Pulmonary Health Hub

HIV infection is an independent risk factor for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), particularly in those with severe immune suppression, new research shows.

The longitudinal study, led by Dr. Kristina Crothers, a pulmonary and critical care specialist at Harborview Medical Center in Seattle, compared the incidence of AECOPD in 43,618 HIV-infected patients with 86,492 uninfected patients participating in the Veterans Aging Cohort Study (AIDS. 2016 Jan 28;30[3]:455-63).

©designer491/Thinkstockphotos.com

Over 234,099 person-years of follow-up, the research team found that HIV-infected individuals had an increased rate of AECOPD compared with uninfected individuals (18.8 vs. 13.3 per 1,000 person-years, P less than .001).

Adjusted models showed that AECOPD risk was greater in HIV-infected individuals overall (IRR 1.54; 95% CI 1.44-1.65), particularly in those with more severe immune suppression when stratified by CD4+ cell count (cells/mcL) compared with uninfected individuals (HIV-infected CD4+ <200: IRR 2.30, 95% CI 2.10-2.53, HIV-infected CD4+ ≥ 200-349: IRR 1.32, 95% CI 1.15-1.51, HIV-infected CD4+ ≥350: IRR 0.99, 95% CI 0.88-1.10).

“These findings support that severity of immune suppression increases risk for AECOPD, likely through greater risk of infection,” Dr. Crothers and her coauthors wrote.

The researchers also found a significant interaction between HIV infection and current smoking and alcohol use, with both conferring a substantially greater risk for AECOPD. This suggests that the increased risk of AECOPD in HIV may be related to enhanced susceptibility to harms from the modifiable risk factors of smoking and unhealthy alcohol use.

Infection with HIV coupled with alcohol use could serve as a ‘double hit’ to increase susceptibility to exacerbations of lung disease, the authors suggested.

“Intervening on these contributing factors may decrease morbidity and costs associated with COPD, particularly in a vulnerable HIV-infected population,” they concluded.

The authors declared no conflicts of interest.

HIV infection is an independent risk factor for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), particularly in those with severe immune suppression, new research shows.

The longitudinal study, led by Dr. Kristina Crothers, a pulmonary and critical care specialist at Harborview Medical Center in Seattle, compared the incidence of AECOPD in 43,618 HIV-infected patients with 86,492 uninfected patients participating in the Veterans Aging Cohort Study (AIDS. 2016 Jan 28;30[3]:455-63).

©designer491/Thinkstockphotos.com

Over 234,099 person-years of follow-up, the research team found that HIV-infected individuals had an increased rate of AECOPD compared with uninfected individuals (18.8 vs. 13.3 per 1,000 person-years, P less than .001).

Adjusted models showed that AECOPD risk was greater in HIV-infected individuals overall (IRR 1.54; 95% CI 1.44-1.65), particularly in those with more severe immune suppression when stratified by CD4+ cell count (cells/mcL) compared with uninfected individuals (HIV-infected CD4+ <200: IRR 2.30, 95% CI 2.10-2.53, HIV-infected CD4+ ≥ 200-349: IRR 1.32, 95% CI 1.15-1.51, HIV-infected CD4+ ≥350: IRR 0.99, 95% CI 0.88-1.10).

“These findings support that severity of immune suppression increases risk for AECOPD, likely through greater risk of infection,” Dr. Crothers and her coauthors wrote.

The researchers also found a significant interaction between HIV infection and current smoking and alcohol use, with both conferring a substantially greater risk for AECOPD. This suggests that the increased risk of AECOPD in HIV may be related to enhanced susceptibility to harms from the modifiable risk factors of smoking and unhealthy alcohol use.

Infection with HIV coupled with alcohol use could serve as a ‘double hit’ to increase susceptibility to exacerbations of lung disease, the authors suggested.

“Intervening on these contributing factors may decrease morbidity and costs associated with COPD, particularly in a vulnerable HIV-infected population,” they concluded.

The authors declared no conflicts of interest.

HIV infection is an independent risk factor for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), particularly in those with severe immune suppression, new research shows.

The longitudinal study, led by Dr. Kristina Crothers, a pulmonary and critical care specialist at Harborview Medical Center in Seattle, compared the incidence of AECOPD in 43,618 HIV-infected patients with 86,492 uninfected patients participating in the Veterans Aging Cohort Study (AIDS. 2016 Jan 28;30[3]:455-63).

©designer491/Thinkstockphotos.com

Over 234,099 person-years of follow-up, the research team found that HIV-infected individuals had an increased rate of AECOPD compared with uninfected individuals (18.8 vs. 13.3 per 1,000 person-years, P less than .001).

Adjusted models showed that AECOPD risk was greater in HIV-infected individuals overall (IRR 1.54; 95% CI 1.44-1.65), particularly in those with more severe immune suppression when stratified by CD4+ cell count (cells/mcL) compared with uninfected individuals (HIV-infected CD4+ <200: IRR 2.30, 95% CI 2.10-2.53, HIV-infected CD4+ ≥ 200-349: IRR 1.32, 95% CI 1.15-1.51, HIV-infected CD4+ ≥350: IRR 0.99, 95% CI 0.88-1.10).

“These findings support that severity of immune suppression increases risk for AECOPD, likely through greater risk of infection,” Dr. Crothers and her coauthors wrote.

The researchers also found a significant interaction between HIV infection and current smoking and alcohol use, with both conferring a substantially greater risk for AECOPD. This suggests that the increased risk of AECOPD in HIV may be related to enhanced susceptibility to harms from the modifiable risk factors of smoking and unhealthy alcohol use.

Infection with HIV coupled with alcohol use could serve as a ‘double hit’ to increase susceptibility to exacerbations of lung disease, the authors suggested.

“Intervening on these contributing factors may decrease morbidity and costs associated with COPD, particularly in a vulnerable HIV-infected population,” they concluded.

The authors declared no conflicts of interest.

Among pregnant women at high risk for having a child with asthma, high doses of vitamin D administered during the third trimester failed to prevent persistent wheezing illness in their children at age 3, according to two separate reports published online Jan. 26 in JAMA.

Both studies were conducted because vitamin D insufficiency during pregnancy is commonplace and is thought to affect fetal immune programming and to contribute to asthma pathogenesis. In addition, observational studies have found an association between low levels of vitamin D in cord blood and later asthma in the child.

© © ©istock/Thinkstock.com

The two randomized, double-blind placebo-controlled clinical trials found that neither 2,800 IU/day nor 4,400 IU/day of vitamin D significantly reduced the risk of persistent wheeze in the offspring through 3 years of age. However, both research groups noted that their studies may have been underpowered to detect a clinically important protective effect, and both recommended longer-term observation of their study participants, as well as further studies using larger sample sizes, higher doses of vitamin D, administration earlier in pregnancy, and postnatal supplementation to establish a definitive result.

In the first study – conducted as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort – 623 Danish women already taking the standard 400 IU of vitamin D₃ during pregnancy were randomly assigned to receive an additional 2,400 IU (315 women) or a matching placebo (308 women) from 22 to 26 weeks’ gestation until delivery. After exclusions, researchers analyzed data on 581 children.

Maternal serum vitamin D levels increased markedly in the active-treatment group. “Correspondingly, the percentage of women with sufficient levels of vitamin D (greater than 30 ng/mL) after the intervention was 81% in the vitamin D group, compared with 44% in the control group,” wrote Dr. Bo L. Chawes of Copenhagen Prospective Studies on Asthma in Childhood, University of Copenhagen, and his associates.

