tumors will lead to development of novel therapeutic approaches, enhance the effective clinical trials, and improve the prognosis," the investigators said.

Epstein-Barr virus-positive diffuse large B-cell lymphoma, or EBV+ DLBCL, represents only a small proportion of DLBCLs, and has an activated B-cell type immunophenotype and a unique gene expression profile and genetic signature that distinguish the neoplasm from EBV-negative DLBCL, according to a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

Further, CD30 expression is more common in EBV+ DLBCL than in EBV-negative DLBCL and confers an adverse outcome, Dr. Ken He Young reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

The findings are based on a study of 451 HIV-negative de novo DLBCL patients who had tissue microarrays from primary biopsy specimens available. All were uniformly treated with rituximab plus chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), said Dr. Young of the department of hematopathology at the University of Texas MD Anderson Cancer Center, Houston (Hematol. Oncol. 2013;31[(Suppl 1]:96-150[abstract 9]).

Of the 451 patients, 27 (6%) had positive EBV-encoded RNA (EBER) test results, defined as reactivity in more than 10% of malignant cells. The median age of the EBV+ and EBV- patients was similar at 61 and 64 years, respectively, as were the presenting clinical characteristics, Dr. Young noted.

However, an activated B-cell type signature occurred in 70% of EBV+ patients, compared with 48% or 49% (based on gene expression profiling and immunohistochemistry using the Visco-Young algorithm, respectively) in the EBV- patients, and CD30 expression occurred in 48% of EBV+ patients, compared with 15% of EBV- patients, he said.

No difference was seen in the expression of BCL2, MYC or both proteins between the EBV+ and EBV- groups, but the EBV+ patients had no detrimental TP53 mutation and only 18% presented rearrangements involving BCL2, C-MYC, or BCL6 genes.

Five-year overall survival appeared inferior in the EBV+ DLBCL patients at 50%, compared with 62% for the EBV- DLBCL patients, even after stratification by age, but the difference between the groups did not reach statistical significance. The same was true for progression-free survival, Dr. Young noted.

Among EBV+ DLBCL patients with CD30 expression, however, the prognosis was dismal, with median overall and progression-free survival of 37% and 35%, respectively, compared with 74% and 56%, respectively, in those with CD30 negative EBV+ DLBCL. These differences were statistically significant, Dr. Young said, adding that gene expression profiling revealed a unique expression signature in EBV+ DLBCL with NF-kB pathway activation.

In a separate report from the International DLBCL Rituximab-CHOP Consortium Program Study published online in May in Blood, Dr. Young and his colleagues explained that EBV+ DLBCL of the elderly, which was initially described 10 years ago, is a provisional entity within the World Health Organization classification system, and is defined as "an EBV-positive monoclonal large B-cell proliferation that occurs in patients greater than 50 years of age and in whom there is no known immunodeficiency or history of lymphoma," (2013;121: 2715-24 [doi:10.1182/blood-2012-10-461848]).

"It is hoped that the improved understanding of these tumors will lead to development of novel therapeutic approaches, enhance the effective clinical trials, and improve the prognosis," the investigators said.

Single-agent ibrutinib therapy was highly effective and well tolerated in 29 patients with chronic lymphocytic leukemia and deletion of part of the short arm of chromosome 17 (del 17p) who were part of a phase II study.

Treatment with the investigational selective Bruton’s tyrosine kinase inhibitor was associated with rapid control of disease in the nodes, spleen, marrow, and blood in both treatment-naive and relapsed/refractory patients, Dr. Adrian Wiestner reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

These findings are notable because patients with chronic lymphocytic leukemia (CLL) and del 17p typically have poor progression-free and overall survival when treated with standard chemoimmunotherapy, Dr. Wiestner said, adding that the potential role of ibrutinib for the treatment of these difficult-to-treat patients will be further investigated.

At a median follow-up of 9 months, 88% of 25 evaluable patients had a nodal response with a median 70% reduction in lymph node size, 48% had a partial response by International Workshop on CLL (IWCLL) criteria, and 40% had a partial response with lymphocytosis. One patient had progressive disease, said Dr. Wiestner of the National Heart, Lung, and Blood Institute, National Institutes of Health.

Of 15 treatment-naïve patients aged 33-82 years, 82% achieved a nodal response, and of 14 relapsed/refractory patients aged 56-79 years, 93% achieved a nodal response. The estimated 12-month event-free survival among the patients, who were the first in the study to reach 9-month median follow-up, was 90%, Dr. Wiestner said.

Also, 22 evaluable patients had a median 46% reduction in splenomegaly (median volume reduction of 446 mL), and tumor burden in bone marrow biopsies of 23 patients decreased by a median of 76% as assessed by immunohistochemistry for CD79a.

The percentage of tumor cells with del 17p decreased by a median of 55% in 15 patients, remained unchanged in 1 patient, and increased in 3 patients.

Treatment-naive patients included adults aged 33-82 years, and relapsed/refractory patients were adults aged 56-79 years. All were treated with 420 mg of oral ibrutinib daily until disease progression; treatment response was assessed every 6 months.

Ibrutinib, which has been granted multiple Breakthrough Therapy designations by the Food and Drug Administration – including a recent designation for the treatment of CLL or small lymphocytic lymphoma with del 17p – was well tolerated; 14% of patients experienced grade 3 or higher nonhematologic toxicities. Two deaths occurred among patients in the study, but were not deemed treatment related.

This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute.

Single-agent ibrutinib therapy was highly effective and well tolerated in 29 patients with chronic lymphocytic leukemia and deletion of part of the short arm of chromosome 17 (del 17p) who were part of a phase II study.

Treatment with the investigational selective Bruton’s tyrosine kinase inhibitor was associated with rapid control of disease in the nodes, spleen, marrow, and blood in both treatment-naive and relapsed/refractory patients, Dr. Adrian Wiestner reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

These findings are notable because patients with chronic lymphocytic leukemia (CLL) and del 17p typically have poor progression-free and overall survival when treated with standard chemoimmunotherapy, Dr. Wiestner said, adding that the potential role of ibrutinib for the treatment of these difficult-to-treat patients will be further investigated.

At a median follow-up of 9 months, 88% of 25 evaluable patients had a nodal response with a median 70% reduction in lymph node size, 48% had a partial response by International Workshop on CLL (IWCLL) criteria, and 40% had a partial response with lymphocytosis. One patient had progressive disease, said Dr. Wiestner of the National Heart, Lung, and Blood Institute, National Institutes of Health.

Of 15 treatment-naïve patients aged 33-82 years, 82% achieved a nodal response, and of 14 relapsed/refractory patients aged 56-79 years, 93% achieved a nodal response. The estimated 12-month event-free survival among the patients, who were the first in the study to reach 9-month median follow-up, was 90%, Dr. Wiestner said.

Also, 22 evaluable patients had a median 46% reduction in splenomegaly (median volume reduction of 446 mL), and tumor burden in bone marrow biopsies of 23 patients decreased by a median of 76% as assessed by immunohistochemistry for CD79a.

The percentage of tumor cells with del 17p decreased by a median of 55% in 15 patients, remained unchanged in 1 patient, and increased in 3 patients.