Persistent wheeze developed in 104 (18%) of the 581 children: 47 (16%) in the vitamin D group and 57 (20%) in the control group, a nonsignificant difference. Similarly, asthma was diagnosed in 79 children: 32 (12%) in the vitamin D group and 47 (14%) in the control group, another nonsignificant difference.

Vitamin D supplementation also made no difference in infants’ levels of C-reactive protein, interleukin-6, tumor necrosis factor–alpha, or CXCL8, nor in the number of upper respiratory tract infections (5.2 per year vs 5.3 per year), the number of lower respiratory tract infections (32% vs 33%), the risk of allergic sensitization as measured by skin prick test or specific IgE level, or the development of eczema (23% vs 25%).

However, the risk of persistent wheeze was higher in children whose mothers’ vitamin D levels were lowest, compared with those whose mothers’ vitamin D levels were in the middle and upper tertiles. And high-dose vitamin D was protective with regard to some secondary endpoints, such as preventing more episodes of “troublesome lung symptoms” (5.9 vs. 7.2).

This finding, together with the study’s somewhat reduced statistical power, mean that a clinically important protective effect cannot be ruled out. In addition, the supplementation dose may have been too low or may have been given too late in the course of pregnancy to produce a significant effect, Dr. Chawes and his associates wrote (JAMA. 2016;315[4]:353-61. doi: 10.1001/jama.2015.18318).In the second study – the Vitamin D Antenatal Asthma Reduction Trial – 876 pregnant women in Boston, St. Louis, and San Diego who were already taking the standard 400 IU of vitamin D were randomly assigned to receive either an additional 4,000 IU/day (440 participants) or a matching placebo (436 participants). Maternal levels of vitamin D rose markedly in the active-treatment group (mean, 39.2 ng/mL), compared with the control group (mean, 26.8 ng/mL), and the proportion of women who achieved higher than “inadequate” levels was much greater (74.9% vs 34.0%), reported Dr. Augusto A. Litonjua of Brigham and Women’s Hospital, Boston, and his associates.

A total of 24.3% of the vitamin D group and 30.4% of the control group developed asthma or recurrent wheeze by age 3 years, a nonsignificant difference. However, the incidence of asthma was so much lower than anticipated in both study groups that the study may have lost statistical power to detect a clinically meaningful difference, according to the investigators (JAMA. 2016;315[4]:362-70. doi: 10.1001/jama.2015.18589).

It remains unclear whether vitamin D supplementation during pregnancy will reduce asthma and persistent wheezing in the offspring. “Larger studies and longer follow-up of the children in this study will be needed to answer the question,” the investigators wrote. “If additional studies identify a significant effect, given the high prevalence of low vitamin D levels in pregnant women, the effect of this inexpensive intervention on child health could be substantial.”

The first study was supported by the Copenhagen Prospective Study on Asthma in Childhood, which is funded by private and public research groups. One of the coauthors reported receiving consulting fees from Chiesi. The Vitamin D Antenatal Asthma Reduction Trial was supported by the U.S. National Heart, Lung, and Blood Institute and the National Centers for Advancing Translational Sciences. The lead author, Dr. Litonjua, reported receiving personal fees from UpToDate and Springer Humana Press; his associates reported ties to numerous industry sources.

Among pregnant women at high risk for having a child with asthma, high doses of vitamin D administered during the third trimester failed to prevent persistent wheezing illness in their children at age 3, according to two separate reports published online Jan. 26 in JAMA.

Both studies were conducted because vitamin D insufficiency during pregnancy is commonplace and is thought to affect fetal immune programming and to contribute to asthma pathogenesis. In addition, observational studies have found an association between low levels of vitamin D in cord blood and later asthma in the child.

© © ©istock/Thinkstock.com

The two randomized, double-blind placebo-controlled clinical trials found that neither 2,800 IU/day nor 4,400 IU/day of vitamin D significantly reduced the risk of persistent wheeze in the offspring through 3 years of age. However, both research groups noted that their studies may have been underpowered to detect a clinically important protective effect, and both recommended longer-term observation of their study participants, as well as further studies using larger sample sizes, higher doses of vitamin D, administration earlier in pregnancy, and postnatal supplementation to establish a definitive result.

In the first study – conducted as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort – 623 Danish women already taking the standard 400 IU of vitamin D₃ during pregnancy were randomly assigned to receive an additional 2,400 IU (315 women) or a matching placebo (308 women) from 22 to 26 weeks’ gestation until delivery. After exclusions, researchers analyzed data on 581 children.

Maternal serum vitamin D levels increased markedly in the active-treatment group. “Correspondingly, the percentage of women with sufficient levels of vitamin D (greater than 30 ng/mL) after the intervention was 81% in the vitamin D group, compared with 44% in the control group,” wrote Dr. Bo L. Chawes of Copenhagen Prospective Studies on Asthma in Childhood, University of Copenhagen, and his associates.

Persistent wheeze developed in 104 (18%) of the 581 children: 47 (16%) in the vitamin D group and 57 (20%) in the control group, a nonsignificant difference. Similarly, asthma was diagnosed in 79 children: 32 (12%) in the vitamin D group and 47 (14%) in the control group, another nonsignificant difference.

Vitamin D supplementation also made no difference in infants’ levels of C-reactive protein, interleukin-6, tumor necrosis factor–alpha, or CXCL8, nor in the number of upper respiratory tract infections (5.2 per year vs 5.3 per year), the number of lower respiratory tract infections (32% vs 33%), the risk of allergic sensitization as measured by skin prick test or specific IgE level, or the development of eczema (23% vs 25%).

However, the risk of persistent wheeze was higher in children whose mothers’ vitamin D levels were lowest, compared with those whose mothers’ vitamin D levels were in the middle and upper tertiles. And high-dose vitamin D was protective with regard to some secondary endpoints, such as preventing more episodes of “troublesome lung symptoms” (5.9 vs. 7.2).

This finding, together with the study’s somewhat reduced statistical power, mean that a clinically important protective effect cannot be ruled out. In addition, the supplementation dose may have been too low or may have been given too late in the course of pregnancy to produce a significant effect, Dr. Chawes and his associates wrote (JAMA. 2016;315[4]:353-61. doi: 10.1001/jama.2015.18318).In the second study – the Vitamin D Antenatal Asthma Reduction Trial – 876 pregnant women in Boston, St. Louis, and San Diego who were already taking the standard 400 IU of vitamin D were randomly assigned to receive either an additional 4,000 IU/day (440 participants) or a matching placebo (436 participants). Maternal levels of vitamin D rose markedly in the active-treatment group (mean, 39.2 ng/mL), compared with the control group (mean, 26.8 ng/mL), and the proportion of women who achieved higher than “inadequate” levels was much greater (74.9% vs 34.0%), reported Dr. Augusto A. Litonjua of Brigham and Women’s Hospital, Boston, and his associates.

A total of 24.3% of the vitamin D group and 30.4% of the control group developed asthma or recurrent wheeze by age 3 years, a nonsignificant difference. However, the incidence of asthma was so much lower than anticipated in both study groups that the study may have lost statistical power to detect a clinically meaningful difference, according to the investigators (JAMA. 2016;315[4]:362-70. doi: 10.1001/jama.2015.18589).

It remains unclear whether vitamin D supplementation during pregnancy will reduce asthma and persistent wheezing in the offspring. “Larger studies and longer follow-up of the children in this study will be needed to answer the question,” the investigators wrote. “If additional studies identify a significant effect, given the high prevalence of low vitamin D levels in pregnant women, the effect of this inexpensive intervention on child health could be substantial.”

The first study was supported by the Copenhagen Prospective Study on Asthma in Childhood, which is funded by private and public research groups. One of the coauthors reported receiving consulting fees from Chiesi. The Vitamin D Antenatal Asthma Reduction Trial was supported by the U.S. National Heart, Lung, and Blood Institute and the National Centers for Advancing Translational Sciences. The lead author, Dr. Litonjua, reported receiving personal fees from UpToDate and Springer Humana Press; his associates reported ties to numerous industry sources.

Among pregnant women at high risk for having a child with asthma, high doses of vitamin D administered during the third trimester failed to prevent persistent wheezing illness in their children at age 3, according to two separate reports published online Jan. 26 in JAMA.

Both studies were conducted because vitamin D insufficiency during pregnancy is commonplace and is thought to affect fetal immune programming and to contribute to asthma pathogenesis. In addition, observational studies have found an association between low levels of vitamin D in cord blood and later asthma in the child.

© © ©istock/Thinkstock.com

The two randomized, double-blind placebo-controlled clinical trials found that neither 2,800 IU/day nor 4,400 IU/day of vitamin D significantly reduced the risk of persistent wheeze in the offspring through 3 years of age. However, both research groups noted that their studies may have been underpowered to detect a clinically important protective effect, and both recommended longer-term observation of their study participants, as well as further studies using larger sample sizes, higher doses of vitamin D, administration earlier in pregnancy, and postnatal supplementation to establish a definitive result.

In the first study – conducted as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort – 623 Danish women already taking the standard 400 IU of vitamin D₃ during pregnancy were randomly assigned to receive an additional 2,400 IU (315 women) or a matching placebo (308 women) from 22 to 26 weeks’ gestation until delivery. After exclusions, researchers analyzed data on 581 children.

Maternal serum vitamin D levels increased markedly in the active-treatment group. “Correspondingly, the percentage of women with sufficient levels of vitamin D (greater than 30 ng/mL) after the intervention was 81% in the vitamin D group, compared with 44% in the control group,” wrote Dr. Bo L. Chawes of Copenhagen Prospective Studies on Asthma in Childhood, University of Copenhagen, and his associates.

Persistent wheeze developed in 104 (18%) of the 581 children: 47 (16%) in the vitamin D group and 57 (20%) in the control group, a nonsignificant difference. Similarly, asthma was diagnosed in 79 children: 32 (12%) in the vitamin D group and 47 (14%) in the control group, another nonsignificant difference.

Vitamin D supplementation also made no difference in infants’ levels of C-reactive protein, interleukin-6, tumor necrosis factor–alpha, or CXCL8, nor in the number of upper respiratory tract infections (5.2 per year vs 5.3 per year), the number of lower respiratory tract infections (32% vs 33%), the risk of allergic sensitization as measured by skin prick test or specific IgE level, or the development of eczema (23% vs 25%).

However, the risk of persistent wheeze was higher in children whose mothers’ vitamin D levels were lowest, compared with those whose mothers’ vitamin D levels were in the middle and upper tertiles. And high-dose vitamin D was protective with regard to some secondary endpoints, such as preventing more episodes of “troublesome lung symptoms” (5.9 vs. 7.2).

This finding, together with the study’s somewhat reduced statistical power, mean that a clinically important protective effect cannot be ruled out. In addition, the supplementation dose may have been too low or may have been given too late in the course of pregnancy to produce a significant effect, Dr. Chawes and his associates wrote (JAMA. 2016;315[4]:353-61. doi: 10.1001/jama.2015.18318).In the second study – the Vitamin D Antenatal Asthma Reduction Trial – 876 pregnant women in Boston, St. Louis, and San Diego who were already taking the standard 400 IU of vitamin D were randomly assigned to receive either an additional 4,000 IU/day (440 participants) or a matching placebo (436 participants). Maternal levels of vitamin D rose markedly in the active-treatment group (mean, 39.2 ng/mL), compared with the control group (mean, 26.8 ng/mL), and the proportion of women who achieved higher than “inadequate” levels was much greater (74.9% vs 34.0%), reported Dr. Augusto A. Litonjua of Brigham and Women’s Hospital, Boston, and his associates.

A total of 24.3% of the vitamin D group and 30.4% of the control group developed asthma or recurrent wheeze by age 3 years, a nonsignificant difference. However, the incidence of asthma was so much lower than anticipated in both study groups that the study may have lost statistical power to detect a clinically meaningful difference, according to the investigators (JAMA. 2016;315[4]:362-70. doi: 10.1001/jama.2015.18589).

It remains unclear whether vitamin D supplementation during pregnancy will reduce asthma and persistent wheezing in the offspring. “Larger studies and longer follow-up of the children in this study will be needed to answer the question,” the investigators wrote. “If additional studies identify a significant effect, given the high prevalence of low vitamin D levels in pregnant women, the effect of this inexpensive intervention on child health could be substantial.”

The first study was supported by the Copenhagen Prospective Study on Asthma in Childhood, which is funded by private and public research groups. One of the coauthors reported receiving consulting fees from Chiesi. The Vitamin D Antenatal Asthma Reduction Trial was supported by the U.S. National Heart, Lung, and Blood Institute and the National Centers for Advancing Translational Sciences. The lead author, Dr. Litonjua, reported receiving personal fees from UpToDate and Springer Humana Press; his associates reported ties to numerous industry sources.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, appears generally safe for young children with cystic fibrosis and a CFTR gating mutation, an open-label, single-arm study shows.

The study, published online Jan. 20, is the first to assess ivacaftor in children aged 2-5 years, suggests that the drug is well tolerated, somewhat improves sweat chloride and nutritional measures, and also might improve pancreatic function, reported Dr. Jane C. Davies of the National Heart & Lung Institute of Imperial College London, and her associates. “Reported side effects are similar to those in the general cystic fibrosis population, although children with previous cystic fibrosis liver disease might have transient rises in transaminase concentrations,” they added.

© CTRPhotos / ThinkStockPhotos.com

Ivacaftor is approved by the Food and Drug Administration for children aged 6 years and older with cystic fibrosis, and it should be even more beneficial if given before patients develop infections and inflammation as a result of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, the researchers noted.

The investigators enrolled children aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the United States, the United Kingdom, and Canada. To establish short-term safety and pharmacokinetics of ivacaftor and its metabolites, nine patients received an oral dose of 50 mg (if they weighed less than 14 kg) or 75 mg (if they weighed 14 kg or more) every 12 hours for 4 days.

To assess longer-term safety, 34 patients received these doses for 24 weeks, followed by an open-label extension study that remains underway (Lancet Respir Med. 2016 Jan 20. doi: 10.1016/S2213-2600[15]00545-7).

The pharmacokinetic analyses indicated that exposure was similar to that reported in adults, the researchers reported. The median Cmin was 536 ng per mL for the 50-mg dose and 580 ng per mL for the 75-mg dose, and median ivacaftor AUC values were 9,840 ng×h/mL and 10,200 ngxh/mL, respectively. The most common adverse events over 6 weeks of treatment included cough (56% of patients) and vomiting (29%). In addition five (15%) patients had liver function test results that were more than eight-fold higher than the upper limit of normal. As a result, four had the study drug interrupted and one discontinued. Hypertransaminasemia was the only serious adverse event considered related to ivacaftor, and the only adverse event leading to treatment discontinuation. By week 24, sweat chloride levels had dropped an average of 47 mmol per L from baseline (standard deviation, 26.2, P less than .0001), weight had dropped by a z score factor of 0.2 (P less than .0001), and BMI had fallen by a factor of 0.4 (P less than .0001).