Treatment-naive patients included adults aged 33-82 years, and relapsed/refractory patients were adults aged 56-79 years. All were treated with 420 mg of oral ibrutinib daily until disease progression; treatment response was assessed every 6 months.

Ibrutinib, which has been granted multiple Breakthrough Therapy designations by the Food and Drug Administration – including a recent designation for the treatment of CLL or small lymphocytic lymphoma with del 17p – was well tolerated; 14% of patients experienced grade 3 or higher nonhematologic toxicities. Two deaths occurred among patients in the study, but were not deemed treatment related.

This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute.

Single-agent ibrutinib therapy was highly effective and well tolerated in 29 patients with chronic lymphocytic leukemia and deletion of part of the short arm of chromosome 17 (del 17p) who were part of a phase II study.

Treatment with the investigational selective Bruton’s tyrosine kinase inhibitor was associated with rapid control of disease in the nodes, spleen, marrow, and blood in both treatment-naive and relapsed/refractory patients, Dr. Adrian Wiestner reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

These findings are notable because patients with chronic lymphocytic leukemia (CLL) and del 17p typically have poor progression-free and overall survival when treated with standard chemoimmunotherapy, Dr. Wiestner said, adding that the potential role of ibrutinib for the treatment of these difficult-to-treat patients will be further investigated.

At a median follow-up of 9 months, 88% of 25 evaluable patients had a nodal response with a median 70% reduction in lymph node size, 48% had a partial response by International Workshop on CLL (IWCLL) criteria, and 40% had a partial response with lymphocytosis. One patient had progressive disease, said Dr. Wiestner of the National Heart, Lung, and Blood Institute, National Institutes of Health.

Of 15 treatment-naïve patients aged 33-82 years, 82% achieved a nodal response, and of 14 relapsed/refractory patients aged 56-79 years, 93% achieved a nodal response. The estimated 12-month event-free survival among the patients, who were the first in the study to reach 9-month median follow-up, was 90%, Dr. Wiestner said.

Also, 22 evaluable patients had a median 46% reduction in splenomegaly (median volume reduction of 446 mL), and tumor burden in bone marrow biopsies of 23 patients decreased by a median of 76% as assessed by immunohistochemistry for CD79a.

The percentage of tumor cells with del 17p decreased by a median of 55% in 15 patients, remained unchanged in 1 patient, and increased in 3 patients.

Treatment-naive patients included adults aged 33-82 years, and relapsed/refractory patients were adults aged 56-79 years. All were treated with 420 mg of oral ibrutinib daily until disease progression; treatment response was assessed every 6 months.

Ibrutinib, which has been granted multiple Breakthrough Therapy designations by the Food and Drug Administration – including a recent designation for the treatment of CLL or small lymphocytic lymphoma with del 17p – was well tolerated; 14% of patients experienced grade 3 or higher nonhematologic toxicities. Two deaths occurred among patients in the study, but were not deemed treatment related.

This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute.

Recovery and functional remission rates at 7 years following first-episode psychosis in patients treated using a dose-reduction/discontinuation strategy during the early stages of remission were more than double those in patients who received maintenance therapy in a randomized controlled trial.

The recovery rate was 40.4% in 52 patients who were randomly assigned to the dose reduction/discontinuation (DR) strategy after experiencing 6 months of remission, compared with 17.6% in 51 patients randomized to receive maintenance therapy for 18 months after 6 months of remission (odds ratio, 3.49). The functional remission rates were 46.2% and 19.6% in the two groups, respectively (OR, 4.62), Dr. Lex Wunderink of Friesland Mental Health Services, Leeuwarden, the Netherlands, and his colleagues reported. The results were published online July 3 in JAMA Psychiatry.

Symptomatic remission, at 69.2% and 66.7% in the groups, respectively, did not differ significantly (JAMA Psychiatry 2013 July 3 [doi: 10.1001/jamapsychiatry.2013.19]).

The findings, which are among the first to demonstrate major advantages of a dose reduction versus maintenance therapy strategy in patients with remission of first-episode psychosis, are also the first to look at long-term outcomes. Earlier studies demonstrated higher relapse rates and no advantages with DR, but those studies had follow-up of no more than 2 years, the investigators noted.

To evaluate the long-term outcome of an early-course DR strategy compared with maintenance therapy, they conducted this 7-year follow-up assessment of 103 out of 128 patients with first-episode psychosis who participated in one of the earlier trials with enrollment, at the start of their first remission, between October 2001 and December 2002.

Of note, time to first relapse during the experimental phase of the trial was about twice as high in the DR group initially, but "the curves then approached each other and came on par at approximately 3 years of follow-up. From then on, the findings were not significantly different," the investigators reported.

"The major issue is, of course, whether these striking results may be attributed to the treatment strategies in the original trial. There were no significant differences in any of the conceivable confounding variables between the two groups. Therefore, it seems likely that the original treatment strategy, be it dose reduction or maintenance therapy, has a profound effect on long-term outcome," they wrote, noting that the differences are largely the result of effects in the domains of functional remission and recovery.

The gains in functional capacity in the DR arm could be associated with the fact that successful discontinuation in the early course of first-episode psychosis was sustained for many years in almost all patients, who, on average, used a lower dose of antipsychotic drugs than did those in the maintenance therapy group.

The psychological impact of having been treated using a dose reduction strategy also might have played a role in the effects on functional capacity, but this was not measured, they said.

"The results of this study lead to the following conclusions: schizophrenia treatment strategy trials should include recovery or functional remission rates as their primary outcome and should also include long-term follow-up for more than 2 years, even up to 7 years or longer," the investigators said. The results "merit replication by other research groups," and underscore a need for also studying other alternative treatment strategies, such as extended-interval dosing strategies, they added.

This study was funded by unconditional grants from Janssen-Cilag Netherlands and Friesland Mental Health Services. The authors reported having no disclosures.

Recovery and functional remission rates at 7 years following first-episode psychosis in patients treated using a dose-reduction/discontinuation strategy during the early stages of remission were more than double those in patients who received maintenance therapy in a randomized controlled trial.

The recovery rate was 40.4% in 52 patients who were randomly assigned to the dose reduction/discontinuation (DR) strategy after experiencing 6 months of remission, compared with 17.6% in 51 patients randomized to receive maintenance therapy for 18 months after 6 months of remission (odds ratio, 3.49). The functional remission rates were 46.2% and 19.6% in the two groups, respectively (OR, 4.62), Dr. Lex Wunderink of Friesland Mental Health Services, Leeuwarden, the Netherlands, and his colleagues reported. The results were published online July 3 in JAMA Psychiatry.

Symptomatic remission, at 69.2% and 66.7% in the groups, respectively, did not differ significantly (JAMA Psychiatry 2013 July 3 [doi: 10.1001/jamapsychiatry.2013.19]).

The findings, which are among the first to demonstrate major advantages of a dose reduction versus maintenance therapy strategy in patients with remission of first-episode psychosis, are also the first to look at long-term outcomes. Earlier studies demonstrated higher relapse rates and no advantages with DR, but those studies had follow-up of no more than 2 years, the investigators noted.

To evaluate the long-term outcome of an early-course DR strategy compared with maintenance therapy, they conducted this 7-year follow-up assessment of 103 out of 128 patients with first-episode psychosis who participated in one of the earlier trials with enrollment, at the start of their first remission, between October 2001 and December 2002.