“Unfortunately, this study could not generate meaningful data on pulmonary function, because only three patients produced research-quality measurements, and we did not provide specific training or quality control in preschool lung function testing,” the investigators said. The results “confirmed a safe and tolerable dose of an acceptable formulation of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation, although liver function seems to require closer monitoring in this age range than in adults, particularly among those with a history of elevated [liver function tests].”

Vertex Pharmaceuticals funded the study. Dr. Davies reported serving on advisory boards for Proteostasis, Pharmaxis, Pulmocide, Novartis, and Vertex Pharmaceuticals, and participating in educational activities for which her institution received payment. Seven coinvestigators also reported financial relationships with Vertex, including three who reported employment with the company.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, appears generally safe for young children with cystic fibrosis and a CFTR gating mutation, an open-label, single-arm study shows.

The study, published online Jan. 20, is the first to assess ivacaftor in children aged 2-5 years, suggests that the drug is well tolerated, somewhat improves sweat chloride and nutritional measures, and also might improve pancreatic function, reported Dr. Jane C. Davies of the National Heart & Lung Institute of Imperial College London, and her associates. “Reported side effects are similar to those in the general cystic fibrosis population, although children with previous cystic fibrosis liver disease might have transient rises in transaminase concentrations,” they added.

© CTRPhotos / ThinkStockPhotos.com

Ivacaftor is approved by the Food and Drug Administration for children aged 6 years and older with cystic fibrosis, and it should be even more beneficial if given before patients develop infections and inflammation as a result of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, the researchers noted.

The investigators enrolled children aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the United States, the United Kingdom, and Canada. To establish short-term safety and pharmacokinetics of ivacaftor and its metabolites, nine patients received an oral dose of 50 mg (if they weighed less than 14 kg) or 75 mg (if they weighed 14 kg or more) every 12 hours for 4 days.

To assess longer-term safety, 34 patients received these doses for 24 weeks, followed by an open-label extension study that remains underway (Lancet Respir Med. 2016 Jan 20. doi: 10.1016/S2213-2600[15]00545-7).

The pharmacokinetic analyses indicated that exposure was similar to that reported in adults, the researchers reported. The median Cmin was 536 ng per mL for the 50-mg dose and 580 ng per mL for the 75-mg dose, and median ivacaftor AUC values were 9,840 ng×h/mL and 10,200 ngxh/mL, respectively. The most common adverse events over 6 weeks of treatment included cough (56% of patients) and vomiting (29%). In addition five (15%) patients had liver function test results that were more than eight-fold higher than the upper limit of normal. As a result, four had the study drug interrupted and one discontinued. Hypertransaminasemia was the only serious adverse event considered related to ivacaftor, and the only adverse event leading to treatment discontinuation. By week 24, sweat chloride levels had dropped an average of 47 mmol per L from baseline (standard deviation, 26.2, P less than .0001), weight had dropped by a z score factor of 0.2 (P less than .0001), and BMI had fallen by a factor of 0.4 (P less than .0001).

“Unfortunately, this study could not generate meaningful data on pulmonary function, because only three patients produced research-quality measurements, and we did not provide specific training or quality control in preschool lung function testing,” the investigators said. The results “confirmed a safe and tolerable dose of an acceptable formulation of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation, although liver function seems to require closer monitoring in this age range than in adults, particularly among those with a history of elevated [liver function tests].”

Vertex Pharmaceuticals funded the study. Dr. Davies reported serving on advisory boards for Proteostasis, Pharmaxis, Pulmocide, Novartis, and Vertex Pharmaceuticals, and participating in educational activities for which her institution received payment. Seven coinvestigators also reported financial relationships with Vertex, including three who reported employment with the company.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, appears generally safe for young children with cystic fibrosis and a CFTR gating mutation, an open-label, single-arm study shows.

The study, published online Jan. 20, is the first to assess ivacaftor in children aged 2-5 years, suggests that the drug is well tolerated, somewhat improves sweat chloride and nutritional measures, and also might improve pancreatic function, reported Dr. Jane C. Davies of the National Heart & Lung Institute of Imperial College London, and her associates. “Reported side effects are similar to those in the general cystic fibrosis population, although children with previous cystic fibrosis liver disease might have transient rises in transaminase concentrations,” they added.

© CTRPhotos / ThinkStockPhotos.com

Ivacaftor is approved by the Food and Drug Administration for children aged 6 years and older with cystic fibrosis, and it should be even more beneficial if given before patients develop infections and inflammation as a result of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, the researchers noted.

The investigators enrolled children aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the United States, the United Kingdom, and Canada. To establish short-term safety and pharmacokinetics of ivacaftor and its metabolites, nine patients received an oral dose of 50 mg (if they weighed less than 14 kg) or 75 mg (if they weighed 14 kg or more) every 12 hours for 4 days.

To assess longer-term safety, 34 patients received these doses for 24 weeks, followed by an open-label extension study that remains underway (Lancet Respir Med. 2016 Jan 20. doi: 10.1016/S2213-2600[15]00545-7).

The pharmacokinetic analyses indicated that exposure was similar to that reported in adults, the researchers reported. The median Cmin was 536 ng per mL for the 50-mg dose and 580 ng per mL for the 75-mg dose, and median ivacaftor AUC values were 9,840 ng×h/mL and 10,200 ngxh/mL, respectively. The most common adverse events over 6 weeks of treatment included cough (56% of patients) and vomiting (29%). In addition five (15%) patients had liver function test results that were more than eight-fold higher than the upper limit of normal. As a result, four had the study drug interrupted and one discontinued. Hypertransaminasemia was the only serious adverse event considered related to ivacaftor, and the only adverse event leading to treatment discontinuation. By week 24, sweat chloride levels had dropped an average of 47 mmol per L from baseline (standard deviation, 26.2, P less than .0001), weight had dropped by a z score factor of 0.2 (P less than .0001), and BMI had fallen by a factor of 0.4 (P less than .0001).

“Unfortunately, this study could not generate meaningful data on pulmonary function, because only three patients produced research-quality measurements, and we did not provide specific training or quality control in preschool lung function testing,” the investigators said. The results “confirmed a safe and tolerable dose of an acceptable formulation of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation, although liver function seems to require closer monitoring in this age range than in adults, particularly among those with a history of elevated [liver function tests].”

Vertex Pharmaceuticals funded the study. Dr. Davies reported serving on advisory boards for Proteostasis, Pharmaxis, Pulmocide, Novartis, and Vertex Pharmaceuticals, and participating in educational activities for which her institution received payment. Seven coinvestigators also reported financial relationships with Vertex, including three who reported employment with the company.

ORLANDO – A “hard and soft” approach to treating atopic dermatitis – treating more frequently while symptoms persist, then pulling back on treatment to keep symptoms at bay – is an effective way to keep the condition manageable for your patients.

“This is not an easy disease to manage, and that’s the key,” explained Dr. Adam Friedman of the George Washington University in Washington, at the Orlando Dermatology Aesthetic and Clinical annual meeting, adding that it’s important to educate patients that atopic dermatitis is “something that they will always have” and does not have one-shot cures.

In this video interview, Dr. Friedman, who is a Dermatology News board member, discusses the best way to talk to new patients about what atopic dermatitis treatment will entail, and offers methods to make management of the disease more effective and, consequently, improve patients’ quality of life.

[email protected]

ORLANDO – A “hard and soft” approach to treating atopic dermatitis – treating more frequently while symptoms persist, then pulling back on treatment to keep symptoms at bay – is an effective way to keep the condition manageable for your patients.

“This is not an easy disease to manage, and that’s the key,” explained Dr. Adam Friedman of the George Washington University in Washington, at the Orlando Dermatology Aesthetic and Clinical annual meeting, adding that it’s important to educate patients that atopic dermatitis is “something that they will always have” and does not have one-shot cures.

In this video interview, Dr. Friedman, who is a Dermatology News board member, discusses the best way to talk to new patients about what atopic dermatitis treatment will entail, and offers methods to make management of the disease more effective and, consequently, improve patients’ quality of life.

[email protected]

ORLANDO – A “hard and soft” approach to treating atopic dermatitis – treating more frequently while symptoms persist, then pulling back on treatment to keep symptoms at bay – is an effective way to keep the condition manageable for your patients.

“This is not an easy disease to manage, and that’s the key,” explained Dr. Adam Friedman of the George Washington University in Washington, at the Orlando Dermatology Aesthetic and Clinical annual meeting, adding that it’s important to educate patients that atopic dermatitis is “something that they will always have” and does not have one-shot cures.

In this video interview, Dr. Friedman, who is a Dermatology News board member, discusses the best way to talk to new patients about what atopic dermatitis treatment will entail, and offers methods to make management of the disease more effective and, consequently, improve patients’ quality of life.

[email protected]

SAN DIEGO – A series of radiomics-derived imaging features may improve the diagnostic accuracy of low-dose CT lung cancer screening and help predict which nodules are at risk of becoming cancers.

“We are providing pretty compelling evidence that there is some utility in this science,” Matthew Schabath, Ph.D., said at a conference on lung cancer translational science sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Radiomics is an emerging field that uses high-throughput extraction to identify hundreds of quantitative features from standard computed tomography (CT) images and mines that data to develop diagnostic, predictive, or prognostic models.

Radiologists first identify a region of interest (ROI) on the CT scan containing either the whole tumor or spatially explicit regions of the tumor called “habitats.” These ROIs are then segmented via computer software before being rendered in three dimensions. Quantitative features are extracted from the rendered volumes and entered into the models, along with other clinical and patient data.

“Right now our tool box is about 219, but by the end of the year we are hoping to have close to 1,000 radiomic features we can extract from a 3-D rendered nodule or tumor,” said Dr. Schabath, of the Moffitt Cancer Center in Tampa, Fla.

Although not without its own challenges, radiomics is a far cry from the current practice that relies on a single CT feature, nodule size, and clinical guidelines to evaluate and follow-up pulmonary nodules, none of which provides clinicians tools to accurately predict the risk or probability of lung cancer development.

Courtesy of Dr. Gillies

CT images are typically thought of as pictures, but in radiomics, “the images are data. That’s really the underlying principle,” he said.

Led by Dr. Robert Gillies, often referred to as the father of radiomics, the researchers extracted and analyzed the 219 radiomic features from nodules in 196 lung cancer cases and in 392 controls who had a positive but benign nodule at the baseline scan and were matched for age, sex, smoking status, and race.

The post hoc, nested case-control study used images and data from the pivotal National Lung Screening Trial, which identified a 20% reduction in lung cancer mortality for low-dose CT screening compared with chest x-rays, but with a 96% false-positive rate, which also highlighted the challenges of LDCT as a screening tool.

Two classes of features were extracted from the images: semantic features, which are commonly used in radiology to describe ROIs, and agnostic features, which are mathematically extracted quantitative descriptors that capture lesion heterogeneity.

Univariable analyses were used to identify statistically significant features (threshold P value less than .05) and a backward elimination process (threshold P less than 0.1) performed to generate the final set of features, Dr. Schabath said.

Courtesy of David Gering, Health Myne Inc.

Separate analyses were performed for predictive and diagnostic features.

In the risk prediction model, eight “highly informative features” were identified, Dr. Schabath said. Five were agnostic and three were semantic – ­circularity of the nodule, volume, and distance from or pleural attachment.

The receiver operating characteristic (ROC) area under the curve for the model was 0.92, with 75% sensitivity and 89% specificity. When the model included only patient demographics, it was no better than flipping a coin for predicting nodules at risk of becoming cancerous (ROC 0.58), he said.

Six highly informative features were identified in the agnostic model, which extracted features from the nodules found at the first and second follow-up interval, Dr. Schabath said. Three were agnostic and three semantic ­– longest diameter, volume, and distance from or pleural attachment.

The ROC for the diagnostic model was 0.89, with 74% sensitivity and 89% specificity.

When an additional analysis was performed using a nodule threshold of less than 15 mm to account for nodule growth over time and smaller nodule size at baseline in controls, the ROC and specificity held steady, but sensitivity dropped off to 59%, he said.

“I think we’re showing a rigorous [statistical] approach by identifying really unique, highly informative features,” Dr. Schabath concluded.

The overlap of volume and distance from or pleural attachment in both the diagnostic and predictive models suggests “there might be something very important about these two features,” he added.

Dr. Schabath stressed that the findings are preliminary and said additional analyses will be run before the results are ready for prime time. Long-term goals are to implement radiomic-based decision support tools and models into radiology reading rooms.

“In the future, we envision that all medical images will be converted to mineable data with the process of radiomics as part of standard of care,” Dr. Gillies said in an interview. “Such data have already shown promise to increase the precision and accuracy of diagnostic images, and hence, will increasingly be used in therapy decision support.”

Among the many challenges that first need to be resolved are that images are often captured with settings and filters that can be different even within a single institution. The inconsistency adds noise to the data that are extracted by computers.

“Hence, the most robust data we have today are generated by radiologists themselves, although this has its own challenges of being time-consuming with inter-reader variability,” Dr. Gillies noted.

Another major challenge is sharing of the image data. Right now, radiomics is practiced at only a few research hospitals and thus, building large cohort studies requires that the images be moved across site. In the future, the researchers anticipate that software can be deployed across sites to enable radiomic feature extraction, which would mean that only the extracted data will have to be shared, he said.

[email protected]

SAN DIEGO – A series of radiomics-derived imaging features may improve the diagnostic accuracy of low-dose CT lung cancer screening and help predict which nodules are at risk of becoming cancers.

“We are providing pretty compelling evidence that there is some utility in this science,” Matthew Schabath, Ph.D., said at a conference on lung cancer translational science sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Radiomics is an emerging field that uses high-throughput extraction to identify hundreds of quantitative features from standard computed tomography (CT) images and mines that data to develop diagnostic, predictive, or prognostic models.

Radiologists first identify a region of interest (ROI) on the CT scan containing either the whole tumor or spatially explicit regions of the tumor called “habitats.” These ROIs are then segmented via computer software before being rendered in three dimensions. Quantitative features are extracted from the rendered volumes and entered into the models, along with other clinical and patient data.

“Right now our tool box is about 219, but by the end of the year we are hoping to have close to 1,000 radiomic features we can extract from a 3-D rendered nodule or tumor,” said Dr. Schabath, of the Moffitt Cancer Center in Tampa, Fla.

Although not without its own challenges, radiomics is a far cry from the current practice that relies on a single CT feature, nodule size, and clinical guidelines to evaluate and follow-up pulmonary nodules, none of which provides clinicians tools to accurately predict the risk or probability of lung cancer development.

Courtesy of Dr. Gillies

CT images are typically thought of as pictures, but in radiomics, “the images are data. That’s really the underlying principle,” he said.