Of note, time to first relapse during the experimental phase of the trial was about twice as high in the DR group initially, but "the curves then approached each other and came on par at approximately 3 years of follow-up. From then on, the findings were not significantly different," the investigators reported.

"The major issue is, of course, whether these striking results may be attributed to the treatment strategies in the original trial. There were no significant differences in any of the conceivable confounding variables between the two groups. Therefore, it seems likely that the original treatment strategy, be it dose reduction or maintenance therapy, has a profound effect on long-term outcome," they wrote, noting that the differences are largely the result of effects in the domains of functional remission and recovery.

The gains in functional capacity in the DR arm could be associated with the fact that successful discontinuation in the early course of first-episode psychosis was sustained for many years in almost all patients, who, on average, used a lower dose of antipsychotic drugs than did those in the maintenance therapy group.

The psychological impact of having been treated using a dose reduction strategy also might have played a role in the effects on functional capacity, but this was not measured, they said.

"The results of this study lead to the following conclusions: schizophrenia treatment strategy trials should include recovery or functional remission rates as their primary outcome and should also include long-term follow-up for more than 2 years, even up to 7 years or longer," the investigators said. The results "merit replication by other research groups," and underscore a need for also studying other alternative treatment strategies, such as extended-interval dosing strategies, they added.

This study was funded by unconditional grants from Janssen-Cilag Netherlands and Friesland Mental Health Services. The authors reported having no disclosures.

Recovery and functional remission rates at 7 years following first-episode psychosis in patients treated using a dose-reduction/discontinuation strategy during the early stages of remission were more than double those in patients who received maintenance therapy in a randomized controlled trial.

The recovery rate was 40.4% in 52 patients who were randomly assigned to the dose reduction/discontinuation (DR) strategy after experiencing 6 months of remission, compared with 17.6% in 51 patients randomized to receive maintenance therapy for 18 months after 6 months of remission (odds ratio, 3.49). The functional remission rates were 46.2% and 19.6% in the two groups, respectively (OR, 4.62), Dr. Lex Wunderink of Friesland Mental Health Services, Leeuwarden, the Netherlands, and his colleagues reported. The results were published online July 3 in JAMA Psychiatry.

Symptomatic remission, at 69.2% and 66.7% in the groups, respectively, did not differ significantly (JAMA Psychiatry 2013 July 3 [doi: 10.1001/jamapsychiatry.2013.19]).

The findings, which are among the first to demonstrate major advantages of a dose reduction versus maintenance therapy strategy in patients with remission of first-episode psychosis, are also the first to look at long-term outcomes. Earlier studies demonstrated higher relapse rates and no advantages with DR, but those studies had follow-up of no more than 2 years, the investigators noted.

To evaluate the long-term outcome of an early-course DR strategy compared with maintenance therapy, they conducted this 7-year follow-up assessment of 103 out of 128 patients with first-episode psychosis who participated in one of the earlier trials with enrollment, at the start of their first remission, between October 2001 and December 2002.

Of note, time to first relapse during the experimental phase of the trial was about twice as high in the DR group initially, but "the curves then approached each other and came on par at approximately 3 years of follow-up. From then on, the findings were not significantly different," the investigators reported.

"The major issue is, of course, whether these striking results may be attributed to the treatment strategies in the original trial. There were no significant differences in any of the conceivable confounding variables between the two groups. Therefore, it seems likely that the original treatment strategy, be it dose reduction or maintenance therapy, has a profound effect on long-term outcome," they wrote, noting that the differences are largely the result of effects in the domains of functional remission and recovery.

The gains in functional capacity in the DR arm could be associated with the fact that successful discontinuation in the early course of first-episode psychosis was sustained for many years in almost all patients, who, on average, used a lower dose of antipsychotic drugs than did those in the maintenance therapy group.

The psychological impact of having been treated using a dose reduction strategy also might have played a role in the effects on functional capacity, but this was not measured, they said.

"The results of this study lead to the following conclusions: schizophrenia treatment strategy trials should include recovery or functional remission rates as their primary outcome and should also include long-term follow-up for more than 2 years, even up to 7 years or longer," the investigators said. The results "merit replication by other research groups," and underscore a need for also studying other alternative treatment strategies, such as extended-interval dosing strategies, they added.

This study was funded by unconditional grants from Janssen-Cilag Netherlands and Friesland Mental Health Services. The authors reported having no disclosures.

Patients who have mucosa-associated lymphoid tissue lymphoma and are treated with chlorambucil plus rituximab have better event-free survival and progression-free survival than do comparable patients treated with either drug alone, according to findings from a randomized phase III study.

In the International Extranodal Lymphoma Study Group study (IELSG-19), 5-year event-free survival was 70% in 131 patients treated with the combination therapy, 52% in 130 patients treated with chlorambucil alone, and 51% in 132 patients treated with rituximab alone. Progression-free survival also was significantly improved in the combination therapy arm compared with the two single-agent arms, Dr. Emanuele Zucca reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

Overall survival at 5 years, however, was similar at about 90% for all three treatment arms, according to Dr. Zucca of the Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona.

Hematologic toxicity was more pronounced in the combination therapy arm than in the single-agent arms, but there were no unexpected severe side effects, Dr. Zucca reported.

IELSG-19 is the largest randomized study to date in MALT lymphoma, and is the first to compare combination chlorambucil and rituximab with both agents alone, he said.

The primary lymphoma site was the stomach in 43% of the393 study participants, and 34% had lymph node involvement. The international prognostic index score was low or low-intermediate in 81%. Just 8% of the patients had prior local therapy, Dr. Zucca said.

Study participants were adults with disseminated extranodal marginal zone B-cell lymphoma or localized disease not amenable to local therapy. Those randomized to the chlorambucil therapy arm received 6 mg/m² of oral chlorambucil daily for 6 weeks, and those who responded or who had stable disease received the same dose daily for 14 consecutive days every 28 days for four cycles. Those in the combination therapy arm received the chlorambucil dosing, plus 375 mg/m² of rituximab intravenously on days 1, 8, 15, 22, 56, 84, 112, and 140. Those in the rituximab-only group received the same rituximab dosing without chlorambucil.

In a published report of the outcomes in patients enrolled in the first two protocol arms (combination therapy and chlorambucil-only therapy), Dr. Zucca and his colleagues noted that survival rates in patients with MALT lymphoma are typically high. The significant differences in event-free survival have not yet translated into improved overall survival (J. Clin. Oncol 2013 Jan. 7 [doi:10.1200/JCO.2011.40.6272]).

Nonetheless, the findings – among the first to demonstrate the activity of chlorambucil with and without rituximab in MALT lymphoma – suggest the combination is a safe and effective approach that could improve outcomes, Dr. Zucca said.

The findings he presented expand upon the initial published analysis by including data from the rituximab-only arm, which was added following a more-rapid-than-expected initial recruitment into the combination and chlorambucil-only arms.

These findings are of note, because aside from H. pylori eradication for localized gastric disease, no consensus exists on the standard therapy for MALT lymphoma, he said.

Several study authors reported serving as consultants for or receiving honoraria from Roche International, which sponsored the IELSG-19 study.

Patients who have mucosa-associated lymphoid tissue lymphoma and are treated with chlorambucil plus rituximab have better event-free survival and progression-free survival than do comparable patients treated with either drug alone, according to findings from a randomized phase III study.

In the International Extranodal Lymphoma Study Group study (IELSG-19), 5-year event-free survival was 70% in 131 patients treated with the combination therapy, 52% in 130 patients treated with chlorambucil alone, and 51% in 132 patients treated with rituximab alone. Progression-free survival also was significantly improved in the combination therapy arm compared with the two single-agent arms, Dr. Emanuele Zucca reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

Overall survival at 5 years, however, was similar at about 90% for all three treatment arms, according to Dr. Zucca of the Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona.

Hematologic toxicity was more pronounced in the combination therapy arm than in the single-agent arms, but there were no unexpected severe side effects, Dr. Zucca reported.

IELSG-19 is the largest randomized study to date in MALT lymphoma, and is the first to compare combination chlorambucil and rituximab with both agents alone, he said.

The primary lymphoma site was the stomach in 43% of the393 study participants, and 34% had lymph node involvement. The international prognostic index score was low or low-intermediate in 81%. Just 8% of the patients had prior local therapy, Dr. Zucca said.

Study participants were adults with disseminated extranodal marginal zone B-cell lymphoma or localized disease not amenable to local therapy. Those randomized to the chlorambucil therapy arm received 6 mg/m² of oral chlorambucil daily for 6 weeks, and those who responded or who had stable disease received the same dose daily for 14 consecutive days every 28 days for four cycles. Those in the combination therapy arm received the chlorambucil dosing, plus 375 mg/m² of rituximab intravenously on days 1, 8, 15, 22, 56, 84, 112, and 140. Those in the rituximab-only group received the same rituximab dosing without chlorambucil.

In a published report of the outcomes in patients enrolled in the first two protocol arms (combination therapy and chlorambucil-only therapy), Dr. Zucca and his colleagues noted that survival rates in patients with MALT lymphoma are typically high. The significant differences in event-free survival have not yet translated into improved overall survival (J. Clin. Oncol 2013 Jan. 7 [doi:10.1200/JCO.2011.40.6272]).

Nonetheless, the findings – among the first to demonstrate the activity of chlorambucil with and without rituximab in MALT lymphoma – suggest the combination is a safe and effective approach that could improve outcomes, Dr. Zucca said.

The findings he presented expand upon the initial published analysis by including data from the rituximab-only arm, which was added following a more-rapid-than-expected initial recruitment into the combination and chlorambucil-only arms.

These findings are of note, because aside from H. pylori eradication for localized gastric disease, no consensus exists on the standard therapy for MALT lymphoma, he said.

Several study authors reported serving as consultants for or receiving honoraria from Roche International, which sponsored the IELSG-19 study.

Patients who have mucosa-associated lymphoid tissue lymphoma and are treated with chlorambucil plus rituximab have better event-free survival and progression-free survival than do comparable patients treated with either drug alone, according to findings from a randomized phase III study.

In the International Extranodal Lymphoma Study Group study (IELSG-19), 5-year event-free survival was 70% in 131 patients treated with the combination therapy, 52% in 130 patients treated with chlorambucil alone, and 51% in 132 patients treated with rituximab alone. Progression-free survival also was significantly improved in the combination therapy arm compared with the two single-agent arms, Dr. Emanuele Zucca reported at the annual International Conference on Malignant Lymphoma in Lugano, Switzerland.

Overall survival at 5 years, however, was similar at about 90% for all three treatment arms, according to Dr. Zucca of the Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona.

Hematologic toxicity was more pronounced in the combination therapy arm than in the single-agent arms, but there were no unexpected severe side effects, Dr. Zucca reported.

IELSG-19 is the largest randomized study to date in MALT lymphoma, and is the first to compare combination chlorambucil and rituximab with both agents alone, he said.

The primary lymphoma site was the stomach in 43% of the393 study participants, and 34% had lymph node involvement. The international prognostic index score was low or low-intermediate in 81%. Just 8% of the patients had prior local therapy, Dr. Zucca said.

Study participants were adults with disseminated extranodal marginal zone B-cell lymphoma or localized disease not amenable to local therapy. Those randomized to the chlorambucil therapy arm received 6 mg/m² of oral chlorambucil daily for 6 weeks, and those who responded or who had stable disease received the same dose daily for 14 consecutive days every 28 days for four cycles. Those in the combination therapy arm received the chlorambucil dosing, plus 375 mg/m² of rituximab intravenously on days 1, 8, 15, 22, 56, 84, 112, and 140. Those in the rituximab-only group received the same rituximab dosing without chlorambucil.

In a published report of the outcomes in patients enrolled in the first two protocol arms (combination therapy and chlorambucil-only therapy), Dr. Zucca and his colleagues noted that survival rates in patients with MALT lymphoma are typically high. The significant differences in event-free survival have not yet translated into improved overall survival (J. Clin. Oncol 2013 Jan. 7 [doi:10.1200/JCO.2011.40.6272]).

Nonetheless, the findings – among the first to demonstrate the activity of chlorambucil with and without rituximab in MALT lymphoma – suggest the combination is a safe and effective approach that could improve outcomes, Dr. Zucca said.

The findings he presented expand upon the initial published analysis by including data from the rituximab-only arm, which was added following a more-rapid-than-expected initial recruitment into the combination and chlorambucil-only arms.

These findings are of note, because aside from H. pylori eradication for localized gastric disease, no consensus exists on the standard therapy for MALT lymphoma, he said.

Several study authors reported serving as consultants for or receiving honoraria from Roche International, which sponsored the IELSG-19 study.

The U.S. Preventive Services Task Force now recommends routine hepatitis C virus screening for individuals at high risk, and one-time screening for adults born between 1945 and 1965.

The recommendation marks a change from 2004 when the U.S. Preventive Services Task Force (USPSTF) recommended against screening in adults not at increased risk, and found insufficient evidence for screening those at high risk. The update, published online June 25 in Annals of Internal Medicine, comes on the heels of a similar recommendation May 10 from the Centers for Disease Control and Prevention (MMWR 2013;62[18]:357-61).

Both the USPSTF and the CDC cite recent evidence that indicates increased HCV risk among baby boomers, as well as substantial evidence of improved outcomes with treatment, and both note that screening could have important public health implications (Ann. Intern. Med. 2013 June 25 [doi:10.7326/0003-4819-159-5-201309030-00672]).

Courtesy US. Dept of Veterans Affairs

"Baby boomers account for three out of four people with hepatitis C," according to Dr. Albert Siu of the USPSTF and the Mount Sinai School of Medicine, New York. "Many people in this age group contracted hepatitis C from a blood transfusion or unknown or unreported high-risk behaviors."

Although many of these adults may be asymptomatic, the evidence is convincing that one-time screening could identify millions who are infected before they develop serious liver disease, Dr. Siu noted in a statement.

The prevalence of HCV infection peaked in 2001 at 3.6 million persons, and the yearly incidence has declined from more than 200,000 cases in the 1980s to 16,000 in 2009.

However, the overrepresentation of those born between 1945 and 1965 among the infected population is concerning, and it may be associated with blood transfusions received before the introduction of screening in 1992. A history of other risk factors for exposure decades earlier could also account for the disease burden in this population, according to the USPSTF report.