Led by Dr. Robert Gillies, often referred to as the father of radiomics, the researchers extracted and analyzed the 219 radiomic features from nodules in 196 lung cancer cases and in 392 controls who had a positive but benign nodule at the baseline scan and were matched for age, sex, smoking status, and race.

The post hoc, nested case-control study used images and data from the pivotal National Lung Screening Trial, which identified a 20% reduction in lung cancer mortality for low-dose CT screening compared with chest x-rays, but with a 96% false-positive rate, which also highlighted the challenges of LDCT as a screening tool.

Two classes of features were extracted from the images: semantic features, which are commonly used in radiology to describe ROIs, and agnostic features, which are mathematically extracted quantitative descriptors that capture lesion heterogeneity.

Univariable analyses were used to identify statistically significant features (threshold P value less than .05) and a backward elimination process (threshold P less than 0.1) performed to generate the final set of features, Dr. Schabath said.

Courtesy of David Gering, Health Myne Inc.

Separate analyses were performed for predictive and diagnostic features.

In the risk prediction model, eight “highly informative features” were identified, Dr. Schabath said. Five were agnostic and three were semantic – ­circularity of the nodule, volume, and distance from or pleural attachment.

The receiver operating characteristic (ROC) area under the curve for the model was 0.92, with 75% sensitivity and 89% specificity. When the model included only patient demographics, it was no better than flipping a coin for predicting nodules at risk of becoming cancerous (ROC 0.58), he said.

Six highly informative features were identified in the agnostic model, which extracted features from the nodules found at the first and second follow-up interval, Dr. Schabath said. Three were agnostic and three semantic ­– longest diameter, volume, and distance from or pleural attachment.

The ROC for the diagnostic model was 0.89, with 74% sensitivity and 89% specificity.

When an additional analysis was performed using a nodule threshold of less than 15 mm to account for nodule growth over time and smaller nodule size at baseline in controls, the ROC and specificity held steady, but sensitivity dropped off to 59%, he said.

“I think we’re showing a rigorous [statistical] approach by identifying really unique, highly informative features,” Dr. Schabath concluded.

The overlap of volume and distance from or pleural attachment in both the diagnostic and predictive models suggests “there might be something very important about these two features,” he added.

Dr. Schabath stressed that the findings are preliminary and said additional analyses will be run before the results are ready for prime time. Long-term goals are to implement radiomic-based decision support tools and models into radiology reading rooms.

“In the future, we envision that all medical images will be converted to mineable data with the process of radiomics as part of standard of care,” Dr. Gillies said in an interview. “Such data have already shown promise to increase the precision and accuracy of diagnostic images, and hence, will increasingly be used in therapy decision support.”

Among the many challenges that first need to be resolved are that images are often captured with settings and filters that can be different even within a single institution. The inconsistency adds noise to the data that are extracted by computers.

“Hence, the most robust data we have today are generated by radiologists themselves, although this has its own challenges of being time-consuming with inter-reader variability,” Dr. Gillies noted.

Another major challenge is sharing of the image data. Right now, radiomics is practiced at only a few research hospitals and thus, building large cohort studies requires that the images be moved across site. In the future, the researchers anticipate that software can be deployed across sites to enable radiomic feature extraction, which would mean that only the extracted data will have to be shared, he said.

[email protected]

SAN DIEGO – A series of radiomics-derived imaging features may improve the diagnostic accuracy of low-dose CT lung cancer screening and help predict which nodules are at risk of becoming cancers.

“We are providing pretty compelling evidence that there is some utility in this science,” Matthew Schabath, Ph.D., said at a conference on lung cancer translational science sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Radiomics is an emerging field that uses high-throughput extraction to identify hundreds of quantitative features from standard computed tomography (CT) images and mines that data to develop diagnostic, predictive, or prognostic models.

Radiologists first identify a region of interest (ROI) on the CT scan containing either the whole tumor or spatially explicit regions of the tumor called “habitats.” These ROIs are then segmented via computer software before being rendered in three dimensions. Quantitative features are extracted from the rendered volumes and entered into the models, along with other clinical and patient data.

“Right now our tool box is about 219, but by the end of the year we are hoping to have close to 1,000 radiomic features we can extract from a 3-D rendered nodule or tumor,” said Dr. Schabath, of the Moffitt Cancer Center in Tampa, Fla.

Although not without its own challenges, radiomics is a far cry from the current practice that relies on a single CT feature, nodule size, and clinical guidelines to evaluate and follow-up pulmonary nodules, none of which provides clinicians tools to accurately predict the risk or probability of lung cancer development.

Courtesy of Dr. Gillies

CT images are typically thought of as pictures, but in radiomics, “the images are data. That’s really the underlying principle,” he said.

Led by Dr. Robert Gillies, often referred to as the father of radiomics, the researchers extracted and analyzed the 219 radiomic features from nodules in 196 lung cancer cases and in 392 controls who had a positive but benign nodule at the baseline scan and were matched for age, sex, smoking status, and race.

The post hoc, nested case-control study used images and data from the pivotal National Lung Screening Trial, which identified a 20% reduction in lung cancer mortality for low-dose CT screening compared with chest x-rays, but with a 96% false-positive rate, which also highlighted the challenges of LDCT as a screening tool.

Two classes of features were extracted from the images: semantic features, which are commonly used in radiology to describe ROIs, and agnostic features, which are mathematically extracted quantitative descriptors that capture lesion heterogeneity.

Univariable analyses were used to identify statistically significant features (threshold P value less than .05) and a backward elimination process (threshold P less than 0.1) performed to generate the final set of features, Dr. Schabath said.

Courtesy of David Gering, Health Myne Inc.

Separate analyses were performed for predictive and diagnostic features.

In the risk prediction model, eight “highly informative features” were identified, Dr. Schabath said. Five were agnostic and three were semantic – ­circularity of the nodule, volume, and distance from or pleural attachment.

The receiver operating characteristic (ROC) area under the curve for the model was 0.92, with 75% sensitivity and 89% specificity. When the model included only patient demographics, it was no better than flipping a coin for predicting nodules at risk of becoming cancerous (ROC 0.58), he said.

Six highly informative features were identified in the agnostic model, which extracted features from the nodules found at the first and second follow-up interval, Dr. Schabath said. Three were agnostic and three semantic ­– longest diameter, volume, and distance from or pleural attachment.

The ROC for the diagnostic model was 0.89, with 74% sensitivity and 89% specificity.

When an additional analysis was performed using a nodule threshold of less than 15 mm to account for nodule growth over time and smaller nodule size at baseline in controls, the ROC and specificity held steady, but sensitivity dropped off to 59%, he said.

“I think we’re showing a rigorous [statistical] approach by identifying really unique, highly informative features,” Dr. Schabath concluded.

The overlap of volume and distance from or pleural attachment in both the diagnostic and predictive models suggests “there might be something very important about these two features,” he added.

Dr. Schabath stressed that the findings are preliminary and said additional analyses will be run before the results are ready for prime time. Long-term goals are to implement radiomic-based decision support tools and models into radiology reading rooms.

“In the future, we envision that all medical images will be converted to mineable data with the process of radiomics as part of standard of care,” Dr. Gillies said in an interview. “Such data have already shown promise to increase the precision and accuracy of diagnostic images, and hence, will increasingly be used in therapy decision support.”

Among the many challenges that first need to be resolved are that images are often captured with settings and filters that can be different even within a single institution. The inconsistency adds noise to the data that are extracted by computers.

“Hence, the most robust data we have today are generated by radiologists themselves, although this has its own challenges of being time-consuming with inter-reader variability,” Dr. Gillies noted.