Of note, many adults in this age group are unaware of their infection.

"A risk-based approach may miss detection of a substantial proportion of the HCV-infected persons in the birth cohort because of a lack of patient disclosure or knowledge about prior risk status," according to the USPSTF report. "As a result, one-time screening for HCV infection in the birth cohort may identify infected patients at earlier stages of disease who could benefit from treatment before developing complications from liver damage."

HCV infection is the leading cause of complications from chronic liver disease. In fact, HCV-related end-stage liver disease is the most common indication for liver transplants among U.S. adults, accounting for more than 30% of cases.

"Studies suggest that about one-half of the recently observed threefold increase in incidence of hepatocellular carcinoma is related to acquisition of HCV infection 2-4 decades earlier," according to the task force report.

The USPSTF concluded that the benefit of screening baby boomers is likely similar to the benefit of screening those at high risk and outweighs any risks of harm, such as the possibility of overtreatment.

The task force also concluded that although birth cohort screening is likely less efficient than risk-based screening, birth cohort screening will likely benefit a greater number of individuals overall. In fact, birth cohort screening provides nearly twice the benefit of risk-based screening, according to a modeling study reviewed by the USPSTF.

The task force concluded with moderate certainty that screening in both the high-risk and baby boomer populations is of moderate net benefit.

Baby boomers not at otherwise increased risk need to be screened only once. Adults at any age who are at increased risk of HCV because of injection drug use should be screened periodically. The USPSTF found no evidence for a specific recommendation regarding screening frequency.

The task force’s recommendations, as well as a fact sheet explaining the recommendation statement, can be viewed here.

The U.S. Preventive Services Task Force now recommends routine hepatitis C virus screening for individuals at high risk, and one-time screening for adults born between 1945 and 1965.

The recommendation marks a change from 2004 when the U.S. Preventive Services Task Force (USPSTF) recommended against screening in adults not at increased risk, and found insufficient evidence for screening those at high risk. The update, published online June 25 in Annals of Internal Medicine, comes on the heels of a similar recommendation May 10 from the Centers for Disease Control and Prevention (MMWR 2013;62[18]:357-61).

Both the USPSTF and the CDC cite recent evidence that indicates increased HCV risk among baby boomers, as well as substantial evidence of improved outcomes with treatment, and both note that screening could have important public health implications (Ann. Intern. Med. 2013 June 25 [doi:10.7326/0003-4819-159-5-201309030-00672]).

Courtesy US. Dept of Veterans Affairs

"Baby boomers account for three out of four people with hepatitis C," according to Dr. Albert Siu of the USPSTF and the Mount Sinai School of Medicine, New York. "Many people in this age group contracted hepatitis C from a blood transfusion or unknown or unreported high-risk behaviors."

Although many of these adults may be asymptomatic, the evidence is convincing that one-time screening could identify millions who are infected before they develop serious liver disease, Dr. Siu noted in a statement.

The prevalence of HCV infection peaked in 2001 at 3.6 million persons, and the yearly incidence has declined from more than 200,000 cases in the 1980s to 16,000 in 2009.

However, the overrepresentation of those born between 1945 and 1965 among the infected population is concerning, and it may be associated with blood transfusions received before the introduction of screening in 1992. A history of other risk factors for exposure decades earlier could also account for the disease burden in this population, according to the USPSTF report.

Of note, many adults in this age group are unaware of their infection.

"A risk-based approach may miss detection of a substantial proportion of the HCV-infected persons in the birth cohort because of a lack of patient disclosure or knowledge about prior risk status," according to the USPSTF report. "As a result, one-time screening for HCV infection in the birth cohort may identify infected patients at earlier stages of disease who could benefit from treatment before developing complications from liver damage."

HCV infection is the leading cause of complications from chronic liver disease. In fact, HCV-related end-stage liver disease is the most common indication for liver transplants among U.S. adults, accounting for more than 30% of cases.

"Studies suggest that about one-half of the recently observed threefold increase in incidence of hepatocellular carcinoma is related to acquisition of HCV infection 2-4 decades earlier," according to the task force report.

The USPSTF concluded that the benefit of screening baby boomers is likely similar to the benefit of screening those at high risk and outweighs any risks of harm, such as the possibility of overtreatment.

The task force also concluded that although birth cohort screening is likely less efficient than risk-based screening, birth cohort screening will likely benefit a greater number of individuals overall. In fact, birth cohort screening provides nearly twice the benefit of risk-based screening, according to a modeling study reviewed by the USPSTF.

The task force concluded with moderate certainty that screening in both the high-risk and baby boomer populations is of moderate net benefit.

Baby boomers not at otherwise increased risk need to be screened only once. Adults at any age who are at increased risk of HCV because of injection drug use should be screened periodically. The USPSTF found no evidence for a specific recommendation regarding screening frequency.

The task force’s recommendations, as well as a fact sheet explaining the recommendation statement, can be viewed here.

The U.S. Preventive Services Task Force now recommends routine hepatitis C virus screening for individuals at high risk, and one-time screening for adults born between 1945 and 1965.

The recommendation marks a change from 2004 when the U.S. Preventive Services Task Force (USPSTF) recommended against screening in adults not at increased risk, and found insufficient evidence for screening those at high risk. The update, published online June 25 in Annals of Internal Medicine, comes on the heels of a similar recommendation May 10 from the Centers for Disease Control and Prevention (MMWR 2013;62[18]:357-61).

Both the USPSTF and the CDC cite recent evidence that indicates increased HCV risk among baby boomers, as well as substantial evidence of improved outcomes with treatment, and both note that screening could have important public health implications (Ann. Intern. Med. 2013 June 25 [doi:10.7326/0003-4819-159-5-201309030-00672]).

Courtesy US. Dept of Veterans Affairs

"Baby boomers account for three out of four people with hepatitis C," according to Dr. Albert Siu of the USPSTF and the Mount Sinai School of Medicine, New York. "Many people in this age group contracted hepatitis C from a blood transfusion or unknown or unreported high-risk behaviors."

Although many of these adults may be asymptomatic, the evidence is convincing that one-time screening could identify millions who are infected before they develop serious liver disease, Dr. Siu noted in a statement.

The prevalence of HCV infection peaked in 2001 at 3.6 million persons, and the yearly incidence has declined from more than 200,000 cases in the 1980s to 16,000 in 2009.

However, the overrepresentation of those born between 1945 and 1965 among the infected population is concerning, and it may be associated with blood transfusions received before the introduction of screening in 1992. A history of other risk factors for exposure decades earlier could also account for the disease burden in this population, according to the USPSTF report.

Of note, many adults in this age group are unaware of their infection.

"A risk-based approach may miss detection of a substantial proportion of the HCV-infected persons in the birth cohort because of a lack of patient disclosure or knowledge about prior risk status," according to the USPSTF report. "As a result, one-time screening for HCV infection in the birth cohort may identify infected patients at earlier stages of disease who could benefit from treatment before developing complications from liver damage."

HCV infection is the leading cause of complications from chronic liver disease. In fact, HCV-related end-stage liver disease is the most common indication for liver transplants among U.S. adults, accounting for more than 30% of cases.

"Studies suggest that about one-half of the recently observed threefold increase in incidence of hepatocellular carcinoma is related to acquisition of HCV infection 2-4 decades earlier," according to the task force report.

The USPSTF concluded that the benefit of screening baby boomers is likely similar to the benefit of screening those at high risk and outweighs any risks of harm, such as the possibility of overtreatment.

The task force also concluded that although birth cohort screening is likely less efficient than risk-based screening, birth cohort screening will likely benefit a greater number of individuals overall. In fact, birth cohort screening provides nearly twice the benefit of risk-based screening, according to a modeling study reviewed by the USPSTF.

The task force concluded with moderate certainty that screening in both the high-risk and baby boomer populations is of moderate net benefit.

Baby boomers not at otherwise increased risk need to be screened only once. Adults at any age who are at increased risk of HCV because of injection drug use should be screened periodically. The USPSTF found no evidence for a specific recommendation regarding screening frequency.

The task force’s recommendations, as well as a fact sheet explaining the recommendation statement, can be viewed here.

Only a month after requiring a restrictive new-drug permit to treat Clostridium difficile infection with fecal transplants, the Food and Drug Administration has changed course.

Citing public pressure, the agency announced June 17 that it "intends to exercise enforcement discretion" regarding the investigational new drug (IND) requirements while the agency develops appropriate policies for the use of fecal microbiota for transplantation (FMT) products under IND.

The change applies only to those using FMT to treat C. difficile infection that fails to respond to standard therapy. Those using FMT for other indications or for research purposes must abide by the IND requirements.

The FDA first announced the biologic designation following a 2-day public workshop in May, stating that the intent of the IND requirement was to ensure safe, effective, and data-driven use of FMT, which is used primarily to treat recurrent C. difficile infection.

"During that workshop, and in subsequent communications, physicians and scientists have expressed concern to FDA that FMT is not appropriate for study under FDA’s investigational new drug application regulations," the latest FDA statement noted. "Some health care providers have stated that applying IND requirements will make FMT unavailable and have suggested that an alternative regulatory approach is needed to ensure the widespread availability of FMT for individuals with C. difficile infection unresponsive to standard therapies."

Treating physicians are strongly encouraged to comply with the IND regulation and must continue to obtain informed consent for the use of FMT products, including, at minimum, information about the investigational status of the products and a discussion of the potential risks associated with their use.

Guidance will be issued regarding the agency’s intentions with respect to "exercising enforcement discretion," according to the FDA statement.

"A lot of people were upset about the IND requirement because it was a barrier to the most effective treatment available for C. difficile infection," Dr. David T. Rubin said in an interview.

Although Dr. Rubin’s area of focus is ulcerative colitis – he developed a protocol for using FMT in that disease and last month obtained an IND permit for a phase I study of its safety and feasibility in ulcerative colitis patients – he explained that C. difficile infection is the condition for which the most data exist.

People who have suffered for years are experiencing significant improvement and even cure with this treatment, said Dr. Rubin, professor of medicine and codirector of the inflammatory bowel disease center at the University of Chicago.

"C. difficile is where it seems to have its best efficacy, and it looks very safe," he said. "Even one dose of the treatment has a greater than 90% success rate."

Because obtaining an IND permit is a rigorous process – it took Dr. Rubin 2 years to obtain his permit – those using FMT for their patients were understandably concerned that patient access to treatment would be hampered. It’s one thing for a pharmaceutical company making an investment in a future salable product to jump through those kind of hoops, he explained, but it’s another entirely for a private physician who wants to offer patients the best available treatment.

The FDA’s decision is one that considers the importance of FMT for the treatment of patients with recurrent C. difficile infection while at the same time working to ensure patient safety and promote high-quality research, he said.

"There is still a whole lot we don’t know about FMT," he added.

Dr. Rubin had no relevant financial disclosures.

Only a month after requiring a restrictive new-drug permit to treat Clostridium difficile infection with fecal transplants, the Food and Drug Administration has changed course.

Citing public pressure, the agency announced June 17 that it "intends to exercise enforcement discretion" regarding the investigational new drug (IND) requirements while the agency develops appropriate policies for the use of fecal microbiota for transplantation (FMT) products under IND.

The change applies only to those using FMT to treat C. difficile infection that fails to respond to standard therapy. Those using FMT for other indications or for research purposes must abide by the IND requirements.

The FDA first announced the biologic designation following a 2-day public workshop in May, stating that the intent of the IND requirement was to ensure safe, effective, and data-driven use of FMT, which is used primarily to treat recurrent C. difficile infection.

"During that workshop, and in subsequent communications, physicians and scientists have expressed concern to FDA that FMT is not appropriate for study under FDA’s investigational new drug application regulations," the latest FDA statement noted. "Some health care providers have stated that applying IND requirements will make FMT unavailable and have suggested that an alternative regulatory approach is needed to ensure the widespread availability of FMT for individuals with C. difficile infection unresponsive to standard therapies."

Treating physicians are strongly encouraged to comply with the IND regulation and must continue to obtain informed consent for the use of FMT products, including, at minimum, information about the investigational status of the products and a discussion of the potential risks associated with their use.

Guidance will be issued regarding the agency’s intentions with respect to "exercising enforcement discretion," according to the FDA statement.

"A lot of people were upset about the IND requirement because it was a barrier to the most effective treatment available for C. difficile infection," Dr. David T. Rubin said in an interview.

Although Dr. Rubin’s area of focus is ulcerative colitis – he developed a protocol for using FMT in that disease and last month obtained an IND permit for a phase I study of its safety and feasibility in ulcerative colitis patients – he explained that C. difficile infection is the condition for which the most data exist.

People who have suffered for years are experiencing significant improvement and even cure with this treatment, said Dr. Rubin, professor of medicine and codirector of the inflammatory bowel disease center at the University of Chicago.

"C. difficile is where it seems to have its best efficacy, and it looks very safe," he said. "Even one dose of the treatment has a greater than 90% success rate."

Because obtaining an IND permit is a rigorous process – it took Dr. Rubin 2 years to obtain his permit – those using FMT for their patients were understandably concerned that patient access to treatment would be hampered. It’s one thing for a pharmaceutical company making an investment in a future salable product to jump through those kind of hoops, he explained, but it’s another entirely for a private physician who wants to offer patients the best available treatment.

The FDA’s decision is one that considers the importance of FMT for the treatment of patients with recurrent C. difficile infection while at the same time working to ensure patient safety and promote high-quality research, he said.

"There is still a whole lot we don’t know about FMT," he added.

Dr. Rubin had no relevant financial disclosures.

Only a month after requiring a restrictive new-drug permit to treat Clostridium difficile infection with fecal transplants, the Food and Drug Administration has changed course.

Citing public pressure, the agency announced June 17 that it "intends to exercise enforcement discretion" regarding the investigational new drug (IND) requirements while the agency develops appropriate policies for the use of fecal microbiota for transplantation (FMT) products under IND.

The change applies only to those using FMT to treat C. difficile infection that fails to respond to standard therapy. Those using FMT for other indications or for research purposes must abide by the IND requirements.

The FDA first announced the biologic designation following a 2-day public workshop in May, stating that the intent of the IND requirement was to ensure safe, effective, and data-driven use of FMT, which is used primarily to treat recurrent C. difficile infection.