Another major challenge is sharing of the image data. Right now, radiomics is practiced at only a few research hospitals and thus, building large cohort studies requires that the images be moved across site. In the future, the researchers anticipate that software can be deployed across sites to enable radiomic feature extraction, which would mean that only the extracted data will have to be shared, he said.

[email protected]

SAN DIEGO – Tobacco researchers are getting one step closer to identifying young smokers particularly susceptible to the carcinogenic effects of smoking, by using large-scale epidemiology studies and DNA adducts data.

“This is not lung cancer screening; this is not early detection of lung cancer; this is detection of susceptible, high-risk individuals, so they can be targeted for cessation, surveillance, and prevention,” said Stephen S. Hecht, Ph.D., professor of cancer prevention at the University of Minnesota Masonic Cancer Center in Minneapolis.

©ricky_68fr/fotolia.com

While nicotine itself is not a carcinogen, each puff of tobacco smoke delivers a mixture of more than 70 established carcinogens, including the potent lung-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Some of these carcinogens are excreted, but many will undergo metabolic activation and interact with a patient’s DNA.

The product of this interaction, called DNA adducts, causes persistent miscoding during DNA replication, leading to the thousands of mutations we see in lung cancer, he explained at a conference on lung cancer translational science sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

The biomarkers of tobacco exposure and metabolism are very well developed, with blood and urinary biomarker panels applied in many studies and validated by mass spectrometry.

Using the Shanghai cohort study, the researchers identified three urinary biomarkers – PheT (r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene), total NNAL (a metabolite of NNK and its glucuronides), and total cotinine (a surrogate for nicotine that includes cotinine and its glucuronides) – that were significantly associated with lung cancer in 950 smokers, even after adjustment for smoking duration and intensity (Cancer Res. 2011;71:6749-57).

A more recent, deeper dive of 735 of those urinary samples, still stable about 20 years after they were taken, looked specifically at polymorphisms in cytochrome P450 2A6 (CYP2A6), the primary enzyme responsible for the oxidation of nicotine and cotinine.

Data currently in press show that CYP2A6 poor metabolizers had a lower risk of lung cancer than the combined group of normal, intermediate, or slow metabolizers (odds ratio, 0.64; P value for trend = .034).

“This is logical because poor metabolizers of nicotine have more unchanged nicotine on board, so they don’t need to smoke as intensely in order to get more nicotine because that nicotine is remaining to a greater extent in its natural form, rather than being metabolized into cotinine, which is not addictive,” Dr. Hecht said.

Recent genomewide-association studies by Dr. Hecht and his colleagues of smokers in the Multiethnic Cohort Study revealed that Japanese Americans had the highest number of low nicotine CYP2A6 metabolizing genotypes of the five ethnic groups analyzed, consistent with their low lung cancer risk.

Urinary biomarker studies showed that levels of total NNAL, 3-hydroxy phenanthrene, a biomarker of polycyclic aromatic hydrocarbon uptake, and S-phenylmercapturic acid (SPMA), a biomarker of benzene exposure, were also significantly higher among African Americans than whites and significantly lower in Japanese Americans than whites, he said.

The findings are consistent with the initial study results published a decade ago (N Engl J Med. 2006;354:333-342), showing that at low levels of smoking (10 cigarettes per day), Japanese Americans and Hispanics had one-third the risk of lung cancer of African Americans or Native Hawaiians (P less than .001). The differences disappeared at higher levels of smoking (30 cigarettes per day).

Results from the new analyses for Native Hawaiians and Hispanics, however, did not fit this pattern, and “we’re not sure what’s going on there and need to do more work,” Dr. Hecht said.

Nicotine equivalent levels in Native Hawaiians were actually lower than would be expected based on their high lung cancer risk, while Hispanics had higher levels than would be expected based on their low risk.

Interestingly, urinary levels of 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein, were found to be unusually high in Native Hawaiians and relatively low in Hispanics, “which may play into their lung cancer risk because acrolein is a very strong toxicant and there is evidence to suggest it is involved in lung cancer,” he said.

While tobacco exposure and metabolism biomarkers have hit their stride, less well developed are the DNA adducts and repair biomarkers that can predict lung cancer susceptibility. This is a critical step because of the role DNA adducts play in the formation of lung cancer mutations, Dr. Hecht said.

A smoker may have a high tobacco exposure as indicated by the urinary biomarkers, but have a low metabolism to form DNA adducts or high DNA repair, which would mean their DNA adduct levels would be low. Conversely, another smoker with low exposure and poor DNA repair may have higher DNA adduct levels, and thus, a greater risk for developing lung cancer.

In addition, the exposure biomarkers are not entirely predictive and thus, will need to be combined with multiple DNA adducts and repair if susceptible smokers are to be identified and targeted for state-of-the art cessation approaches and surveillance, he said.

Using high-level mass spectrometry, the researchers have been able to readily measure formaldehyde DNA adducts and tobacco-specific 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)–releasing DNA adducts in human oral cells. Levels of the HPB adduct were unusually high at 12-45 pmol/mg, which is similar to what is seen in animals when exposed to NNK at a much higher dose than smokers take in.

“So this is a real lead,” said Dr. Hecht, who reported having no relevant conflicts of interest.

[email protected]

SAN DIEGO – Tobacco researchers are getting one step closer to identifying young smokers particularly susceptible to the carcinogenic effects of smoking, by using large-scale epidemiology studies and DNA adducts data.

“This is not lung cancer screening; this is not early detection of lung cancer; this is detection of susceptible, high-risk individuals, so they can be targeted for cessation, surveillance, and prevention,” said Stephen S. Hecht, Ph.D., professor of cancer prevention at the University of Minnesota Masonic Cancer Center in Minneapolis.

©ricky_68fr/fotolia.com

While nicotine itself is not a carcinogen, each puff of tobacco smoke delivers a mixture of more than 70 established carcinogens, including the potent lung-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Some of these carcinogens are excreted, but many will undergo metabolic activation and interact with a patient’s DNA.

The product of this interaction, called DNA adducts, causes persistent miscoding during DNA replication, leading to the thousands of mutations we see in lung cancer, he explained at a conference on lung cancer translational science sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

The biomarkers of tobacco exposure and metabolism are very well developed, with blood and urinary biomarker panels applied in many studies and validated by mass spectrometry.

Using the Shanghai cohort study, the researchers identified three urinary biomarkers – PheT (r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene), total NNAL (a metabolite of NNK and its glucuronides), and total cotinine (a surrogate for nicotine that includes cotinine and its glucuronides) – that were significantly associated with lung cancer in 950 smokers, even after adjustment for smoking duration and intensity (Cancer Res. 2011;71:6749-57).

A more recent, deeper dive of 735 of those urinary samples, still stable about 20 years after they were taken, looked specifically at polymorphisms in cytochrome P450 2A6 (CYP2A6), the primary enzyme responsible for the oxidation of nicotine and cotinine.

Data currently in press show that CYP2A6 poor metabolizers had a lower risk of lung cancer than the combined group of normal, intermediate, or slow metabolizers (odds ratio, 0.64; P value for trend = .034).

“This is logical because poor metabolizers of nicotine have more unchanged nicotine on board, so they don’t need to smoke as intensely in order to get more nicotine because that nicotine is remaining to a greater extent in its natural form, rather than being metabolized into cotinine, which is not addictive,” Dr. Hecht said.