"During that workshop, and in subsequent communications, physicians and scientists have expressed concern to FDA that FMT is not appropriate for study under FDA’s investigational new drug application regulations," the latest FDA statement noted. "Some health care providers have stated that applying IND requirements will make FMT unavailable and have suggested that an alternative regulatory approach is needed to ensure the widespread availability of FMT for individuals with C. difficile infection unresponsive to standard therapies."

Treating physicians are strongly encouraged to comply with the IND regulation and must continue to obtain informed consent for the use of FMT products, including, at minimum, information about the investigational status of the products and a discussion of the potential risks associated with their use.

Guidance will be issued regarding the agency’s intentions with respect to "exercising enforcement discretion," according to the FDA statement.

"A lot of people were upset about the IND requirement because it was a barrier to the most effective treatment available for C. difficile infection," Dr. David T. Rubin said in an interview.

Although Dr. Rubin’s area of focus is ulcerative colitis – he developed a protocol for using FMT in that disease and last month obtained an IND permit for a phase I study of its safety and feasibility in ulcerative colitis patients – he explained that C. difficile infection is the condition for which the most data exist.

People who have suffered for years are experiencing significant improvement and even cure with this treatment, said Dr. Rubin, professor of medicine and codirector of the inflammatory bowel disease center at the University of Chicago.

"C. difficile is where it seems to have its best efficacy, and it looks very safe," he said. "Even one dose of the treatment has a greater than 90% success rate."

Because obtaining an IND permit is a rigorous process – it took Dr. Rubin 2 years to obtain his permit – those using FMT for their patients were understandably concerned that patient access to treatment would be hampered. It’s one thing for a pharmaceutical company making an investment in a future salable product to jump through those kind of hoops, he explained, but it’s another entirely for a private physician who wants to offer patients the best available treatment.

The FDA’s decision is one that considers the importance of FMT for the treatment of patients with recurrent C. difficile infection while at the same time working to ensure patient safety and promote high-quality research, he said.

"There is still a whole lot we don’t know about FMT," he added.

Dr. Rubin had no relevant financial disclosures.

ORLANDO – Thromboprophylaxis for 3 weeks after discharge following abdominal surgery is more cost effective than is inpatient thromboprophylaxis alone, given certain base case assumptions, according to a decision tree analysis.

The findings, which incorporate both cost- and patient-related factors, provide clarity for clinicians about when extended duration thromboprophylaxis is appropriate, Dr. James C. Iannuzzi said at the annual Digestive Disease Week.

The analysis indicates that extended-duration thromboprophylaxis with low-molecular-weight heparin for 3 weeks after discharge is preferable to 7 days of inpatient-only thromboprophylaxis in cases where venous thromboembolism (VTE) risk is estimated at 0.88% to 2.39%; patient preferences regarding costs and medication administration, including the need for self-administered injection of low-molecular-weight heparin (LMWH), should be considered in these cases, said Dr. Iannuzzi of surgical health outcomes and research enterprise at the University of Rochester (N.Y.) Medical Center.

Extended-duration thromboprophylaxis dominates in cases in which the estimated VTE risk exceeds 2.39%, he said.

"Current guidelines are inconsistent about what metrics should be used, which makes it difficult for providers to decide whether extended-duration thromboprophylaxis would be beneficial. This likely plays a significant role in the current lack of adherence to guidelines," he said in an interview, adding. "This study was really aimed at providing clinicians a better cut-off for when it should be used, incorporating both the cost and patient perspective."

To assess cost effectiveness of thromboprophylaxis, Dr. Iannuzzi and his colleagues compared extended-duration treatment for 21 days after discharge (following 7 days of inpatient prophylaxis) with inpatient prophylaxis alone in a hypothetical case involving abdominal oncologic resection without complications in an otherwise healthy 45-year-old male patient.

Willingness to pay was set at $50,000 per quality-adjusted life-year (QALY), and the probabilities of various factors and scenarios were determined based on the available literature – much of it coming from the orthopedic literature. Costs were in U.S. 2013 dollars adjusted using the consumer price index; effectiveness was based on QALY (utility considered over 1 year), and cost effectiveness was evaluated using an incremental cost-effectiveness ratio, Dr. Iannuzzi explained.

Sensitivity analyses were performed to assess uncertainty within the model, with particular interest in the threshold for cost effectiveness based on VTE incidence, he said.

The endpoints were pulmonary embolism or deep vein thrombosis with attendant costs and assigned effectiveness evaluated by QALY, he said.

Based on the predetermined probabilities, and assuming an annualized cost of $23,248 for pulmonary embolism, $21,540 for deep vein thrombosis, $14,363 for post-thrombotic syndrome, $706 for generic LMWH, and $872 for brand-name LMWH, the threshold for the relative cost effectiveness of extended-duration thromboprophylaxis was VTE probability of 1.65% for brand-name LMWH, and 0.88% for generic LMWH.

"The 0.88% threshold is near the range of most major abdominal surgeries, which highlights the importance of using extended-duration thromboprophylaxis. However, the model was sensitive to changes in medication costs and patient values until postdischarge VTE risk exceeded 2.4%," Dr. Iannuzzi explained, adding that the model sensitivity in the 0.88% to 2.39% range is the reason why it is important to consider the patient perspective and the availability of generic LWMH in such cases.

He and his colleagues recently developed a risk score to help with postdischarge VTE prediction and to guide decision-making. The risk score, published online in May in the Journal of Vascular Surgery (J. Vasc. Surg. 2013 [doi:10.106/j.jvs.2012.12.073]), considers patient, operative, and early outcome factors to identify patients at increased risk.

The current findings, which pave the way for patient-centered decision making, use cost effectiveness of extended-duration thromboprophylaxis as a measure for risk, and should inform future guidelines’ definition of high risk. They also suggest that while a blanket approach to prophylaxis is not warranted, payers should cover the cost of extended-duration treatment.

"When cost was analyzed alone – without taking patient discomfort and the burden of self-injections into account, the threshold for cost effectiveness was much lower, suggesting that from the payer perspective, significant cost savings would be derived by increasing extended-duration thromboprophylaxis use," he explained.

Dr. Iannuzzi reported having no disclosures.

ORLANDO – Thromboprophylaxis for 3 weeks after discharge following abdominal surgery is more cost effective than is inpatient thromboprophylaxis alone, given certain base case assumptions, according to a decision tree analysis.

The findings, which incorporate both cost- and patient-related factors, provide clarity for clinicians about when extended duration thromboprophylaxis is appropriate, Dr. James C. Iannuzzi said at the annual Digestive Disease Week.

The analysis indicates that extended-duration thromboprophylaxis with low-molecular-weight heparin for 3 weeks after discharge is preferable to 7 days of inpatient-only thromboprophylaxis in cases where venous thromboembolism (VTE) risk is estimated at 0.88% to 2.39%; patient preferences regarding costs and medication administration, including the need for self-administered injection of low-molecular-weight heparin (LMWH), should be considered in these cases, said Dr. Iannuzzi of surgical health outcomes and research enterprise at the University of Rochester (N.Y.) Medical Center.

Extended-duration thromboprophylaxis dominates in cases in which the estimated VTE risk exceeds 2.39%, he said.

"Current guidelines are inconsistent about what metrics should be used, which makes it difficult for providers to decide whether extended-duration thromboprophylaxis would be beneficial. This likely plays a significant role in the current lack of adherence to guidelines," he said in an interview, adding. "This study was really aimed at providing clinicians a better cut-off for when it should be used, incorporating both the cost and patient perspective."

To assess cost effectiveness of thromboprophylaxis, Dr. Iannuzzi and his colleagues compared extended-duration treatment for 21 days after discharge (following 7 days of inpatient prophylaxis) with inpatient prophylaxis alone in a hypothetical case involving abdominal oncologic resection without complications in an otherwise healthy 45-year-old male patient.

Willingness to pay was set at $50,000 per quality-adjusted life-year (QALY), and the probabilities of various factors and scenarios were determined based on the available literature – much of it coming from the orthopedic literature. Costs were in U.S. 2013 dollars adjusted using the consumer price index; effectiveness was based on QALY (utility considered over 1 year), and cost effectiveness was evaluated using an incremental cost-effectiveness ratio, Dr. Iannuzzi explained.

Sensitivity analyses were performed to assess uncertainty within the model, with particular interest in the threshold for cost effectiveness based on VTE incidence, he said.

The endpoints were pulmonary embolism or deep vein thrombosis with attendant costs and assigned effectiveness evaluated by QALY, he said.

Based on the predetermined probabilities, and assuming an annualized cost of $23,248 for pulmonary embolism, $21,540 for deep vein thrombosis, $14,363 for post-thrombotic syndrome, $706 for generic LMWH, and $872 for brand-name LMWH, the threshold for the relative cost effectiveness of extended-duration thromboprophylaxis was VTE probability of 1.65% for brand-name LMWH, and 0.88% for generic LMWH.

"The 0.88% threshold is near the range of most major abdominal surgeries, which highlights the importance of using extended-duration thromboprophylaxis. However, the model was sensitive to changes in medication costs and patient values until postdischarge VTE risk exceeded 2.4%," Dr. Iannuzzi explained, adding that the model sensitivity in the 0.88% to 2.39% range is the reason why it is important to consider the patient perspective and the availability of generic LWMH in such cases.

He and his colleagues recently developed a risk score to help with postdischarge VTE prediction and to guide decision-making. The risk score, published online in May in the Journal of Vascular Surgery (J. Vasc. Surg. 2013 [doi:10.106/j.jvs.2012.12.073]), considers patient, operative, and early outcome factors to identify patients at increased risk.

The current findings, which pave the way for patient-centered decision making, use cost effectiveness of extended-duration thromboprophylaxis as a measure for risk, and should inform future guidelines’ definition of high risk. They also suggest that while a blanket approach to prophylaxis is not warranted, payers should cover the cost of extended-duration treatment.

"When cost was analyzed alone – without taking patient discomfort and the burden of self-injections into account, the threshold for cost effectiveness was much lower, suggesting that from the payer perspective, significant cost savings would be derived by increasing extended-duration thromboprophylaxis use," he explained.

Dr. Iannuzzi reported having no disclosures.

ORLANDO – Thromboprophylaxis for 3 weeks after discharge following abdominal surgery is more cost effective than is inpatient thromboprophylaxis alone, given certain base case assumptions, according to a decision tree analysis.

The findings, which incorporate both cost- and patient-related factors, provide clarity for clinicians about when extended duration thromboprophylaxis is appropriate, Dr. James C. Iannuzzi said at the annual Digestive Disease Week.

The analysis indicates that extended-duration thromboprophylaxis with low-molecular-weight heparin for 3 weeks after discharge is preferable to 7 days of inpatient-only thromboprophylaxis in cases where venous thromboembolism (VTE) risk is estimated at 0.88% to 2.39%; patient preferences regarding costs and medication administration, including the need for self-administered injection of low-molecular-weight heparin (LMWH), should be considered in these cases, said Dr. Iannuzzi of surgical health outcomes and research enterprise at the University of Rochester (N.Y.) Medical Center.

Extended-duration thromboprophylaxis dominates in cases in which the estimated VTE risk exceeds 2.39%, he said.

"Current guidelines are inconsistent about what metrics should be used, which makes it difficult for providers to decide whether extended-duration thromboprophylaxis would be beneficial. This likely plays a significant role in the current lack of adherence to guidelines," he said in an interview, adding. "This study was really aimed at providing clinicians a better cut-off for when it should be used, incorporating both the cost and patient perspective."

To assess cost effectiveness of thromboprophylaxis, Dr. Iannuzzi and his colleagues compared extended-duration treatment for 21 days after discharge (following 7 days of inpatient prophylaxis) with inpatient prophylaxis alone in a hypothetical case involving abdominal oncologic resection without complications in an otherwise healthy 45-year-old male patient.

Willingness to pay was set at $50,000 per quality-adjusted life-year (QALY), and the probabilities of various factors and scenarios were determined based on the available literature – much of it coming from the orthopedic literature. Costs were in U.S. 2013 dollars adjusted using the consumer price index; effectiveness was based on QALY (utility considered over 1 year), and cost effectiveness was evaluated using an incremental cost-effectiveness ratio, Dr. Iannuzzi explained.

Sensitivity analyses were performed to assess uncertainty within the model, with particular interest in the threshold for cost effectiveness based on VTE incidence, he said.

The endpoints were pulmonary embolism or deep vein thrombosis with attendant costs and assigned effectiveness evaluated by QALY, he said.

Based on the predetermined probabilities, and assuming an annualized cost of $23,248 for pulmonary embolism, $21,540 for deep vein thrombosis, $14,363 for post-thrombotic syndrome, $706 for generic LMWH, and $872 for brand-name LMWH, the threshold for the relative cost effectiveness of extended-duration thromboprophylaxis was VTE probability of 1.65% for brand-name LMWH, and 0.88% for generic LMWH.

"The 0.88% threshold is near the range of most major abdominal surgeries, which highlights the importance of using extended-duration thromboprophylaxis. However, the model was sensitive to changes in medication costs and patient values until postdischarge VTE risk exceeded 2.4%," Dr. Iannuzzi explained, adding that the model sensitivity in the 0.88% to 2.39% range is the reason why it is important to consider the patient perspective and the availability of generic LWMH in such cases.

He and his colleagues recently developed a risk score to help with postdischarge VTE prediction and to guide decision-making. The risk score, published online in May in the Journal of Vascular Surgery (J. Vasc. Surg. 2013 [doi:10.106/j.jvs.2012.12.073]), considers patient, operative, and early outcome factors to identify patients at increased risk.

The current findings, which pave the way for patient-centered decision making, use cost effectiveness of extended-duration thromboprophylaxis as a measure for risk, and should inform future guidelines’ definition of high risk. They also suggest that while a blanket approach to prophylaxis is not warranted, payers should cover the cost of extended-duration treatment.

"When cost was analyzed alone – without taking patient discomfort and the burden of self-injections into account, the threshold for cost effectiveness was much lower, suggesting that from the payer perspective, significant cost savings would be derived by increasing extended-duration thromboprophylaxis use," he explained.

Dr. Iannuzzi reported having no disclosures.