Recent genomewide-association studies by Dr. Hecht and his colleagues of smokers in the Multiethnic Cohort Study revealed that Japanese Americans had the highest number of low nicotine CYP2A6 metabolizing genotypes of the five ethnic groups analyzed, consistent with their low lung cancer risk.

Urinary biomarker studies showed that levels of total NNAL, 3-hydroxy phenanthrene, a biomarker of polycyclic aromatic hydrocarbon uptake, and S-phenylmercapturic acid (SPMA), a biomarker of benzene exposure, were also significantly higher among African Americans than whites and significantly lower in Japanese Americans than whites, he said.

The findings are consistent with the initial study results published a decade ago (N Engl J Med. 2006;354:333-342), showing that at low levels of smoking (10 cigarettes per day), Japanese Americans and Hispanics had one-third the risk of lung cancer of African Americans or Native Hawaiians (P less than .001). The differences disappeared at higher levels of smoking (30 cigarettes per day).

Results from the new analyses for Native Hawaiians and Hispanics, however, did not fit this pattern, and “we’re not sure what’s going on there and need to do more work,” Dr. Hecht said.

Nicotine equivalent levels in Native Hawaiians were actually lower than would be expected based on their high lung cancer risk, while Hispanics had higher levels than would be expected based on their low risk.

Interestingly, urinary levels of 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein, were found to be unusually high in Native Hawaiians and relatively low in Hispanics, “which may play into their lung cancer risk because acrolein is a very strong toxicant and there is evidence to suggest it is involved in lung cancer,” he said.

While tobacco exposure and metabolism biomarkers have hit their stride, less well developed are the DNA adducts and repair biomarkers that can predict lung cancer susceptibility. This is a critical step because of the role DNA adducts play in the formation of lung cancer mutations, Dr. Hecht said.

A smoker may have a high tobacco exposure as indicated by the urinary biomarkers, but have a low metabolism to form DNA adducts or high DNA repair, which would mean their DNA adduct levels would be low. Conversely, another smoker with low exposure and poor DNA repair may have higher DNA adduct levels, and thus, a greater risk for developing lung cancer.

In addition, the exposure biomarkers are not entirely predictive and thus, will need to be combined with multiple DNA adducts and repair if susceptible smokers are to be identified and targeted for state-of-the art cessation approaches and surveillance, he said.

Using high-level mass spectrometry, the researchers have been able to readily measure formaldehyde DNA adducts and tobacco-specific 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)–releasing DNA adducts in human oral cells. Levels of the HPB adduct were unusually high at 12-45 pmol/mg, which is similar to what is seen in animals when exposed to NNK at a much higher dose than smokers take in.

“So this is a real lead,” said Dr. Hecht, who reported having no relevant conflicts of interest.

[email protected]

SAN DIEGO – Tobacco researchers are getting one step closer to identifying young smokers particularly susceptible to the carcinogenic effects of smoking, by using large-scale epidemiology studies and DNA adducts data.

“This is not lung cancer screening; this is not early detection of lung cancer; this is detection of susceptible, high-risk individuals, so they can be targeted for cessation, surveillance, and prevention,” said Stephen S. Hecht, Ph.D., professor of cancer prevention at the University of Minnesota Masonic Cancer Center in Minneapolis.

©ricky_68fr/fotolia.com

While nicotine itself is not a carcinogen, each puff of tobacco smoke delivers a mixture of more than 70 established carcinogens, including the potent lung-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Some of these carcinogens are excreted, but many will undergo metabolic activation and interact with a patient’s DNA.

The product of this interaction, called DNA adducts, causes persistent miscoding during DNA replication, leading to the thousands of mutations we see in lung cancer, he explained at a conference on lung cancer translational science sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

The biomarkers of tobacco exposure and metabolism are very well developed, with blood and urinary biomarker panels applied in many studies and validated by mass spectrometry.

Using the Shanghai cohort study, the researchers identified three urinary biomarkers – PheT (r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene), total NNAL (a metabolite of NNK and its glucuronides), and total cotinine (a surrogate for nicotine that includes cotinine and its glucuronides) – that were significantly associated with lung cancer in 950 smokers, even after adjustment for smoking duration and intensity (Cancer Res. 2011;71:6749-57).

A more recent, deeper dive of 735 of those urinary samples, still stable about 20 years after they were taken, looked specifically at polymorphisms in cytochrome P450 2A6 (CYP2A6), the primary enzyme responsible for the oxidation of nicotine and cotinine.

Data currently in press show that CYP2A6 poor metabolizers had a lower risk of lung cancer than the combined group of normal, intermediate, or slow metabolizers (odds ratio, 0.64; P value for trend = .034).

“This is logical because poor metabolizers of nicotine have more unchanged nicotine on board, so they don’t need to smoke as intensely in order to get more nicotine because that nicotine is remaining to a greater extent in its natural form, rather than being metabolized into cotinine, which is not addictive,” Dr. Hecht said.

Recent genomewide-association studies by Dr. Hecht and his colleagues of smokers in the Multiethnic Cohort Study revealed that Japanese Americans had the highest number of low nicotine CYP2A6 metabolizing genotypes of the five ethnic groups analyzed, consistent with their low lung cancer risk.

Urinary biomarker studies showed that levels of total NNAL, 3-hydroxy phenanthrene, a biomarker of polycyclic aromatic hydrocarbon uptake, and S-phenylmercapturic acid (SPMA), a biomarker of benzene exposure, were also significantly higher among African Americans than whites and significantly lower in Japanese Americans than whites, he said.

The findings are consistent with the initial study results published a decade ago (N Engl J Med. 2006;354:333-342), showing that at low levels of smoking (10 cigarettes per day), Japanese Americans and Hispanics had one-third the risk of lung cancer of African Americans or Native Hawaiians (P less than .001). The differences disappeared at higher levels of smoking (30 cigarettes per day).

Results from the new analyses for Native Hawaiians and Hispanics, however, did not fit this pattern, and “we’re not sure what’s going on there and need to do more work,” Dr. Hecht said.

Nicotine equivalent levels in Native Hawaiians were actually lower than would be expected based on their high lung cancer risk, while Hispanics had higher levels than would be expected based on their low risk.

Interestingly, urinary levels of 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein, were found to be unusually high in Native Hawaiians and relatively low in Hispanics, “which may play into their lung cancer risk because acrolein is a very strong toxicant and there is evidence to suggest it is involved in lung cancer,” he said.

While tobacco exposure and metabolism biomarkers have hit their stride, less well developed are the DNA adducts and repair biomarkers that can predict lung cancer susceptibility. This is a critical step because of the role DNA adducts play in the formation of lung cancer mutations, Dr. Hecht said.

A smoker may have a high tobacco exposure as indicated by the urinary biomarkers, but have a low metabolism to form DNA adducts or high DNA repair, which would mean their DNA adduct levels would be low. Conversely, another smoker with low exposure and poor DNA repair may have higher DNA adduct levels, and thus, a greater risk for developing lung cancer.

In addition, the exposure biomarkers are not entirely predictive and thus, will need to be combined with multiple DNA adducts and repair if susceptible smokers are to be identified and targeted for state-of-the art cessation approaches and surveillance, he said.

Using high-level mass spectrometry, the researchers have been able to readily measure formaldehyde DNA adducts and tobacco-specific 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)–releasing DNA adducts in human oral cells. Levels of the HPB adduct were unusually high at 12-45 pmol/mg, which is similar to what is seen in animals when exposed to NNK at a much higher dose than smokers take in.

“So this is a real lead,” said Dr. Hecht, who reported having no relevant conflicts of interest.

[email protected]